Inflammatory and Metabolic Biomarker Assessment in a Randomized Presurgical Trial of Curcumin and Anthocyanin Supplements in Patients with Colorectal Adenomas.

Colorectal cancer prevention is crucial for public health, given its high mortality rates, particularly in young adults. The early detection and treatment of precancerous lesions is key to preventing carcinogenesis progression. Natural compounds like curcumin and anthocyanins show promise in impeding adenomatous polyp progression in preclinical models. We conducted a randomized, double-blind, placebo-controlled, phase II presurgical trial in 35 patients with adenomatous polyps to explore the biological effects of curcumin and anthocyanins on circulating biomarkers of inflammation and metabolism. No significant difference in biomarker changes by treatment arm was observed. However, the network analysis before treatment revealed inverse correlations between adiponectin and BMI and glycemia, as well as direct links between inflammatory biomarkers and leptin and BMI. In addition, a considerable inverse relationship between adiponectin and grade of dysplasia was detected after treatment (corr = -0.45). Finally, a significant increase in IL-6 at the end of treatment in subjects with high-grade dysplasia was also observed (p = 0.02). The combined treatment of anthocyanins and curcumin did not result in the direct modulation of circulating biomarkers of inflammation and metabolism, but revealed a complex modulation of inflammatory and metabolic biomarkers of colon carcinogenesis.

Cost-effectiveness of direct surgery versus preoperative octreotide therapy for growth-hormone secreting pituitary adenomas.

PURPOSE: The objective of this study was to compare the cost-effectiveness of preoperative octreotide therapy followed by surgery versus the standard treatment modality for growth-hormone secreting pituitary adenomas, direct surgery (that is, surgery without preoperative treatment) from a public third-party payer perspective. METHODS: We developed an individual-level state-transition microsimulation model to simulate costs and outcomes associated with preoperative octreotide therapy followed by surgery and direct surgery for patients with growth-hormone secreting pituitary adenomas. Transition probabilities, utilities, and costs were estimated from recent published data and discounted by 3% annually over a lifetime time horizon. Model outcomes included lifetime costs [2020 United States (US) Dollars], quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: Under base case assumptions, direct surgery was found to be the dominant strategy as it yielded lower costs and greater health effects (QALYs) compared to preoperative octreotide strategy in the second-order Monte Carlo microsimulation. The ICER was most sensitive to probability of remission following primary therapy and duration of preoperative octreotide therapy. Accounting for joint parameter uncertainty, direct surgery had a higher probability of demonstrating a cost-effective profile compared to preoperative octreotide treatment at 77% compared to 23%, respectively. CONCLUSIONS: Using standard benchmarks for cost-effectiveness in the US ($100,000/QALY), preoperative octreotide therapy followed by surgery may not be cost-effective compared to direct surgery for patients with growth-hormone secreting pituitary adenomas but the result is highly sensitive to initial treatment failure and duration of preoperative treatment.

Depression and Impulsivity Self-Assessment Tools to Identify Dopamine Agonist Side Effects in Patients With Pituitary Adenomas.

Background: Dopamine agonists (DA) are the first line therapy for prolactinoma and symptomatic hyperprolactinemia; use as an adjuvant treatment for acromegaly and Cushing's disease is rare. Some patients develop de novo psychiatric symptoms or have exacerbation of pre-existing conditions during DA therapy. A practical, clinically sensitive depression and impulse control disorders (ICD; particularly hypersexuality and gambling disorders) detection tool is important for identifying at risk patients. The Barratt Impulsivity Scale (BIS-11) and the 9-item Patient Health Questionnaire (PHQ-9) are sensitive in identifying impulsivity and depression. Objective: Detail use of the BIS-11 and PHQ-9 as screening tools for depression and ICD in patients with pituitary disease at a high-volume academic pituitary center. Methods: DA-treated and naïve patients with pituitary disease were included. Patients with a known history of depression or psychiatric disorder were excluded. PHQ-9 standardized interpretation criteria were utilized to classify depression severity. For BIS-11, threshold was established based on previous studies. Statistical analysis was with SPSS version 25. Results: Seventy-six DA-treated and 27 naïve patients were included. Moderate and moderately severe depression were more prevalent in DA-treated patients; severe depression only found in DA-treated patients. A normal BIS-11 score was noted in 76.69%; higher scores (not significant) were noted in DA-treated patients. There was a positive correlation between higher BIS-11 and PHQ-9 scores; higher in DA-treated patients (r = 0.52, p < 0.001) than DA-naïve patients. Patients with BIS-11 scores ≥60 were younger and received lower cumulative DA doses compared to patients with BIS scores <60. There was no association between male sex and BIS-11 ≥60 and male sex did not increase the odds of increased scores (OR = 0.66, CI95% 0.25-1.76, p = 0.41). No significant difference was found for macroadenoma, prolactin levels, testosterone levels, hypogonadism, testosterone replacement in men, and increased impulsivity or depression scores. Conclusion: Use of PHQ-9 and BIS-11 is practical for routine screening of depression and ICD during outpatient pituitary clinic visits for patients with pituitary disease both naïve to treatment and during DA therapy. We recommend close follow-up after initiation of DA therapy for younger patients, regardless of dose.

Patient-reported outcomes of parenteral somatostatin analogue injections in 195 patients with acromegaly.

BACKGROUND: Long-acting somatostatin analogues delivered parenterally are the most widely used medical treatment in acromegaly. This patient-reported outcomes survey was designed to assess the impact of chronic injections on subjects with acromegaly. METHODS: The survey was conducted in nine pituitary centres in Germany, UK and The Netherlands. The questionnaire was developed by endocrinologists and covered aspects of acromegaly symptoms, injection-related manifestations, emotional and daily life impact, treatment satisfaction and unmet medical needs. RESULTS: In total, 195 patients participated, of which 112 (57%) were on octreotide (Sandostatin LAR) and 83 (43%) on lanreotide (Somatuline Depot). The majority (>70%) of patients reported acromegaly symptoms despite treatment. A total of 52% of patients reported that their symptoms worsen towards the end of the dosing interval. Administration site pain lasting up to a week following injection was the most frequently reported injection-related symptom (70% of patients). Other injection site reactions included nodules (38%), swelling (28%), bruising (16%), scar tissue (8%) and inflammation (7%). Injection burden was similar between octreotide and lanreotide. Only a minority of patients received injections at home (17%) and 5% were self-injecting. Over a third of patients indicated a feeling of loss of independence due to the injections, and 16% reported repeated work loss days. Despite the physical, emotional and daily life impact of injections, patients were satisfied with their treatment, yet reported that modifications that would offer major improvement over current care would be 'avoiding injections' and 'better symptom control'. CONCLUSION: Lifelong injections of long-acting somatostatin analogues have significant burden on the functioning, well-being and daily lives of patients with acromegaly.

Cost-effectiveness analysis of two therapeutic schemes in the treatment of acromegaly: a retrospective study of 168 cases.

PURPOSE: This study aimed to estimate the cost effectiveness of two therapeutic schemes, including preoperative medical therapy and surgery as primary therapy. METHODS: A total of 168 acromegaly cases were retrospectively investigated for a comparative evaluation of surgery and preoperative medical therapy. A Markov model was developed to simulate treatment cost-effectiveness and progression of acromegaly. RESULTS: Overall effectiveness of preoperative medical therapy was significantly higher than surgery in acromegalic patients with macroadenoma. In addition, life expectancy, and cost per life-year gained were slightly higher in the preoperative medical therapy group than in the initial surgery group when patients received surgery as a secondary treatment. Interestingly, preoperative medical therapy achieved a significant increase in life expectancy and reduced cost for patients who received long-term medical therapy as secondary treatment. CONCLUSIONS: In acromegalic patients with macroadenoma, the cost-effectiveness analysis revealed more satisfactory outcomes in preoperative therapy, compared with primary surgery.

Aggressive tumors and difficult choices in acromegaly.

PURPOSE: The current article looks at some of the factors associated with pituitary adenomas displaying unusually aggressive biological and clinical behaviour in patients with acromegaly. METHODS: This was a retrospective, narrative review of previously published evidence chosen at the authors' discretion and presented from the perspective of a Latin American case study. FINDINGS AND CONCLUSIONS: Although most pituitary tumors in acromegalic patients are benign and non-aggressive many can behave more aggressively, compromising local surrounding structures. These lesions tend to respond poorly to somatostatin analogs, have a higher risk of recurrence after surgery and, thus, a worse prognosis. Patients with more aggressive tumors constitute a particular challenge, as they often require several therapeutic approaches and may be difficult to manage, especially when options are restricted due to limited resources.

The role of primary pharmacological therapy in acromegaly.

BACKGROUND AND OBJECTIVES: Primary pharmacological therapy may be the only viable treatment option for many patients with acromegaly, especially those presenting with advanced disease with large inoperable tumors. Long-acting somatostatin analogs are currently the first-line treatment of choice in this setting, where they provide biochemical control and reduce tumor size in a significant proportion of patients. We herein present a brief overview of the role of primary pharmacological therapy in the treatment of acromegaly within the context of Latin America and support this with a representative case study. CASE DESCRIPTION: A 20 year old male presented with clinical and biochemical evidence of acromegaly. The glucose-suppressed growth hormone (GH) was 5.3 µg/L, his insulin-like growth factor-1(IGF-1) was 3.5 times the ULN and serum prolactin greater than 4,000 µg/L. Pituitary MRI revealed a large and invasive mass, extending superiorly into the optic chiasm and laterally into the left cavernous sinus. He was treated with a combination of octreotide and cabergoline with remarkable clinical improvement, normalization of GH and IGF-1 values and striking shrinkage of the adenoma. CONCLUSION: This case illustrates how effective the pharmacological therapy of acromegaly can be and yet at the same time, raises several important issues such as the need for life-long treatment with costly medications such as the somatostatin analogs. Access to these agents may be limited in regions where resources are restricted and clinicians face challenges in order to make the most efficient use of available options.

Global quantitative assessment of the colorectal polyp burden in familial adenomatous polyposis by using a web-based tool.

BACKGROUND: Accurate measures of the total polyp burden in familial adenomatous polyposis (FAP) are lacking. Current assessment tools include polyp quantitation in limited-field photographs and qualitative total colorectal polyp burden by video. OBJECTIVE: To develop global quantitative tools of the FAP colorectal adenoma burden. DESIGN: A single-arm, phase II trial. PATIENTS: Twenty-seven patients with FAP. INTERVENTION: Treatment with celecoxib for 6 months, with before-treatment and after-treatment videos posted to an intranet with an interactive site for scoring. MAIN OUTCOME MEASUREMENTS: Global adenoma counts and sizes (grouped into categories: <2 mm, 2-4 mm, and >4 mm) were scored from videos by using a novel Web-based tool. Baseline and end-of-study adenoma burden results were summarized by using 5 models. Correlations between pairs of reviewers were analyzed for each model. RESULTS: Interobserver agreement was high for all 5 measures of polyp burden. Measures that used both polyp count and polyp size had better interobserver agreement than measures based only on polyp count. The measure in which polyp counts were weighted according to diameter, calculated as (1) × (no. of polyps <2 mm) + (3) × (no. of polyps 2-4 mm) + (5) × (no. of polyps >4 mm) had the highest interobserver agreement (Pearson r = 0.978 for two gastroenterologists, 0.786 and 0.846 for the surgeon vs each gastroenterologist). Treatment reduced the polyp burden by these measurements in 70% to 89% of patients (P < .001). LIMITATIONS: Phase II study. CONCLUSION: This novel, Web-based polyp scoring method provides a convenient and reproducible way to quantify the global colorectal adenoma burden in FAP patients and a framework for developing a clinical staging system for FAP.

Combination aspirin and/or calcium chemoprevention with colonoscopy in colorectal cancer prevention: cost-effectiveness analyses.

BACKGROUND: Clinical and cohort studies have shown that low-dose aspirin and calcium are effective low-risk strategies for primary prevention of colorectal cancer (CRC). We compared the cost-effectiveness of aspirin and calcium chemoprevention used with colonoscopy for primary prevention of CRCs. METHODS: Markov chain Monte Carlo simulations for a population of 100,000 persons, with a colonoscopy compliance rate of 50%, were used for the analysis. If adenomas were detected, colonoscopy was repeated every 4 years until no adenomas were evident. Data sources included adenoma transition rates, initial adenoma and CRC incidences, and treatment complication rates from existing literature. Age-adjusted U.S. standard population mortality rates were used and costs were from Medicare reimbursement data. The target population was U.S. adults, undergoing CRC screening from ages 50 to 75 years. RESULTS: Outcomes included incremental cost-effectiveness ratios (ICER), life-years saved (LYS), and cancer-free years saved (CFYS). The ICER per LYS for colonoscopy alone dominated compared with no screening. Compared with colonoscopy alone, colonoscopies with aspirin (ICER = $12,950/LYS) or calcium (ICER = $13,041/LYS) were the next most cost-effective strategies. ICERs per CFYS were $3,061 and $2,317 for aspirin and calcium, respectively, when added to colonoscopy. Sensitivity analyses indicated that initial prevalence of adenomas was a main determinant of prevention cost-effectiveness. CONCLUSION: Low-dose aspirin or calcium supplementation may be beneficial when added to colonoscopy, for optimum CRC prevention, at small incremental costs. IMPACT: Cost-effectiveness analyses suggest that aspirin and calcium in combination with colonoscopies are cost-effective for CRC prevention in average-risk populations.

Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly.

OBJECTIVE: To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly. DESIGN: This is a cross-sectional study in two tertiary referral centers in The Netherlands. PATIENTS AND METHODS: One hundred and eight patients with acromegaly, in whom transsphenoidal (n=101, 94%) or transcranial (n=7, 6%) surgery was performed. Subsequently, 46 (43%) received additional radiotherapy and 41 (38%) were on postoperative treatment with SSTA because of persistent or recurrent disease at the time of study. All subjects filled in standardized questionnaires measuring HR-QoL. Disease control at the time of study was assessed by local IGF1 SDS. RESULTS: IGF1 SDS were slightly higher in patients treated with SSTA in comparison with patients without use of SSTA (0.85±1.52 vs 0.25±1.21, P=0.026), but the percentage of patients with insufficient control (IGF1 SDS >2) was not different (17 vs 9%, P=0.208). Patients using SSTA reported poorer scores on most subscales of the RAND-36 and the acromegaly QoL and on all subscales of the multidimensional fatigue inventory-20. A subgroup analysis in patients with similar IGF1 levels (SSTA+, n=26, IGF1 SDS 0.44±0.72 vs SSTA-, n=44, IGF1 SDS 0.41±0.65) revealed worse scores on physical functioning, physical fatigue, reduced activity, vitality, and general health perception across all HR-QoL questionnaires in patients treated with SSTA. CONCLUSION: QoL is impaired in association with the need for prolonged postoperative therapy by SSTA in patients with acromegaly despite similar IGF1 levels.

Estimation of recurrence of colorectal adenomas with dependent censoring using weighted logistic regression.

In colorectal polyp prevention trials, estimation of the rate of recurrence of adenomas at the end of the trial may be complicated by dependent censoring, that is, time to follow-up colonoscopy and dropout may be dependent on time to recurrence. Assuming that the auxiliary variables capture the dependence between recurrence and censoring times, we propose to fit two working models with the auxiliary variables as covariates to define risk groups and then extend an existing weighted logistic regression method for independent censoring to each risk group to accommodate potential dependent censoring. In a simulation study, we show that the proposed method results in both a gain in efficiency and reduction in bias for estimating the recurrence rate. We illustrate the methodology by analyzing a recurrent adenoma dataset from a colorectal polyp prevention trial.

Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status.

BACKGROUND: Aggressive pituitary tumours are associated with substantial morbidity and mortality. Treatment options are often limited, and chemotherapy has been reserved as salvage therapy although historically results have often been disappointing. However, temozolomide, an oral alkylating agent, has recently demonstrated significant activity against these tumours. A DNA repair protein, 06-methylguanine-DNA methyltransferase (MGMT) has been suggested as a biomarker to predict response to temozolomide in pituitary tumours. MATERIALS AND METHODS: This paper will review the current literature on temozolomide and pituitary tumours and discuss the recent controversy surrounding the value of determining the MGMT status in this tumour group. A PubMed search was performed to retrieve articles, using the terms 'pituitary tumour' and 'temozolomide'. RESULTS: Overall, 24/40 (60%) of the published cases demonstrated a response to temozolomide therapy. The highest response rates were seen amongst prolactinomas (73%) and ACTH-secreting tumours (60%), whilst nonfunctioning pituitary tumours exhibit lower response rates (40%). Responsivity is typically evident in the first 3 months of therapy and may be dramatic and sustained. Low MGMT expression, as determined by immunohistochemistry, is associated with a high response rate (76%), whilst high MGMT expression has not been associated with responses. MGMT promoter methylation does not correlate with temozolomide response. CONCLUSIONS: Temozolomide is the first chemotherapeutic agent to show substantial response rates in aggressive pituitary tumours. MGMT immunohistochemistry, but not MGMT methylation analysis, shows promise as a predictive tool. Prospective clinical trials are now necessary to more accurately determine the efficacy of this agent in this patient group.

Current pharmacotherapy for acromegaly: a review.

Acromegaly is associated with considerable morbidity and excess mortality; however, after effective treatment, both morbidity and mortality risks improve. Growth hormone excess in acromegaly can be controlled in many patients by pharmacotherapy alone, and with a combination of transsphenoidal surgery and pharmacotherapy in almost all patients. Since the clinical introduction of pegvisomant, a growth hormone-receptor antagonist, the role of radiotherapy is restricted. This review focuses on the treatment options for acromegaly (e.g., surgery, radiotherapy and pharmacotherapy with the depot preparations of the somatostatin analogues octreotide long-acting release formulation, lanreotide slow-release formulation and lanreotide Autogel, the growth hormone antagonist pegvisomant and the dopamine agonist cabergoline). Pharmacological characteristics of these drugs and the clinical and adverse effects are discussed individually and in relation to the other treatment modalities. The evidence for biochemical goals aimed at during medical treatment and the costs of pharmacotherapy are discussed. A new treatment algorithm is proposed, in which the choice between primary medical treatment and primary surgery is individualised, dependent on adenoma size and extension, patient factors (age, preference for therapy, contraindication for surgery), surgical experience of the centre and octreotide sensitivity of the adenoma. The high cost of lifelong medical treatment, especially of pegvisomant, must be weighed against the cost of a single surgical procedure.

Radioiodine or surgery for toxic thyroid adenoma: dissecting an important decision. A cost-effectiveness analysis.

OBJECTIVE: To examine the cost effectiveness of therapeutic strategies for toxic thyroid adenoma. DESIGN: Markov state transition decision analytic model. SETTING: Ambulatory and inpatient. PATIENTS: Hypothetical cohort of 40- year-old women with toxic thyroid adenomas. Patient age was varied in sensitivity analyses. Data on the prevalence of coincident thyroid cancer, complications, and treatment efficacies were derived from a systematic review of the literature. INTERVENTIONS: Thyroid lobectomy after a 3 month-course of antithyroid drugs (ATDs), high-dose (<555 MBq) radioactive iodine (RAI), low-dose (>555 MBq) RAI, and lifelong ATDs. MEASUREMENTS AND MAIN RESULTS: Outcomes were measured in quality-adjusted life years (QALYs). Costs were estimated from the health care system perspective. Future costs and effectiveness were discounted at 3% per year. For a 40- year-old woman, surgery was the most effective, while low-dose RAI was the least costly. The marginal cost-effectiveness of surgery versus low-dose RAI was $13,183 per QALY. Surgery was less costly and more effective than lifelong ATDs. RAI was more effective than surgery if surgical mortality exceeded 0.90% (base-case 0.001%). Surgery provided relatively inexpensive gains (<$50,000 per QALY) in quality-adjusted life expectancy in patients less than 74 years of age. CONCLUSIONS: For most patients less than 60 years of age, surgery is an effective strategy with a reasonable cost. However, for any given patient, surgical mortality, therapeutic costs and preference must be considered in choosing an appropriate therapy.

[Long-term results of ultrasound-guided ethanol injections in patients with autonomous thyroid nodules and hyperthyroidism]. / Langzeitergebnisse der ultraschallgesteuerten Alkoholinstillation bei Patienten mit fokaler Schilddrüsenautonomie und Hyperthyreose.

AIM: The aim of this study was to evaluate the long-term efficacy of treatment of autonomous thyroid nodules with percutaneous ethanol injection under ultrasound guidance. PATIENTS AND METHODS: In a period of 56 months, 20 patients (13 women and seven men, mean age 67.5 +/- 12.3 years) with autonomous toxic thyroid nodules were treated with percutaneous ethanol injection under ultrasound guidance. Ethanol was injected percutaneously on an outpatient basis for a mean of 2.85 +/- 1.1 injections per patient, mainly depending on the nodule's size. The mean volume of injected ethanol was 4.63 ml. The median follow-up time was 763 +/- 452 days. RESULTS: The injection was well tolerated by the patients, a mild to moderate local pain occurred in 21% of sessions. Undesirable effects were not serious and only transient and receded. Major complications like transient dysphonia or common jugular vein thrombosis have not been observed. After a mean time of 50 +/- 23 days an euthyroid state with normalized basal levels of TSH, fT3 and fT4 was maintained in 16 patients (80%), while four patients (20%) did not completely respond to the treatment. In this patients a therapy with methimazole was carried out. The rate of reduction in the nodular volume was 60.8%. CONCLUSION: The percutaneous ethanol injection appears to be an effective, harmless and low-cost alternative treatment of autonomous thyroid nodules, especially in older and multimorbid patients.

Assessment by computed tomography of the response of pituitary macroadenomas to bromocriptine.

Eleven patients with large pituitary tumours and with extrasellar extension were studied prospectively to assess the response of these tumours to bromocriptine. Five out of the six patients with high serum prolactin due to prolactinomas showed rapid and dramatic reduction in tumour size when treated with bromocriptine. In contrast, none of the five patients with non-functioning tumours showed any change in tumour size on computed tomography.