Adenoma Formation In Patients Research Articles

High childhood serum triglyceride concentrations associate with hepatocellular adenoma development in patients with glycogen storage disease type Ia

Background & AimsGlycogen storage disease type Ia (GSDIa) is an inborn error of carbohydrate metabolism caused by pathogenic variants in the glucose-6-phosphatase catalytic subunit 1 (G6PC1) gene and is associated with hepatocellular adenoma (HCA) formation. Data on risk factors for HCA occurrence in GSDIa are scarce. We investigated HCA development in relation to sex, G6PC1 genotype, and serum triglyceride concentration (TG).MethodsAn observational study of patients with genetically confirmed GSDIa ≥12 years was performed. Patients were categorised for sex; presence of 2, 1, or 0 predicted severe G6PC1 variant (PSV); and median TG during childhood (<12 years; stratified for above/below 5.65 mmol/L, i.e. 500 mg/dl).ResultsFifty-three patients (23 females) were included, of which 26 patients developed HCA at a median (IQR) age of 21 (17–25) years. At the age of 25 years, 48% of females and 30% of males had developed HCA (log-rank p = 0.045). Two-thirds of patients with GSDIa carried 2 PSVs, 20% carried 1, and 13% carried none. Neither the number of PSVs nor any specific G6PC1 variants were associated with HCA occurrence. Childhood TG was 3.4 (3.0–4.2) mmol/L in males vs. 5.6 (4.0–7.9) mmol/L in females (p = 0.026). Childhood TG >5.65 mmol/L was associated with HCA development at younger age, compared with patients with childhood TG <5.65 mmol/L (18 vs. 33 years; log-rank p = 0.001). Cox regression analysis including TG, sex, and TG–sex interaction correction revealed childhood TG >5.65 mmol/L as an independent risk factor for HCA development (hazard ratio [HR] 6.0; 95% CI 1.2–29.8; p = 0.028).ConclusionsIn patients with GSDIa, high childhood TG was associated with an increased risk of HCA, and earlier onset of HCA development, independent of sex-associated hypertriglyceridaemia, and G6PC1 genotype.Lay summaryGlycogen storage disease type Ia (GSDIa) is a rare, inherited metabolic disease that can be complicated by liver tumours (hepatocellular adenomas), which in turn may cause bleeding or progress to liver cancer. Risk factors associated with hepatocellular adenoma formation in patients with GSDIa are largely unknown. In our study, we found that high serum triglyceride concentrations during childhood, but not specific genetic variants, were associated with increased risk of hepatocellular adenoma diagnosis later in life.

Abstract PR01: Right-sided colonic biofilms are associated with adenoma formation in patients with Lynch syndrome

Abstract Colonic bacterial biofilms are an emerging manifestation in colorectal cancer (CRC); they exhibit carcinogenic properties and are frequently present on right-sided cancerous lesions. Whether bacterial biofilms propose a risk factor for early carcinogenesis in humans is yet unresolved. Therefore, we studied bacterial biofilms in tandem with adenoma formation in patients with Lynch syndrome (LS). LS patients carry a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, resulting in a variable predisposition to develop colonic cancerous lesions. A total of 100 LS patients were included in our study, consisting of 23 MLH1, 24 MSH2, 36 MSH6, and 17 PMS2 MMR variants. During regular screening colonoscopies, normal-appearing forceps biopsies were taken from colon ascendens (right colon) and descendens (left colon). Biopsies were screened for bacterial biofilms using fluorescent in situ hybridization by targeting bacterial 16s rRNA. The frequency of colorectal adenomas (tubular adenomas and [tubulo]villous adenomas) before and during colonoscopy was registered. Overall, 60% of patients presented with a biofilm, of which most were right-sided (right-sided: 25%, both sides: 21%, left-sided: 14%). Interestingly, adenomas were more frequently present in patients with a right-sided biofilm (right-sided: 64%, both sides: 58%) than in patients with a left-sided biofilm (29%) or no biofilm (38%). The occurrence of bacterial biofilms was not correlated with age, BMI, or MMR-variant. Statistical analysis revealed that right-sided bacterial biofilms correlated with right-sided adenomas (Pearson: 0.272, p=0.007) and left-sided adenomas (Pearson: 0.227, p=0.026), while left-sided biofilms were not correlated with left- or right-sided adenomas (Pearson: 0.037, p=0.718 and -.127, p=.213). To model the probability of right-sided adenoma formation, we performed a binary logistic regression analysis and found that age (odds ratio: 1.065 [CI: 1.024; 1.108, p=0.002]) and right-sided biofilms (odds ratio: 3.020 [CI: 1.151; 7.926, p=0.025]) significantly contributed. Our data suggest that right-sided bacterial biofilms are a hallmark for high-risk LS patients and may play a role in early carcinogenesis. This abstract is also being presented as Poster A06. Citation Format: Carlijn Bruggeling, Vera Witjes, Daniel Garza, Milou Fransen, Joyce Krekels, Tanya Bisseling, Mariëtte van Kouwen, Nicoline Hoogerbrugge, Sebastian Lücker, Bas Dutilh, Iris Nagtegaal, Annemarie Boleij. Right-sided colonic biofilms are associated with adenoma formation in patients with Lynch syndrome [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR01.

The effect of ursodesoxycholic acid on duodenal adenomas in familial adenomatous polyposis: a prospective randomized placebo‐control trial

Duodenal adenomas occur in about 90% of patients with familial adenomatous polyposis (FAP) and are the second cause of death of patients who have had a prophylactic proctocolectomy. Studies suggest that biliary acids have a role in the development of duodenal adenomas. The aim of this study was to evaluate the impact of ursodesoxycholic acid (UDCA) on duodenal adenoma formation in patients with FAP. A randomized, double-blinded, placebo-controlled study was carried out of 71 patients (20-65 years) who already had a restorative proctocolectomy. Subjects received either 10 mg/kg of UDCA orally per day or a placebo tablet for 24 months. The Spigelman severity score was determined after duodenal axial and lateral view endoscopy at 12 and 24 months. At 2 years 55 patients had completed the entire period of treatment. At the end of the follow-up period, nine (25%) patients in the UDCA group and seven (20%) in the placebo group had a decrease in the Spigelman score (P = 0.6142). Patients receiving UDCA had no side-effects (0%) compared with four (14%) in the placebo group (P = 0.0392). UDCA had no effect on the development of duodenal adenomas in FAP patients (NCT: 00134758).

Covering the Cover

Covering the Cover

Chemoprevention of colorectal cancer with cyclooxygenase-2 inhibitors: two steps forward, one step back

Chronic inflammation is a tissue-specific process implicated in several diseases of an aging population, including cancer, cardiovascular disease, and arthritis. Cyclooxygenase-2 (COX-2) is a mediator of acute and chronic inflammation, and drugs designed to specifically target this enzyme have achieved widespread clinical use. Unfortunately, randomised trials of selective COX-2 inhibitors for cancer prevention have shown that beneficial effects in one type of tissue can be accompanied by toxic effects in another. These trials documented a significant reduction in adenoma formation in patients at high risk for colorectal cancer, with reductions in advanced disease occurrence from 28-66% over 3 years. As a result, these studies provided important evidence for the involvement of COX-2 in early colorectal tumorigenesis. In the same patients, however, these placebo-controlled clinical trials revealed a little-understood relation between COX-2 and maintenance of cardiovascular integrity. During the 3 years of treatment, patients who received selective COX-2 inhibitors were 1.3-3.4-times more likely to have serious cardiovascular events than those treated with placebo. This article will discuss the biological rationale for using selective COX-2 inhibitors in cancer chemoprevention, and outline new avenues of research into toxic effects and tissue specificity that are necessary to allow their successful use in patients at risk for colorectal cancer.

New occurrence and recurrence of neoplasms within 5 years of a screening colonoscopy.

The fear that colorectal adenomas were missed on initial colonoscopy or that new adenomas have developed is often a rationale for repeating a colonoscopic examination. The aim of this study was to delineate risk factors associated with recurrence of colorectal adenomas after an initial baseline screening colonoscopy. The study population comprised 875 subjects who underwent a baseline screening colonoscopy followed by a second examination 1-5 yr later. Multiple logistic regression was used to assess the influence of potential risk factors on the occurrence or recurrence of colorectal adenomas, the strength of the influence being expressed as an OR with a 95% CI. Colorectal adenomas were detected in 484 of all patients (55%) at baseline colonoscopy. Within a 1- to 5-yr time interval, 181 patients (37%) had recurrent adenomas (adenomas were removed during the first colonoscopy) and 73 patients (19%) had newly developed adenomas (adenomas were absent on the first colonoscopy). The occurrence of adenomas at baseline screening colonoscopy was the only factor associated with an increased risk for the recurrence of adenomas at follow-up (OR = 2.51, 95% CI = 1.77-3.55). Recurrence was associated with multiple baseline adenomas (4.45, 2.98-6.64) and baseline adenomas larger than 1 cm (2.62, 1.99-3.11). Recurrence was not associated with histology type or family history of colorectal cancer. There was a significant trend for adenomas to recur in the same proximal or distal segment as the baseline adenomas (p = 0.02). Colon adenomas tend to recur with greater frequency if the adenomas removed at baseline were either large or multiple. Although patients with large adenomas or multiple adenomas at baseline screening colonoscopy are at a 2.6- to 4.5-fold risk for recurrence of adenomas, the rate of de novo adenoma formation in patients without baseline adenomas may be large enough to warrant repeat colonoscopy at some time in the future. The exact timing of the follow-up colonoscopy needs to be determined.

New occurrence and recurrence of neoplasms within 5 years of a screening colonoscopy

OBJECTIVE: The fear that colorectal adenomas were missed on initial colonoscopy or that new adenomas have developed is often a rationale for repeating a colonoscopic examination. The aim of this study was to delineate risk factors associated with recurrence of colorectal adenomas after an initial baseline screening colonoscopy. METHODS: The study population comprised 875 subjects who underwent a baseline screening colonoscopy followed by a second examination 1–5 yr later. Multiple logistic regression was used to assess the influence of potential risk factors on the occurrence or recurrence of colorectal adenomas, the strength of the influence being expressed as an OR with a 95% CI. RESULTS: Colorectal adenomas were detected in 484 of all patients (55%) at baseline colonoscopy. Within a 1- to 5-yr time interval, 181 patients (37%) had recurrent adenomas (adenomas were removed during the first colonoscopy) and 73 patients (19%) had newly developed adenomas (adenomas were absent on the first colonoscopy). The occurrence of adenomas at baseline screening colonoscopy was the only factor associated with an increased risk for the recurrence of adenomas at follow-up (OR = 2.51, 95% CI = 1.77–3.55). Recurrence was associated with multiple baseline adenomas (4.45, 2.98–6.64) and baseline adenomas larger than 1 cm (2.62, 1.99–3.11). Recurrence was not associated with histology type or family history of colorectal cancer. There was a significant trend for adenomas to recur in the same proximal or distal segment as the baseline adenomas ( p = 0.02). CONCLUSIONS: Colon adenomas tend to recur with greater frequency if the adenomas removed at baseline were either large or multiple. Although patients with large adenomas or multiple adenomas at baseline screening colonoscopy are at a 2.6- to 4.5-fold risk for recurrence of adenomas, the rate of de novo adenoma formation in patients without baseline adenomas may be large enough to warrant repeat colonoscopy at some time in the future. The exact timing of the follow-up colonoscopy needs to be determined.

Characterization of Adrenal Autonomy in Cushing's Syndrome: A Comparison betweenin Vivoandin VitroResponsiveness of the Adrenal Gland

We measured cortisol and precursor steroid production in response to ACTH, cholera toxin, and forskolin by the dispersed adrenocortical cells prepared from the adrenal glands of 10 patients with different forms of Cushing's syndrome. The cells prepared from the hyperplastic adrenal glands from 4 patients with Cushing's disease responded in a dose-dependent manner to ACTH, cholera toxin, and forskolin. The adrenal cells prepared from 4 encapsulated adrenal adenomas showed no (n = 2), a lowered (n = 1), or a clear (n = 1) response of cortisol release to ACTH. The cells prepared from the adrenal glands of 1 patient with dysplastic micronodular adrenal glands showed a limited response to ACTH, while the cells from an adrenocortical carcinoma, which secreted very little cortisol per cell, were unresponsive to ACTH, cholera toxin, and forskolin. The reaction of the dispersed adrenal cells from these 10 patients to ACTH, cholera toxin, and forskolin showed a close correlation (P less than 0.001 in all instances). This suggests that the defect in autonomous glands is not located at the level of the ACTH receptor, but, rather, involves the adenylate cyclase complex as a whole or its coupling to cAMP-dependent protein kinase. The release into the medium of the cortisol precursors deoxycortisol, 17-hydroxyprogesterone, and progesterone showed that the four autonomous nodules were characterized by a significantly higher deoxycortisol/cortisol ratio in the medium (P less than 0.01), suggesting a relative blockade of 11 beta-hydroxylase in these adrenal adenomas. This was further substantiated in cells from several adrenals by a significant increase in the release of these precursors in response to ACTH in the absence of a cortisol response. We conclude the following. 1) Adrenal adenoma formation in patients with Cushing's syndrome is accompanied by a parallel decrease in the stimulation of the release of steroid hormones in response to ACTH, cholera toxin, and forskolin. This points to a defect in the adenoma cells beyond the ACTH receptor. 2) Adrenal adenoma formation in patients with Cushing's syndrome is accompanied by a relative blockade of 11 beta-hydroxylase activity. 3) By comparing the preoperative dynamic tests of the pituitary-adrenal axis, the plasma ACTH concentration, the morphology of the adrenal glands, and their in vitro responsiveness, a gradual transition from pituitary to (partial) adrenal autonomy could be recognized in several patients.