Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma-a case report and review.

Introduction: 24-Hydroxylase, encoded by the CYP24A1 gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in CYP24A1 result in PTH-independent hypercalcaemia with high levels of 1,25(OH)2D3. The variety of clinical manifestations depends on age, and underlying genetic predisposition mutations can lead to fatal infantile hypercalcaemia among neonates, whereas adult symptoms are usually mild. Aim of the study: We report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the CYP24A1 gene and a review of similar cases. Case presentation: We report the case of a 58-year-old woman diagnosed initially with primary hyperparathyroidism. Preoperatively, the suspected mass adjoining the upper pole of the left lobe of the thyroid gland was found via ultrasonography and confirmed by 99mTc scintigraphy and biopsy as the parathyroid gland. The patient underwent parathyroidectomy (a histopathology report revealed parathyroid adenoma), which led to normocalcaemia. After 10 months, vitamin D supplementation was introduced due to deficiency, and the calcium level remained within the reference range. Two years later, biochemical tests showed recurrence of hypercalcaemia with suppressed parathyroid hormone levels and elevated 1,25(OH)2D3 concentrations. Further investigation excluded the most common causes of PTH-independent hypercalcaemia, such as granulomatous disease, malignancy, and vitamin D intoxication. Subsequently, vitamin D metabolites were measured using LC-MS/MS, which revealed high levels of 25(OH)D3, low levels of 24,25(OH)2D3 and elevated 25(OH)2D3/24,25(OH)2D3 ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the CYP24A1 gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively). Conclusions: The diagnostic process for hypercalcaemia becomes complicated when multiple causes of hypercalcaemia coexist. The measurement of vitamin D metabolites using LC-MS/MS may help to identify carriers of CYP24A1 mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the CYP24A1 gene and introducing personalized treatment.

Transanal minimally invasive surgery for benign and malignant rectal lesions: midterm outcomes from a tertiary center.

BACKGROUND: Although transanal minimally invasive surgery (TAMIS) for rectal neoplasia has gained wide acceptance, the mid-term and long-term outcomes are not widely reported in the literature. OBJECTIVE: Describe the mid-term outcomes of patients who underwent TAMIS for benign and malignant rectal lesions in a single center. DESIGN: Retrospective cohort study. SETTINGS: Tertiary referral center. PATIENTS AND METHODS: Demographic, clinical, and oncological outcomes of patients who underwent TAMIS between January 2015 and December 2022 were prospectively collected. The indication for TAMIS was based on the National Comprehensive Cancer Network guidelines. The follow up for the cancer patients included clinical examination, tumor markers every 6 months and MRI rectum at the end of one year. In addition, colonoscopy and CT scan at years one and three and a final CT scan and colonoscopy at year five. MAIN OUTCOME MEASURES: Mid-term oncological and clinical outcome. RESULTS: Thirty elective TAMIS procedures included adenocarcinoma for 33.3% (n=10) of the patients, 20% (n=6) neuroendocrine tumor and the 40% (n=12) were adenomatous lesions. Negative resection margins were achieved in all malignant lesions. Perioperative complications occurred in 2 patients (6.6%), one patient had breaching into the peritoneal cavity, and postoperative hypotension occurred in another patient. The median follow-up time was 23 months (range: 5-72 months). Two patients with adenoma and positive margins developed recurrent adenoma (6.6%) and one patient with initial polypectomy biopsy of adenocarcinoma, had TAMIS with histopathology of adenoma and distant metastasis had developed. CONCLUSIONS: TAMIS for local excision of rectal neoplasia is a valid option with favorable mid-term outcomes provided there is adherence to careful selection criteria. LIMITATIONS: Retrospective nature and small number of the patients.

Dual-energy CT in the differentiation between adrenal adenomas and metastases: Usefulness of material density maps and monochromatic images.

OBJECTIVE: To evaluate the behavior of adrenal adenomas and metastases with dual-energy CT, analyzing the attenuation coefficient in monochromatic images at three different levels of energy (45, 70, and 140 keV) and the tissue concentrations of fat, water, and iodine in material density maps, with the aim of establishing optimal cutoffs for differentiating between these lesions and comparing our results against published evidence. MATERIALS AND METHODS: This retrospective case-control study included oncologic patients diagnosed with adrenal metastases in the 6-12 months prior to the study who were followed up in our hospital between January and June 2020. For each case (patient with metastases) included in the study, we selected a control (patient with an adrenal adenoma) with a nodule of similar size. All patients were studied with a rapid-kilovoltage-switching dual-energy CT scanner, using a biphasic acquisition protocol. We analyzed the concentration of iodine in paired water-iodine images, the concentration of fat in the paired water-fat images, and the concentration of water in the paired iodine-water and fat-water images, in both the arterial and portal phases. We also analyzed the attenuation coefficient in monochromatic images (at 55, 70, and 140 keV) in the arterial and portal phases. RESULTS: In the monochromatic images, in both the arterial and portal phases, the attenuation coefficient at all energy levels was significantly higher in the group of patients with metastases than in the group of patients with adenomas. This enabled us to calculate the optimal cutoffs for classifying lesions as adenomas or metastases, except for the arterial phase at 55 KeV, where the area under the receiver operating characteristic curve (AUC) for the estimated threshold (0.68) was not considered accurate enough to classify the lesions. For the arterial phase at 70 keV, the AUC was 0.76 (95% CI: 0.663‒0.899); the optimal cutoff (42.4 HU) yielded 92% sensitivity and 60% specificity. For the arterial phase at 140 keV, the AUC was 0.94 (95% CI: 0.894‒0.999); the optimal cutoff (18.9 HU) yielded 88% sensitivity and 94% specificity). For the portal phase at 55 keV, the AUC was 0.76 (95% CI: 0.663‒0.899); the optimal cutoff (95.4 HU) yielded 68% sensitivity and 84% specificity. For the portal phase at 70 keV, the AUC was 0.82 (95% CI: 0.757‒0.955); the optimal cutoff (58.4 HU) yielded 80% sensitivity and 84% specificity. For the portal phase at 140 keV, the AUC was 0.9 (95% CI: 0.834‒0.987); the optimal cutoff (16.35 HU) yielded 96% sensitivity and 84% specificity. In the material density maps, in the arterial phase, significant differences were found only for the iodine-water pair, where the concentration of water was higher in the group with metastases (1018.8 ±â€¯7.6 mg/cm3 vs. 998.6 ±â€¯8.0 mg/cm3 for the group with adenomas, p < 0.001). The AUC was 0.97 (95% CI: 0.893‒0.999); the optimal cutoff (1012.5 mg/cm3) yielded 88% sensitivity and 96% specificity. The iodine-water pair was also significantly higher in metastases (1019.7 ±â€¯12.1 mg/cm3 vs. 998.5 ±â€¯9.1 mg/cm3 in adenomas, p < 0.001). The AUC was 0.926 (95% CI: 0.807‒0.977); the optimal cutoff (1009.5 mg/cm3) yielded 92% sensitivity and 92% specificity. Although significant results were also observed for the fat-water pair in the portal phase, the AUC was insufficient to enable a sufficiently accurate cutoff for classifying the lesions. No significant differences were found in the fat-water maps or iodine-water maps in the arterial or portal phase or in the water-fat map in the arterial phase. CONCLUSIONS: Monochromatic images show differences between the behavior of adrenal adenomas and metastases in oncologic patients studied with intravenous-contrast-enhanced CT, where the group of metastases had higher attenuation than the group of adenomas in both the arterial and portal phases; this pattern is in line with the evidence published for adenomas. Nevertheless, to our knowledge, no other publications report cutoffs for this kind of differentiation in contrast-enhanced monochromatic images obtained in rapid-kilovoltage-switching dual-energy CT scanners, and this is the first new contribution of our study. Regarding the material density maps, our results suggest that the water-iodine pair is a good tool for differentiating between adrenal adenomas and metastases, in both the arterial and portal phases. We propose cutoffs for differentiating these lesions, although to our knowledge no cutoffs have been proposed for portal-phase contrast-enhanced images obtained with rapid-kilovoltage-switching dual-energy CT scanners.

Growth rates and histopathological outcomes of small (6-9 mm) colorectal polyps based on CT colonography surveillance and endoscopic removal.

BACKGROUND AND AIMS: The natural history of small polyps is not well established and rests on limited evidence from barium enema studies decades ago. Patients with one or two small polyps (6-9 mm) at screening CT colonography (CTC) are offered CTC surveillance at 3 years but may elect immediate colonoscopy. This practice allows direct observation of the growth of subcentimetre polyps, with histopathological correlation in patients undergoing subsequent polypectomy. DESIGN: Of 11 165 asymptomatic patients screened by CTC over a period of 16.4 years, 1067 had one or two 6-9 mm polyps detected (with no polyps ≥10 mm). Of these, 314 (mean age, 57.4 years; M:F, 141:173; 375 total polyps) elected immediate colonoscopic polypectomy, and 382 (mean age 57.0 years; M:F, 217:165; 481 total polyps) elected CTC surveillance over a mean of 4.7 years. Volumetric polyp growth was analysed, with histopathological correlation for resected polyps. Polyp growth and regression were defined as volume change of ±20% per year, with rapid growth defined as +100% per year (annual volume doubling). Regression analysis was performed to evaluate predictors of advanced histology, defined as the presence of cancer, high-grade dysplasia (HGD) or villous components. RESULTS: Of the 314 patients who underwent immediate polypectomy, 67.8% (213/314) harboured adenomas, 2.2% (7/314) with advanced histology; no polyps contained cancer or HGD. Of 382 patients who underwent CTC surveillance, 24.9% (95/382) had polyps that grew, while 62.0% (237/382) remained stable and 13.1% (50/382) regressed in size. Of the 58.6% (224/382) CTC surveillance patients who ultimately underwent colonoscopic resection, 87.1% (195/224) harboured adenomas, 12.9% (29/224) with advanced histology. Of CTC surveillance patients with growing polyps who underwent resection, 23.2% (19/82) harboured advanced histology vs 7.0% (10/142) with stable or regressing polyps (OR: 4.0; p<0.001), with even greater risk of advanced histology in those with rapid growth (63.6%, 14/22, OR: 25.4; p<0.001). Polyp growth, but not patient age/sex or polyp morphology/location were significant predictors of advanced histology. CONCLUSION: Small 6-9 mm polyps present overall low risk to patients, with polyp growth strongly associated with higher risk lesions. Most patients (75%) with small 6-9 mm polyps will see polyp stability or regression, with advanced histology seen in only 7%. The minority of patients (25%) with small polyps that do grow have a 3-fold increased risk of advanced histology.

[Correlation between Helicobacter pylori enrichment and clinical and pathological characteristics of colorectal adenoma].

Objective: Aim to observe the enrichment of Helicobacter pylori (Hp) in adenoma tissue of patients with colorectal adenoma and analyze its effect on the clinical and pathological characteristics of colorectal adenoma. Methods: The data of 1 622 cases of gastroenteroscopy in the Endoscopy Center of Wenzhou Integrated Traditional Chinese and Western Medicine Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine from January 2019 to June 2021 were collected retrospectively. The general data, gastric HP infection, clinical and pathological features, HP methyl blue special staining, HP immunohistochemical staining and toll-like receptor5(TLR5) protein immunofluorescence of colorectal adenomas were compared between the colorectal adenoma group (743 cases) and the control group (879 cases). Results: There were 743 cases in the colorectal adenoma group, aged (54.5±12.3) years, and 56.0% were male. There were 879 cases in the control group, aged (55.6±12.1), and 58.4% were male. Gastric Hp was positive in 361 cases in the colorectal adenoma group with a positive rate of 48.6% and in 331 cases in the control group with a positive rate of 37.7%. The difference was statistically significant (P<0.001). Gastric HP infection significantly increased the risk of Hp enrichment in colorectal adenomas (OR=28.590;95%CI:18.554-44.055; P<0.001). At the same time, Hp enrichment in colorectal adenomas was the promoting factor of positive events in adenoma diameter, pathological adenoma type, and adenoma malignancy (RR=0.804,3.163,3.089,2.463, P<0.001). It was also found that the expression of TLR5 protein was increased in HP-enriched adenomas. Conclusion: There is a positive correlation between gastric HP infection and intestinal HP enrichment. The effect of intestinal HP enrichment on the clinical and pathological characteristics of colorectal adenoma is statistically significant, and its tumor-promoting effect may be related to the upregulation of mucosal TLR5 protein.

[Shenbai Jiedu Fang inhibits AOM/DSS-induced colorectal adenoma formation and carcinogenesis in mice via miRNA-22-mediated regulation of the PTEN/PI3K/AKT signaling pathway].

OBJECTIVE: To observe the inhibitory effect of Shenbai Jiedu Fang (SBJDF, a compound recipe of traditional Chinese herbal drugs) on chemically induced carcinogenesis of colorectal adenoma in mice and explore the role of PTEN/PI3K/AKT signaling pathway in mediating this effect. METHODS: Four-week-old male C57BL/6 mice were randomly divided into control group (n=10), AOM/DSS model group (n=20), low-dose (14 g/kg) SBJDF group (n=10) and high-dose (42 g/kg) SBJDF group (n= 10). In the latter 3 groups, the mice were treated with azoxymethane (AOM) and dextran sodium sulphate (DSS) to induce carcinogenesis of colorectal adenoma. In the two SBJDF treatment groups, SBJDF was administered daily by gavage during the modeling. The survival rate, body weight, general condition of the mice, and intestinal adenoma formation and carcinogenesis were observed. The expressions of proteins associated with the PTEN/PI3K/AKT signaling pathway in the intestinal tissue were detected using immunohistochemistry. RESULTS: Compared with those in the model group, the mice treated with SBJDF, especially at the high dose, showed a significantly lower incidence of intestinal carcinogenesis and had fewer intestinal tumors with smaller tumor volume. Pathological examination showed the occurrence of adenocarcinoma in the model group, while only low-grade and high-grade neoplasia were found in low-dose SBJDF group; the mice treated with high-dose SBJDF showed mainly normal mucosal tissues in the intestines with only a few lesions of low-grade neoplasia of adenoma. Compared with those in the control group, the mice in the model group had significantly elevated plasma miRNA-222 level (P < 0.05), which was obviously lowered in the two SBJDF groups (P < 0.01). The results of immunohistochemistry revealed that compared with the model group, the two SBJDF groups, especially the high-dose group, had significantly up-regulated expressions of PTEN, P-PTEN and GSK-3ß and down-regulated expressions of p-GSK-3 ß, PI3K, AKT, P-AKT, ß-catenin, c-myc, cyclinD1 and survivin in the intestinal tissues. CONCLUSION: SBJDF can significantly inhibit colorectal adenoma formation and carcino-genesis in mice possibly through regulating miRNA-222 and affecting PTEN/PI3K/AKT signaling pathway.

Parathyroid carcinoma during pregnancy: a novel pathogenic CDC73 mutation - a case report.

BACKGROUND: Parathyroid carcinoma is an uncommon cause of PTH-dependent hypercalcemia. Only a handful of cases have been reported of parathyroid carcinoma during pregnancy. CASE PRESENTATION: Twenty-four - Year - old female presented with proximal myopathy was found to have hypercalcemia. Her serum corrected total calcium was - 15 mg/dl (8.5 - 10.3), serum phosphate - 2.3 mg/dl (2.5 - 4.5), intact PTH - 118 pg/ml (20 - 80), Vitamin D - 15 ng/ml and Urine Ca/Cr ratio - 2.1 (0.1 - 0.2). Her CECT-neck revealed a well-defined mass lesion posterior to the right lobe of the thyroid - 2.6 cm × 2.5 cm × 2.9 cm in size. She was started on vitamin D supplementation, and she underwent right lower focal parathyroidectomy. Her PTH levels normalized following surgery. Her histology revealed an atypical parathyroid adenoma. She was treated with calcium and vitamin D. Her follow up was uneventful. One year following initial surgery the patient became pregnant and at 16 weeks of POA, the patient presented with a rapidly enhancing neck mass for one week duration. Her biochemical investigations were suggestive of a recurrence of primary hyperparathyroidism. Her ultrasound scan of the neck revealed a well-defined discreate hypoechoic nodule, superior to the thyroid isthmus which was confirmed by a non-contrast MRI scan of the neck. She underwent an uncomplicated second trimester parathyroid tumour excision with normalization of post op PTH. Her histology revealed a parathyroid carcinoma with vascular and capsular invasion. Her genetic studies revealed a novel frameshift mutation of the CDC73 gene. She was treated with calcium and vitamin D supplementation and closely followed up with ionized calcium and PTH levels which were normal throughout the pregnancy. She had an uncomplicated caesarean section at a POA of 37 weeks. Currently she is twelve weeks post-partum, in remission of disease. CONCLUSION: This case shows the importance of stringent follow up of atypical parathyroid adenoma patients, the benefit of second trimester surgery in management of hypercalcemia due to parathyroid carcinoma during pregnancy and the importance of identifying the novel CDC73 gene mutation.

Association of Helicobacter pylori enrichment in colorectal adenoma tissue on clinical and pathological features of adenoma.

OBJECTIVE: To investigate the enrichment of Helicobacter pylori (Hp) in adenoma tissue of patients with colorectal adenoma, and analyze the correlation between the enrichment and the clinical and pathological characteristics of colorectal adenoma. METHODS: The data of 1,622 patients undergoing gastrointestinal endoscopy in the Endoscopy Center of Wenzhou Integrated Traditional Chinese and Western Medicine Hospital affiliated to Zhejiang University of Traditional Chinese Medicine from January 2019 to June 2021 were retrospectively collected. The general data, gastric Hp infection, clinical and pathological features of colorectal adenoma, methylene blue staining of adenoma Hp, immunohistochemistry of adenoma Hp and immunofluorescence staining of adenoma TLR5 protein. were compared between the colorectal adenoma group (743 cases) and the control group (879 cases). RESULTS: There were 361 gastric Hp positive cases in the colorectal adenoma group, with a positive rate of 48.59%, and 331 gastric Hp positive cases in the control group, with a positive rate of 37.66%, and the difference was statistically significant (P < 0.001). Gastric Hp infection significantly correlates with the Hp enrichment in colorectal adenomas (OR: 28.449; 95%CI: 18.188-44.500; P < 0.001). Moreover, we found that Hp enrichment in colorectal adenomas was correlated with the diameter, pathological type, and malignancy of adenoma (OR: 3.536; 3.652; 2.833; all P < 0.001). Expression TLR5 protein was also increased in Hp-enriched adenoma tissue. CONCLUSION: There is a correlation between gastric Hp infection and intestinal Hp enrichment. The intestinal Hp enrichment significantly correlates with the clinical and pathological characteristics of colorectal adenomas, and its tumor-promoting effect may be related to the up-regulation of mucosal TLR5 expression.

Omega-3 polyunsaturated fatty acids: moving towards precision use for prevention and treatment of colorectal cancer.

Data from experimental studies have demonstrated that marine omega-3 polyunsaturated fatty acids (O3FAs) have anti-inflammatory and anticancer properties. In the last decade, large-scale randomised controlled trials of pharmacological delivery of O3FAs and prospective cohort studies of dietary O3FA intake have continued to investigate the relationship between O3FA intake and colorectal cancer (CRC) risk and mortality. Clinical data suggest that O3FAs have differential anti-CRC activity depending on several host factors (including pretreatment blood O3FA level, ethnicity and systemic inflammatory response) and tumour characteristics (including location in the colorectum, histological phenotype (eg, conventional adenoma or serrated polyp) and molecular features (eg, microsatellite instability, cyclooxygenase expression)). Recent data also highlight the need for further investigation of the effect of O3FAs on the gut microbiota as a possible anti-CRC mechanism, when used either alone or in combination with other anti-CRC therapies. Overall, these data point towards a precision approach to using O3FAs for optimal prevention and treatment of CRC based on mechanistic understanding of host, tumour and gut microbiota factors that predict anticancer activity of O3FAs.

Endolymphatic sac tumor: single-institution series of seven cases with updated review of literature.

BACKGROUND: Endolymphatic sac tumour (ELST) is a rare low-grade locally aggressive neoplasm arising from the endolymphatic duct or sac. It presents mostly with vestibulo-cochlear symptoms either sporadically or as part of von Hippel-Lindau (VHL) syndrome. Micro-neurosurgical excision remains the cornerstone of therapy with the role of radiotherapy (RT) being controversial. This is a clinico-pathological analysis of consecutive ELST patients presenting to a single-institution in India. METHODS: Neuropathology database of a tertiary-care comprehensive cancer centre was searched electronically to identify consecutive patients with histopathological diagnosis of ELST registered at the institute over last one decade. Data regarding demographic profile, clinical presentation, histopathological features, treatment details and outcomes were retrieved from electronic medical records for this retrospective analysis. RESULTS: Electronic search identified seven unique patients with biopsy-proven ELST registered at the institute between 2009 and 2020. Median age of the study cohort was 39 years (range 24-65 years) with strong male predilection (5:2 ratio) and left-sided preponderance (71%). Most common presenting symptoms were hearing loss (86%) and earache (71%) on affected side followed by headache (43%). All patients underwent maximal safe resection at initial diagnosis and were followed-up closely with periodic surveillance imaging. Two patients underwent salvage RT using high-precision conformal techniques at recurrence/progression. CONCLUSION: ELST is a rare low-grade locally aggressive neoplasm that arises generally as part of VHL syndrome or sometimes sporadically. Gross total resection provides the best chance of cure with RT being reserved for unresectable disease, large residue, medical inoperability, or as salvage therapy for recurrent/progressive tumor.

ATP1A1 Mutant in Aldosterone-Producing Adenoma Leads to Cell Proliferation.

The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with ATP1A1 mutation. ATP1A1 L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in ATP1A1 mutated APA were more abundant than those in non-functioning adrenocortical adenoma or KCNJ5 mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in ATP1A1 mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an ATP1A1 mutant APA.

Autoimmune gastritis concomitant with gastric adenoma and subacute combined degeneration of the spinal cord.

A 62-year-old woman was referred to our department for further investigation of anaemia. Blood test showed macrocytic anaemia. Oesophagogastroduodenoscopy (OGD) revealed proximal-predominant gastric atrophy and flat elevated lesion in the gastric body. Several days after OGD, she complained of gait disturbance and was diagnosed with subacute combined degeneration of the spinal cord. Furthermore, laboratory tests showed positive for both anti-parietal cell and anti-intrinsic factor antibodies, as well as increased serum gastrin level and decreased pepsinogen I level, which confirmed the diagnosis of autoimmune gastritis (AIG). Anaemia and neurological symptoms were improved after vitamin B12 supplementation. Subsequently, the patient underwent gastric endoscopic submucosal dissection; histopathological examination revealed gastric adenoma. AIG can cause gastric neoplasms and vitamin B12 deficiency, with the latter resulting in pernicious anaemia and neurological disorders. These diseases are treatable but potentially life-threatening. This case highlights the importance of early diagnosis of AIG and proper management of its comorbidities.

Gastroenterology visitation and reminders predict surveillance uptake for patients with adenomas with high-risk features.

Individuals diagnosed with colorectal adenomas with high-risk features during screening colonoscopy have increased risk for the development of subsequent adenomas and colorectal cancer. While US guidelines recommend surveillance colonoscopy at 3 years in this high-risk population, surveillance uptake is suboptimal. To inform future interventions to improve surveillance uptake, we sought to assess surveillance rates and identify facilitators of uptake in a large integrated health system. We utilized a cohort of patients with a diagnosis of ≥ 1 tubular adenoma (TA) with high-risk features (TA ≥ 1 cm, TA with villous features, TA with high-grade dysplasia, or ≥ 3 TA of any size) on colonoscopy between 2013 and 2016. Surveillance colonoscopy completion within 3.5 years of diagnosis of an adenoma with high-risk features was our primary outcome. We evaluated surveillance uptake over time and utilized logistic regression to detect factors associated with completion of surveillance colonoscopy. The final cohort was comprised of 405 patients. 172 (42.5%) patients successfully completed surveillance colonoscopy by 3.5 years. Use of a patient reminder (telephone, electronic message, or letter) for due surveillance (adjusted odds = 1.9; 95%CI = 1.2-2.8) and having ≥ 1 gastroenterology (GI) visit after diagnosis of an adenoma with high-risk features (adjusted odds = 2.6; 95%CI = 1.6-4.2) significantly predicted surveillance colonoscopy completion at 3.5 years. For patients diagnosed with adenomas with high-risk features, surveillance colonoscopy uptake is suboptimal and frequently occurs after the 3-year surveillance recommendation. Patient reminders and visitation with GI after index colonoscopy are associated with timely surveillance completion. Our findings highlight potential health system interventions to increase timely surveillance uptake for patients diagnosed with adenomas with high-risk features.

Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Patients with Colorectal Adenoma in a Clinical Trial.

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.

Effects of Supplemental Calcium and Vitamin D on Circulating Biomarkers of Gut Barrier Function in Patients with Colon Adenoma: A Randomized Clinical Trial.

Gut barrier dysfunction promotes chronic inflammation, contributing to several gastrointestinal diseases, including colorectal cancer. Preliminary evidence suggests that vitamin D and calcium could prevent colorectal carcinogenesis, in part, by influencing gut barrier function. However, relevant human data are scarce. We tested the effects of supplemental calcium (1,200 mg/day) and/or vitamin D3 (1,000 IU/day) on circulating concentrations of biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide IgA and IgG, measured via ELISA) from baseline to 1 and 3 or 5 years postbaseline among 175 patients with colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. We also assessed factors associated with baseline concentrations of these biomarkers. We found no appreciable effects of supplemental vitamin D3 and/or calcium on individual or aggregate biomarkers of gut permeability. At baseline, a combined permeability score (the summed concentrations of all four biomarkers) was 14% lower among women (P = 0.01) and 10% higher among those who consumed >1 serving per day of red or processed meats relative to those who consumed none (P trend = 0.03). The permeability score was estimated to be 49% higher among participants with a body mass index (BMI) > 35 kg/m2 relative to those with a BMI < 22.5 kg/m2 (P trend = 0.17). Our results suggest that daily supplemental vitamin D3 and/or calcium may not modify circulating concentrations of gut permeability biomarkers within 1 or 3-5 years, but support continued investigation of modifiable factors, such as diet and excess adiposity, that could affect gut permeability. PREVENTION RELEVANCE: Calcium and vitamin D may be involved in regulating and maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which results in exposure of the host to luminal bacteria, endotoxins, and antigens leading to potentially cancer-promoting endotoxemia and chronic colon inflammation. While our results suggest that daily supplementation with these chemopreventive agents does not modify circulating concentrations of gut permeability biomarkers, they support continued investigation of other potential modifiable factors, such as diet and excess adiposity, that could alter gut barrier function, to inform the development of treatable biomarkers of risk for colorectal neoplasms and effective colon cancer preventive strategies.

Correlation of perioperative biochemical variables with single adenoma weight in patients with primary hyperparathyroidism.

BACKGROUND: Single parathyroid adenoma is the main cause of primary hyperparathyroidism (PHPT), with surgery remaining the gold standard for its treatment. The ability to preoperatively predict the parathyroid adenoma size and could facilitate the decision about the extent of surgical exploration. It is reasonable to hypothesize that the perioperative levels of PHPT-related variables (i.e. calcium, parathormone, phosphate) may predict the adenoma weight or/and demonstrate whether the adenoma is successfully removed or not. Aim of this study is to explore the relationship between perioperative biochemical values and adenoma weight. Secondarily, we investigated the relationship between adenoma weight and uni-/bilateral neck exploration. METHODS: Retrospective study of all patients undergone surgery for primary hyperparathyroidism due to single adenoma in a tertiary university hospital in Germany during a 6-year period. Following variables were analyzed: preoperative serum calcium, phosphorus and parathormone, intraoperative parathormone before and after adenoma excision, intraoperative PTH decrease, postoperative serum calcium and parathormone (PTHpostop-pg/ml), calcium and PTH decrease. Bivariate correlations were calculated by the Spearman's correlation test at the 95% significance level. RESULTS: A total of 339 patients were included in the study. The median age of the patients was 60 years (range 21-90) and 77% were females. The median adenoma weight was 1 g (range 0.1-11). Adenoma weight correlated strong with maximum adenoma diameter (r = 0.72, p < 0.05), moderate with preoperative parathormone (r = 0.44) and parathormone decrease (r = 0.27), whereas there was no correlation with the intraoperative PTH decrease (r = 0.02). There was also a borderline (moderate to weak) correlation with pre- and postoperative calcium levels (r = 0.21 and r = 0.23 respectively) and a negative borderline correlation with phosphorus (r = - 0.21). Patients who required bilateral neck exploration, had significantly lighter adenomas (median weight 0.8 g vs 1.1 g, p = 0.005). CONCLUSIONS: We conclude that preoperative PTH levels may only serve as an approximate guide to adenoma weight, as direct preoperative prediction is not possible. Serum calcium levels, PTH and calcium decrease correlate only weak with adenoma weight. Patients who require bilateral neck exploration, have significantly (20-25%) lighter adenomas.

Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents.

Sesamin (SSM) and sesamolin (SesA) are the two major furofuran lignans of sesame oil and they have been previously noticed to exert various biological actions. However, their modulatory actions on different types of ionic currents in electrically excitable cells remain largely unresolved. The present experiments were undertaken to explore the possible perturbations of SSM and SesA on different types of ionic currents, e.g., voltage-gated Na+ currents (INa), erg-mediated K+ currents (IK(erg)), M-type K+ currents (IK(M)), delayed-rectifier K+ currents (IK(DR)) and hyperpolarization-activated cation currents (Ih) identified from pituitary tumor (GH3) cells. The exposure to SSM or SesA depressed the transient and late components of INa with different potencies. The IC50 value of SSM needed to lessen the peak or sustained INa was calculated to be 7.2 or 0.6 µM, while that of SesA was 9.8 or 2.5 µM, respectively. The dissociation constant of SSM-perturbed inhibition on INa, based on the first-order reaction scheme, was measured to be 0.93 µM, a value very similar to the IC50 for its depressant action on sustained INa. The addition of SSM was also effective at suppressing the amplitude of resurgent INa. The addition of SSM could concentration-dependently inhibit the IK(M) amplitude with an IC50 value of 4.8 µM. SSM at a concentration of 30 µM could suppress the amplitude of IK(erg), while at 10 µM, it mildly decreased the IK(DR) amplitude. However, the addition of neither SSM (10 µM) nor SesA (10 µM) altered the amplitude or kinetics of Ih in response to long-lasting hyperpolarization. Additionally, in this study, a modified Markovian model designed for SCN8A-encoded (or NaV1.6) channels was implemented to evaluate the plausible modifications of SSM on the gating kinetics of NaV channels. The model demonstrated herein was well suited to predict that the SSM-mediated decrease in peak INa, followed by increased current inactivation, which could largely account for its favorable decrease in the probability of the open-blocked over open state of NaV channels. Collectively, our study provides evidence that highlights the notion that SSM or SesA could block multiple ion currents, such as INa and IK(M), and suggests that these actions are potentially important and may participate in the functional activities of various electrically excitable cells in vivo.

Seizure and coma secondary to Conn's syndrome: a case report.

BACKGROUND: Conn's syndrome is a curable condition if identified properly. It is characterized by autonomous secretion of aldosterone from the adrenal gland cortex. Its morbidity is related to the increased risk of cardiovascular diseases. CASE PRESENTATION: We report the case of a 48-year-old man of African descent presenting with generalized tonic-clonic seizure and coma secondary to hypertensive encephalopathy. A biochemical evaluation revealed a very high aldosterone level and an undetectable renin level, both are compatible with primary aldosteronism. The presentation of the following confirms the diagnosis of primary aldosteronism: spontaneous hypokalemia, an undetectable renin level, and a high aldosterone level. Abdominal computed tomography revealed a left adrenal adenoma. Adrenal venous sampling confirmed lateralization of aldosterone excretion from the left adrenal gland. Our patient underwent left laparoscopic adrenalectomy that confirmed a left functional adrenal adenoma. After 12 months of follow up, his hypertension was controlled on only one antihypertensive drug which was down from four drugs preoperatively. CONCLUSION: Conn's syndrome, in this case, was complicated by coma secondary to seizure. Adrenalectomy normalized the hypokalemia and improved resistant hypertension. Potassium supplementation and several antihypertensives were discontinued as our patient became normokalemic and normotensive on one antihypertensive agent.

Adrenal Adenomas versus Metastases: Diagnostic Performance of Dual-Energy Spectral CT Virtual Noncontrast Imaging and Iodine Maps.

Background Dual-energy CT allows virtual noncontrast (VNC) attenuation and iodine density measurements from contrast material-enhanced examination, potentially enabling adrenal lesion characterization. However, data regarding diagnostic performance remain limited, and combined diagnostic values have never been investigated. Purpose To determine whether VNC attenuation, iodine density, and combination of the two allow reliable differentiation between adrenal adenomas and metastases. Materials and Methods This retrospective study included patients with adrenal lesions who underwent unenhanced and portal venous phase dual-energy CT between January 2017 and December 2018. Unenhanced, contrast-enhanced, and VNC attenuation, as well as iodine density, were measured for each lesion. Agreement between unenhanced and VNC attenuation was assessed by using Wilcoxon rank-sum test, Pearson correlation coefficient, and Bland-Altman plot. The ratio of iodine density to VNC attenuation was calculated for lesions with positive VNC attenuation. Each parameter was compared between adenomas and metastases; diagnostic performance was evaluated by using the area under the receiver operating characteristic curve (AUC) with sensitivity and specificity. Results A total of 149 patients (mean age, 65 years ± 13 [standard deviation]; 89 men; 98 patients with 104 adenomas; 51 patients with 56 metastases) were evaluated. VNC attenuation showed strong positive correlation with unenhanced attenuation (r = 0.92) but resulted in overestimates of adenoma attenuation (mean bias, +11 HU; P < .001) and was less sensitive (P = .03) in the diagnosis of adenomas compared with unenhanced attenuation (sensitivity of 79% [81 of 102] [95% confidence interval {CI}: 70%, 87%] and specificity of 95% [53 of 56] [95% CI: 85%, 99%] versus sensitivity of 85% [87 of 102] [95% CI: 77%, 92%] and specificity of 96% [54 of 56] [95% CI: 88%, 100%], with thresholds of ≤29 HU and ≤22 HU, respectively). Contrast-enhanced attenuation had no discriminatory ability (AUC, 0.54; 95% CI: 0.45, 0.62). Iodine density yielded moderate performance (sensitivity of 78% [80 of 102] [95% CI: 69%, 86%] and specificity of 71% [40 of 56] [95% CI: 58%, 83%], with a threshold of ≥1.82 mg/mL). The iodine-to-VNC ratio was higher in adenomas than in metastases (mean, 14.5 vs 4.6; P < .001), with sensitivity of 95% (97 of 102; 95% CI: 89%, 98%) and specificity of 95% (53 of 56; 95% CI: 85%, 99%), with a threshold of 6.7 or greater. Conclusion Contrast-enhanced dual-energy CT during the portal venous phase enabled accurate differentiation between adrenal adenomas and metastases by combining virtual noncontrast attenuation and iodine density. Virtual noncontrast imaging alone led to overestimates of adenoma attenuation, and iodine density alone had limited discriminatory utility. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Hindman and Megibow in this issue.

Dysplastic Aberrant Crypt Foci: Biomarkers of Early Colorectal Neoplasia and Response to Preventive Intervention.

The discovery of aberrant crypt foci (ACF) more than three decades ago not only enhanced our understanding of how colorectal tumors form, but provided new opportunities to detect lesions prior to adenoma development and intervene in the colorectal carcinogenesis process even earlier. Because not all ACF progress to neoplasia, it is important to stratify these lesions based on the presence of dysplasia and establish early detection methods and interventions that specifically target dysplastic ACF (microadenomas). Significant progress has been made in characterizing the morphology and genetics of dysplastic ACF in both preclinical models and humans. Image-based methods have been established and new techniques that utilize bioactivatable probes and capture histologic abnormalities in vivo are emerging for lesion detection. Successful identification of agents that target dysplastic ACF holds great promise for intervening even earlier in the carcinogenesis process to maximize tumor inhibition. Future preclinical and clinical prevention studies should give significant attention to assessing the utility of dysplastic ACF as the earliest identifiable biomarker of colorectal neoplasia and response to therapy.See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention.