Page 23 – Practical Gastro

A large number of pediatric acute liver failure (ALF) cases occur with no diagnosed etiology, and there is concern that potential genetic mutations affecting outcome may be present in such patients. Techniques such as next generation sequencing (typically defined as fast massively parallel sequencing) can determine a human genome in less than one day, and the authors of this study looked at the capacity of such screening techniques to determine genetic causes of ALF in children. This retrospective study of pediatric patients seen in a tertiary pediatric hospital in London looked at all cases of ALF over an 18year period in which stored blood was available. Included study patients had no evidence of chronic liver disease. Additionally, such patients needed to have laboratory evidence of ALF defined as having an international normalized ration (INR) ≥ 1.5 not corrected by Vitamin K with associated hepatic encephalopathy or having an INR ≥ 2 with or without hepatic encephalopathy. Clinical characteristics were obtained for all patients, and children with ALF were determined to have an indeterminate cause of disease if no known cause of ALF could be found. Additionally, blood samples underwent next generation sequencing to evaluate for 64 mutations causing genetic and metabolic liver disease in children, exome sequencing to evaluate the entire genome of the affected child and unaffected parents, or sequence variant filtration to determine potential disease-causing variants.

Next generation sequencing occurred in 41 patients while 4 patients underwent exome sequencing. Next generation sequencing identified eight children with either heterozygous or homozygous ALF-causing mutations of NBAS, TWINK, CPT1A, MPV17, DLD, POLG, and SUCLG1. Exome sequencing found mutations in all four children including mutations in LARS1, FAH1, NPC1, and DLD. Interestingly, those children with biallelic variants of such mutations presented with ALF at a significantly younger age and were significantly more likely to die from liver failure. Thus, this study shows that using genetic testing to diagnose unknown causes of ALF in children is beneficial in elucidating primary causes of hepatic disease. This aspect is especially important since liver transplantation for mitochondrial DNA mutations is controversial depending on the mutation as other organs besides the liver can be affected. This study shows that sequencing the genome for pediatric ALF is important to determine causality and outcome, and more work is urgently needed to make such testing easily available and affordable.

Hegarty R, Gibson P, Sambrotta M, Strautnieks S, Foskett P, Ellard S, Baptista J, Lillis S, Bansal S, Vara R, Dhawan A, Grammatikopoulos T, Thompson R. Study of acute liver failure in children using next generation sequencing technology. Journal of Pediatrics 2021; 236: 124-130.

^{John Pohl, M.D., Book Editor,} ^{is on the Editorial Board of Practical Gastroenterology}

Vancomycin to Prevent Clostrioides difficile Infection in Children

Oral vancomycin is used as a treatment for Clostrioides difficile infection (CDI), and adult studies suggest that vancomycin can be used as a preventative therapy to stop recurrence of CDI in patients receiving antibiotics for other reasons. However, no relevant data exists in children, and the authors of this study looked at the effectiveness of this intervention in children at a single academic health system.

This retrospective study occurred over 6 years and included all children with CDI diagnosed by polymerase chain reaction. Patients were identified who had a prior CDI, had a subsequent outpatient or inpatient encounter, and then required intravenous antibiotic usage during the encounter. This group was then divided into patients who did or did not receive oral vancomycin prophylaxis. Patient demographics were obtained on all patients including the identification of NAP1 (North American pulsed-field gel electrophoresis type 1) strains, use of acid suppression medication, and use of probiotics. Oral vancomycin prophylaxis was defined as dosing of 10 mg / kg every 12 hours during antibiotic administration and for 5 days afterwards.

A total of 148 patients were initially identified; however, the final study patient number after utilizing exclusion criteria consisted of 74 patients (30 receiving oral vancomycin prophylaxis; 44 not receiving oral vancomycin prophylaxis). Patients were statistically similar regarding demographics and comorbidities although more males received oral vancomycin prophylaxis (not significant). Most patients had a history of malignancy or immune suppression. There was no difference between groups in regard to acid suppression use or probiotic use. Hospital length of stay was longer in patients who received oral vancomycin prophylaxis. Most patients had only one prior CDI, and most patients had received antibiotics within 3 months of CDI. Oral vancomycin prophylaxis was more common in patients who had received fluoroquinolones and carbapenems. Oral vancomycin prophylaxis also was significantly more common in patients receiving 2 or more classes of antibiotics and receiving a longer duration of antibiotics. Patients who did not receive oral vancomycin prophylaxis were statistically more likely to have CDI recurrence. No vancomycinresistant enterococci infection occurred in any patient within 8 weeks of vancomycin exposure. Univariate and multivariate analysis demonstrated that receiving oral vancomycin prophylaxis was the only significant factor associated with a reduced risk of CDI.

Oral vancomycin prophylaxis shows the potential of reducing CDI in at-risk pediatric patients with prior CDI. This is a retrospective study, and prospective data is needed to determine optimal timing and duration of oral vancomycin use. Additionally, the risk of vancomycin resistant enterococci infection still remains a concern in such patients.

^{Bao H, Lighter J, Dubrovskaya Y, Merchan C, Siegfried J, Papadopoulos J, ShinPung J. Oral vancomycin as secondary prophylaxis for Clostrioides difficile infection. Pediatrics 2021; 148: e2020031807.}

FROM THE LITERATURE

High SVR in Treatment of HCV with Suboptimal Dosing Adherence

The impact of efficacy for treatment with directacting antiviral drugs in the treatment of HCV infection with suboptimal adherence, particularly with shorter treatment durations was evaluated further. Evaluation with post-hoc analyses evaluated adherence (based on pill count), in patients prescribed 8- or 12- week Glecaprevir/ Pibrentasvir (G/P), the impact of nonadherence on the SVR at post-treatment week 12 (SVR12), and the factors associated with nonadherence and efficacy in patients interrupting G/P treatment.

Data was pooled from 10 phase 3 clinical trials of treatment-naïve patients with HCV genotype 1-6, without cirrhosis, with compensated cirrhosis (treatment adherence analysis), and 13 phase 3 clinical trials of all patients with HCV (interruption analysis).

A total of 2,149 patients were included. Overall meet adherence was 99.4%. Over the treatment duration, adherence decreased (week 0-4 – 100%; weeks 5-8 – 98.3%, and weeks 9-12; 97.1%). The percentage of patients with greater than 80% or 90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% and remained high in nonadherent patients in a modified ITT population.

Psychiatric disorders were associated with less than 80% adherence and shorter treatment duration was associated with greater than 80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of greater than 1 day with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. The findings support the impact of treatment duration and adherence rate and further reinforce the concept of “treatment forgiveness” with directacting antivirals.

Zamor, P., Brown, A., Dylla, D., et al. “HighSustained Virologic Response Rates of Glecaprevir/Pibrentasvir in Patients with Dosing Interruption or Suboptimal Adherence.” American Journal of Gastroenterology; Vol. 116, September 2021, pp. 1897-1904.

^{Murray H. Cohen, DO, “From the Literature” Editor, is on the Editorial Board of Practical Gastroenterology.}

FROM THE LITERATURE

USDA Efficacy in PBC with Compensated Cirrhosis

A retrospective cohort study of veterans, predominantly men with PBC and compensated cirrhosis were evaluated to assess the association of response to UDCA with the development of all-cause and liver-related mortality for transplantation, hepatic decompensation, and HCC-using, competing risk time-updating Cox proportional hazards models. A total of 501 subjects with PBC and compensated cirrhosis, including 287 UDCA responders, (1692.8 patient-years {PY} of follow-up) and 214 partial responders (838.9 PY of follow-up). The unadjusted rates of hepatic decompensation (3.8 vs 7.9 per 100 PY), and liverrelated death or transplantation (3.7 vs 6.2 per PY), were lower in UDCA responders compared with partial responders. UDCA response was associated with a lower risk of hepatic decompensation (subhazard ratio {sHR} 0.54), death from any cause or transplantation (aHR 0.49), and liverrelated death or transplantation (sHR 0.40), but not HCC (sHR 0.39). In a sensitivity analysis, the presence of portal hypertension was associated with the highest UDCA-associated effect.

It was concluded that UDCA response is associated with a reduction in decompensation, all-cause, and liver-related death or transplantation in a cohort of predominantly male patients with cirrhosis, with the highest benefit in patients with portal hypertension.

^{John, B., Khakoo, N., Schwartz, K., et al. “Ursodeoxycholic Acid Response is Associated with Reduced Mortality in Primary Biliary Cholangitis with Compensated Cirrhosis.” American Journal of Gastroenterology; Vol. 116, September 2021, pp. 1913-1923.}

FROM THE LITERATURE

Ranitidine and Bladder Cancer

With knowledge that the carcinogen N-nitrosodimethylamine and increased urinary content of that component in humans, utilizing that drug to investigate whether ranitidine use is associated with increased bladder cancer risk, a nested, case-control study was conducted within the Primary Care Clinical Informatics Unit Research database, containing general practice records from Scotland. Bladder cancer cases, diagnosed between 1999 and 2011 were identified and matched with up to 5 controls, based on age, sex, general practice and date of registration.

Ranitidine, other H2 receptor agonists and proton pump inhibitors were identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals were calculated using conditional logistic regression after adjusting for comorbidities and smoking.

A total of 3260 cases were reviewed with 14,037 controls. There was evidence of increased risk of bladder cancer in ranitidine users, compared with nonusers (OR = 1.22), which was more marked with use over 3 years of ranitidine therapy (OR = 1.43). By contrast, there was little evidence of any association between PPI use and bladder cancer risk, based on any use (OR = 0.98), or over 3 years of use (OR = 0.98).

In this large population-based study, the use of ranitidine, particularly long-term, was associated with an increased risk of bladder cancer.

^{Cardwell, C., McDowell, R., Hughes, C., et al. “Exposure to Ranitidine and Risk of Bladder Cancer: A Nested, Case-Control Study.” American Journal of Gastroenterology; Vol. 116, August 2021, pp. 1612}–^1619.

FROM THE LITERATURE

Steatosis and Steatohepatitis Effects on Patients with Chronic Hepatitis B

To investigate the impact of fatty liver disease (FLD) on liver disease severity in a large North American cohort with chronic hepatitis B viral infection, liver biopsies from 420 hepatitis B surface antigen-positive adults that were enrolled in the Hepatitis B Research Network and who were not on HBV therapy in the previous month were evaluated for inflammation and fibrosis. Steatohepatitis was based on steatosis, hepatocyte ballooning, with or without Mallory-Denk bodies and perisinusoidal fibrosis. The models evaluated factors associated with steatohepatitis, and the association of steatohepatitis with fibrosis and longitudinal ALT, AST, and Fibrosis-4.

The median age was 42 years and 62.5% were male, 79.5% were Asian. A total of 132 (31.4%) patients had FLD (77 – 18.3%), steatosis only, 55 – 13.1% had steatohepatitis. Older age, overweight/obesity and diabetes were associated with steatohepatitis. Steatohepatitis versus no FLD was associated with 1.6% times higher risk of advanced fibrosis at baseline and there was indication of higher incident cirrhosis rate during followup. Steatohepatitis versus no FLD was also independently associated with 1.39 times higher ALT, 1.25 times higher Fibrosis-4. It was concluded that coexisting steatosis occurred in nearly one-third of adults of which 13% had steatohepatitis with chronic hepatitis B viral infection in this North American cohort who underwent liver biopsies. Steatohepatitis was associated with advanced fibrosis and higher biochemical measures of hepatic inflammation over time. There is indication for screening for and managing metabolic abnormalities in patients with HBV to prevent disease progression in HBV.

^{Khalili, M., Kleiner, D., King, W., et al. for the Hepatitis B Research Network (HBRN). “Hepatic Steatosis and Steatohepatitis in a Large North American Cohort of Adults with Chronic Hepatitis B.” American Journal of Gastroenterology; Vol. 116, August 2021, pp. 1686-1697.}

FROM THE LITERATURE

Updated Evaluation of Tegaserod for IBS-C

An integrated analysis on patient-reported outcomes relevant to current practice in the use of Tegaserod in IBS-C was carried out using data from four 12-week, randomized, placebo-controlled trials, evaluating that medication at 6 mg b.i.d. in patients with IBS-C. Two groups were analyzed. All were women younger than 65 years, without a history of cardiovascular ischemic events. The primary end point was subjective global assessment of IBS-C symptom relief. Responders rated themselves “considerably,” or “completely relieved” greater than 50% of the time, or at least “somewhat relieved” 100% of the time over the last 4 weeks.

The population included 2,939 (Tegaserod 1,478; placebo 1,461) and 2,752 (Tegaserod 1,386; placebo 1,366) participants, respectively. The pooled odds ratios for clinical response during the last four weeks of the overall and indicated populations, clinical response rate for Tegaserod during the last four weeks were 43.3% and 44.1% vs. 35.9% and 36.5% with placebo. Adverse events were similar between groups. No significant cardiovascular event related to Tegaserod was observed in patients with one or less than one cardiac risk factor.

It was concluded that Tegaserod 6 mg b.i.d. reduced IBS-C symptoms in overall and US Food and Drug Administration indicated populations, including women aged less than 65 years with no history of cardiovascular ischemic events.

^{Shah, E., Lacy, B., Chey, W., et al. “Tegaserod for Irritable Bowel Syndrome with Constipation in Women Younger than 65 Years without Cardiovascular Disease: Pooled Analyses of 4 Controlled Trials.” American Journal of Gastroenterology; Vol. 116, August 2021, pp. 1601-1611.}

FROM THE LITERATURE

Red Meat Consumption and Risk of Non-Alcoholic Fatty Liver Disease

To evaluate the association between meat consumption and risk of NAFLD in the Golestan Cohort Study (GCS), 50,045 participants were enrolled, age 40 to 75 years in Iran. Dietary information was collected using a 116-item, semi-quantitative food frequency questionnaire at baseline (2004 to 2008). A random sample of 1612 cohort members participated in a liver-focused study in 2011. NAFLD was ascertained through ultrasound.

Total red meat consumption and total white meat consumption were categorized into quartiles, based on the CGS population, with the first quartile as the reference group. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI).

The median intake of total red meat was 17 grams per day and total white meat was 53 grams per day. During follow-up, 505 individuals (37.7%) were diagnosed with NAFLD and 124 of them (9.2%), had elevated ALT. High total red meat consumption (OR = 1.59) and organ meat consumption (OR = 1.70) were associated with NAFLD. Total white meat, chicken or fish consumption did not show significant association with NAFLD.

^{Hashimean, M., Merat, S., Poustchi, H., et al. “Red Meat Consumption and Risk of Non-Alcoholic Fatty Liver Disease in a Population With Low Meat Consumption: The Golestan Cohort Study.” American Journal of Gastroenterology; Vol. 116, August 2021; pp. 1657 – 1675}.

FRONTIERS IN ENDOSCOPY, SERIES #76

Contrast Enhanced EUS: Current Technology Status

Kathryn Schmidt,

Douglas G. Adler

Contrast-enhanced endoscopic ultrasound (CE-EUS) is a tool used to enhance the endoscopic ultrasound evaluation of lymph nodes, solid pancreatic lesions, pancreatic cystic neoplasms, pancreatitis, gallbladder lesions, gastrointestinal wall lesions, and small liver lesions. This article discusses general principles of CE-EUS, indications for CE-EUS, and the relative value of CE-EUS compared to conventional EUS.

INTRODUCTION

CE-EUS is a noninvasive diagnostic technique that allows endoscopists to better visualize certain lesions and more accurately distinguish between benign and malignant masses. Some studies have shown that CE-EUS has advantages over conventional EUS and other imaging modalities. The addition of contrast to EUS has not been widely adopted in the USA, but it has been utilized more frequently in recent years, allowing for more widely available data to assess its ability to expand the diagnostic capabilities of EUS. CE-EUS has potential utility in many clinical scenarios; studies have described its use in the evaluation of lymph nodes, solid pancreatic lesions, pancreatic cystic neoplasms, pancreatitis,ns and more accurately gallbladder lesions, gastrointestinal wall lesions, and small liver lesions.

General Principles of Ultrasound and Contrast

CE-EUS is an advanced endoscopic technique that combines high-resolution ultrasound of internal organs with the administration of intravenous contrast agents. Unlike the iodinated contrast used in CT imaging, microbubbles of air or gases make up the contrast medium used in ultrasound. Microbubbles of air allow for enhancement on ultrasound due to the change in resistance at the tissue-fluid-gas interfaces. This contrast is distributed intravascularly, which improves identification and enhancement of blood vessels and microcirculation. (Figure 1.) EUS contrast agents are different from CT or MR contrast agents in that the contrast does not leave the intravascular space. The size and distribution of the microbubbles improve visualization of tumor microcirculation. This is useful to endoscopists as

the unique vascularization behaviors exhibited by inflammatory lesions, necrosis, and malignancy are distinguishable by CE-EUS. The duration of enhancement after a bolus injection of contrast varies among contrast agents, but is typically two to ten minutes.

CE-EUS procedures do not require radiation.

Beyond this, another potential advantage of CEEUS over CT and MRI include improved real-time imaging of fine vascular structures and visualization of microflow patterns within lesions, allowing endoscopists to more accurately distinguish between inflammatory lesions and malignant ones. Critically, CE-EUS can also be performed without obtaining screening bloodwork or concern for poor renal function. This review provides endoscopists with the basic knowledge regarding the clinical applications of and indications for CE-EUS as well as the advantages and disadvantages of CE-EUS.

Applications of CE-EUS

CE-EUS may be utilized as a diagnostic tool in examining lymph nodes, cystic pancreatic lesions, solid pancreatic masses, acute and chronic pancreatitis, sequela of pancreatitis, gallbladder lesions, subepithelial lesions, and small liver lesions. CE-EUS is particularly useful in distinguishing cystic and neoplastic lesions from other pathologies.

Lymph nodes

Accurate and timely diagnosis of the presence of malignant adenopathy is important as it affects subsequent management and patient outcomes. EUS is often used to evaluate mediastinal, abdominal, and pelvic lymph nodes. Based on size, shape, borders, architecture, echogenicity, vascular pattern, and distance of lymph nodes from the neoplasia, clinicians can make some assessment as to whether the lymph node is of malignant or benign etiology. Patients with malignant adenopathy have lymph nodes that are rounder, darker, larger, closer to the primary tumor, and more homogeneous than those of patients without malignant adenopathy. The presence of at least one lymph node of one cm or greater within one cm of the tumor and with a morphology score, calculated based on the sum of roundness, homogeneity, and echogenicity, of 14 or greater had a positive predictive value for malignant adenopathy of 81%.

One study showed that no single morphologic feature of the lymph node independently predicted malignant invasion. If all four features of malignant involvement (size greater than one cm, hypoechoic, distinct margins, and round shape) were present in the same lymph node, the accuracy for predicting malignant invasion was 80%; however, all four features were only present in 25% of malignant lymph nodes, allowing for confident differentiation between malignant and benign etiology in about 25% of cases. Accuracy of diagnosis is improved when EUS is complimented by fine needle aspiration (FNA) or fine needle biopsy (FNB). While EUS is useful in the evaluation of adenopathy, it is difficult to diagnose lymph node metastasis with EUS images alone. Kanamori et al. evaluated benign and malignant mediastinal and abdominal lymph nodes with CE-EUS based on blood flow patterns. In the retrospective portion of the study, EUS revealed lymph nodes (22 benign, 24 malignant) in the mediastinum or abdominal cavity in 46 patients. The sensitivity, specificity, and accuracy rate for detecting malignancy based on the morphologic classification in this particular study were 88.2%, 77.3%, and 82.1%, respectively. In all 24 patients with malignant adenopathy, an enhancement defect was observed on CE-EUS. During the prospective portion of the study, authors evaluated the enhancement effects and diagnostic capabilities of CE-EUS in the same 46 patients; the sensitivity, specificity, and accuracy rate of CE-EUS were 100%, 81.8%, and 92.0%, respectively. Authors concluded that CE-EUS is a useful diagnostic tool in differentiating benign and malignant adenopathy. Other investigations failed to recommend CEEUS as a diagnostic tool for lymphadenopathy. Lisotti et al. conducted a meta-analysis to examine the diagnostic accuracy of CE-EUS in distinguishing between benign and malignant lymphadenopathy and ultimately concluded that CE-EUS had inadequate sensitivity. However, the investigators did find that contrast harmonic-EUS (CH-EUS) may be useful for diagnostic purposes based on sensitivity and specificity. Harmonic ultrasonic imaging is a novel method that produces images based on non-linear (a term to describe the response of a system to the applied echo-signal) acoustic effects of ultrasound interactions with tissues or microbubble contrast agents.

Pancreas

Pancreatitis

The specificity of differentiation between malignant and benign lesions of the pancreas in patients with chronic pancreatitis is variable with a wide range reported (33%-75%), but studies have shown that perfusion characteristics of microvessels as seen on CE-EUS may provide clinicians with a more useful method to differentiate between pancreatic carcinoma and chronic pancreatitis.In one study, investigators compared conventional EUS to CE-EUS in evaluating possible pancreatic carcinoma in 86 patients with pancreatitis. With conventional EUS, study investigators reported a sensitivity and specificity of 73.2% and 83.3%, respectively, for pancreatic carcinoma. With CE-EUS, sensitivity and specificity improved to 91.1% (in 51 of 56 patients with malignant pancreatic lesion) and 93.3% (in 28 of 30 patients with chronic inflammatory pancreatic disease), respectively. While pancreatic carcinoma appears as a hypo-enhanced lesion, mass-forming chronic

pancreatitis (as well as autoimmune pancreatitis) present as hyper-enhanced pseudotumors. The investigators concluded that CE-EUS does improve differentiation between pancreatic carcinoma and chronic pancreatitis in comparison to conventional EUS.

CE-EUS has been shown to be an effective imaging method to differentiate between pancreatic carcinoma and autoimmune pancreatitis, which is recognized to be a difficult distinction to make. In a study by Hocke et al., with the exception of one patient (who showed a normal vascularization pattern), all lesions caused by autoimmune pancreatitis showed hypervascularization while lesions caused by pancreatic cancer showed hypovascularization. (Figure 2.) While only case studies exist, CE-EUS may also allow clinicians to depict and interpret vascular complications associated with pancreatitis more accurately. CH-

EUS may even be beneficial in evaluating the therapeutic response to steroids in the treatment of immunoglobulin G4-negative focal autoimmune pancreatitis.

Pancreatic solid tumors

CE-EUS has been shown to be a useful diagnostic method in identifying pancreatic masses. Specifically, CE-EUS has been shown to be effective in differentiating small solid pancreatic tumors. Dietrich et al. prospectively evaluated the role of contrast-enhanced endoscopic Doppler ultrasound (CE-EDUS) in the characterization the pancreatic lesions during the arterial phase with the vascularity of the residual pancreatic parenchyma in 93 patients with undetermined, solitary, predominantly solid, lesions <40 mm, and a definite histologically proven diagnosis. In 57 of 62 patients with adenocarcinoma, hypovascularity of the tumor was noted using CE-EDUS while all other pancreatic lesions (20 neuroendocrine tumors, ten serous microcystic adenomas, and one teratoma) revealed an isovascular or hypervascular pattern. Investigators concluded that the hypovascularity of pancreatic tumors using CEEUS indicates malignancy with 92% sensitivity and 100% specificity.

Cystic lesions of the pancreas

Some cystic pancreatic lesions carry an elevated risk of malignancy, including intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). Differentiating mural nodules from mucous clots or even simple intracystic debris in IPMNs is useful as mural nodules within a cyst and main duct involvement suggest an increased potential for underlying malignancy; however, this can be difficult to assess with conventional EUS which has high sensitivity, but poor specificity. Yamashita et al. and Harima et al. have shown that specificity is greater with the addition of contrast. CE-EUS with utilization of Doppler and or harmonic modes can raise the specificity even more. CE-EUS shows no vascularity in mural clots, but does show vascularity in mural nodules.17,18 CE-EUS is useful in evaluating the malignant potential of IPMNs. Most pancreatic cancers appear as solid lesions with hypoenhancement on CEEUS. While CE-EUS has similar sensitivity to that of conventional EUS in identifying mural nodules, the specificity of CE-EUS for the evaluation of these mural nodules is nearly double that seen with conventional EUS, likely due to the improved analysis of vascularity patterns. Kamata et al. reported that endoscopists identified mural nodules more accurately through CE-EUS as compared to conventional EUS, providing sensitivity and specificity values of 97% and 75%, respectively, for CE-EUS and 97% and 40%, respectively, for conventional EUS.24

Biliary tract

Studies have demonstrated that CE-EUS is useful in differentiating infiltrating and exophytic carcinoma of the gallbladder from benign gallbladder pathologies including chronic cholecystitis and cholesterol polyps, the latter two of which show an intact three-layer structure on imaging. Adenosquamous carcinoma, cholesterol polyps and chronic cholecystitis do not enhance with and differentiation of solid pancreatic tumors. Investigators compared the vascular pattern of

EUS upon administration of EUS contrast agents, while most adenocarcinomas of the gallbladder do.²⁶ CE-EUS can also distinguish neoplasia of the gallbladder from sludge (which does not enhance). Typically, carcinomas of the gallbladder show hyperenhancement during the arterial phase and hypoenhancement during the venous phase. CE-EUS allows for visualization of the depth of invasion in the gallbladder wall which can differentiate T1b from T1a lesions. CE-EUS may also be useful in assessing complications of acute cholecystitis; perforation may be suspected if there is no enhancement of the gallbladder wall.²⁵

Differentiating between cholesterol polyps and adenomas is of particular importance; while cholesterol polyps are benign and do not require resection, adenomas may transform into malignant lesions. In one study, the sensitivity and specificity of CH-EUS in making this distinction was low: 75% and 67%, respectively. However, to increase the diagnostic accuracy of CH-EUS in this scenario, the study investigators applied a quantitative perfusion analysis and only assessed the malignant potential of gallbladder polyps larger than ten mm given that gallbladder polyps less than ten mm are typically managed through observation. When accounting for perfusion defects and considering the presence of irregular vessels as predictors of malignancy, the sensitivity and specificity of CHEUS in diagnosing malignant polyps were 94% and 93%, respectively. The sensitivity, specificity, and accuracy of CE-EUS in the diagnosis of carcinoma of the gallbladder has been reported as high as 90%, 98%, and 96%, respectively. In a study using CEEUS to diagnose carcinoma of the gallbladder, investigators assessed gallbladder wall thickening, noting a sensitivity, specificity, and accuracy of 90%, 98%, and 94%, respectively. In another study using CE-EUS to diagnose carcinoma of the gallbladder, investigators used irregular intratumoral vessels and heterogeneous perfusion defects as outcome parameters, and demonstrated high sensitivity and specificity, 93% and 91%, respectively.

Subepithelial Lesions (SEL)

Endoscopists can visualize the microvasculature of SELs in greater detail through CE-EUS.

Gastrointestinal stromal tumors (GIST) often demonstrate arterial hyperenhancement and central necrosis, which is typically not displayed in other subepithelial lesions, so CE-EUS may be helpful in distinguishing GISTs from benign SEL. The sensitivity and specificity for the hyperenhancement of GISTs ranges from 85% to 100% and from 79% to 100%, respectively. In predicting likelihood of high-grade GISTs specifically, investigators have assessed for the presence of irregular intratumoral vessels, citing a much broader range for sensitivity and specificity – from 54% to 100% and from 63% to 100%, respectively.

Liver

When evaluating patients with liver disease, CEEUS may help to diagnose small liver lesions and be useful for targeting tissue sampling, but in general, the utility of CE-EUS in these scenarios is limited as EUS is unable to visualize the entire liver, with portions of the right lobe being very hard to clearly identify. Despite this limitation, CE-EUS still offers advantages in examination of the liver during the late

phase of contrast-enhancement; this makes it particularly useful during biopsies requiring direct guidance of the needle when lesions are poorly visualized with conventional gray-scale ultrasound. Despite the need for more research, it is thought that adding contrast to EUS, allowing for improved visualization of the microvasculature and tumor architecture, does help endoscopists to better differentiate between malignant and benign lesions in the liver.

Oh et al. conducted a study comparing the use of CE-EUS and traditional EUS in the diagnosis of hepatic masses in 30 patients. The authors found that 73.3% of hepatic masses were visible by traditional EUS. With CE-EUS, 93.3% of hepatic masses were visible and able to be distinguished from the surrounding liver parenchyma. Authors concluded that the addition of contrast improved diagnostic accuracy. In another study, Minaga et al. demonstrated that there is an additive role of CEEUS (to traditional EUS or multidetector CT scan) in the identification of metastasis of pancreatic adenocarcinoma to the liver. They found that CEEUS was associated with a significantly higher detection rate of left-lobe metastasis; the diagnostic

accuracy of CE-EUS was 98.5% compared to 91.1% for traditional EUS and 90.5% for CT scans. Additionally, tissue obtained via CE-EUS resulted in improved diagnostic accuracy, including for lesions less than one cm in diameter.

Overall Value Assessment and Conclusion

It is important to note that CE-EUS is to some extent dependent on the operator’s skill and experience. Ultimately, CE-EUS is a tool that facilitates decision making and offers additional and complementary information beyond what conventional EUS can provide – with minimal risk to the patient. The addition of contrast has the potential to help clinicians delineate benign from malignant pathology, guide therapeutic procedures, and better characterize vasculature.

Ultrasound contrast agents have an excellent safety profile, and the incidence of patients having a major adverse event in response to contrast is similar to that of MR contrast agents and lower than that of CT contrast agents. Additionally, CE-EUS can be performed on patients who have not had labs prior to the procedure since ultrasound contrast agents are not cardio-, hepato-, or nephro-toxic.

Future studies comparing the diagnostic capabilities and financial burden of traditional EUS and CE-EUS in specific clinical scenarios will help to better determine the role of this modality in clinical practice. From a time consideration, the procedure is only minimally extended with the addition of EUS contrast agents, although depending on the operator’s experience, the time (and accuracy) of his or her interpretation of the imaging study will vary. The value of contrast agents in enhancing diagnostic accuracy in EUS in certain clinical scenarios is well-established. We conclude that CEEUS is a low-risk, complementary imaging study in many clinical scenarios as described previously. While CE-EUS is not critical to performing EUS, given its safety profile and potential benefit, it should be considered if available.

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FROM THE LITERATURE

Colorectal Cancer in 18- to 49-Year-Olds

To evaluate CRC detection rates in a large, integrated healthcare system to assess treatment outcomes in younger CRC patients and to determine factors that could aid in identifying these individuals, confirmed cases of CRC were analyzed using a cancer database spanning from 1985 to 2017, from a large, integrated healthcare system composed of 15 hospitals, 150 outpatient clinics and 20 outpatient oncology clinics. Three cohorts were evaluated (18-44 years, 45-49 years and greater than 50 years).

Significant increases in CRC detection were seen in the cohort aged 18-44 (annual change 2.7%), and the cohort age 45-49 (annual percentage change 4.15%). The higher proportion of AfricanAmericans, Hispanic and obese subjects were seen in the younger cohorts. A family history of CRC was found in 49% of the patients aged 18-44 and 38% of patients aged 45-50. Patients younger than age 50 were more likely to have metastases at diagnosis (6.8%) vs. the cohort over 50 (4.15%).

Survival was better in younger cohorts and they were more likely to receive multimodality treatment (surgery with chemotherapy or radiation). Survival probability was similar in different ethnic groups.

It was concluded that CRC is increasing at similar rates in young people aged 18-44 and 4549, and that they are more likely to present with advanced disease needing multimodality treatment. A family history identifies some patients less than 50 years of age. Young patients presented with changes in bowel habit, rectal bleeding, anemia, and weight loss should include colonoscopy in evaluation. Rectal and anal symptoms should prompt careful physical and endoscopic evaluation.

^{Vakil, N., Ciezki, K., Singh, M. “Colorectal Cancer in 18- to 49-year-olds: Rising Rates, Presentation, and Outcome in a Large Integrated Health System.” Gastrointestinal Endoscopy; Vol. 94, No. 3, 2021; pp. 618-626.}