The Challenges of Implementing Artificial Intelligence into Surgical Practice.

BACKGROUND: Artificial intelligence is touted as the future of medicine. Classical algorithms for the detection of common bile duct stones (CBD) have had poor clinical uptake due to low accuracy. This study explores the challenges of developing and implementing a machine-learning model for the prediction of CBD stones in patients presenting with acute biliary disease (ABD). METHODS: All patients presenting acutely to Christchurch Hospital over a two-year period with ABD were retrospectively identified. Clinical data points including lab test results, demographics and ethnicity were recorded. Several statistical techniques were utilised to develop a machine-learning model. Issues with data collection, quality, interpretation and barriers to implementation were identified and highlighted. RESULTS: Issues with patient identification, coding accuracy, and implementation were encountered. In total, 1315 patients met inclusion criteria. Incorrect international classification of disease 10 (ICD-10) coding was noted in 36% (137/382) of patients recorded as having CBD stones. Patients with CBD stones were significantly older and had higher aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and gamma-glutamyl transferase (GGT) levels (p < 0.001). The no information rate was 81% (1070/1315 patients). The optimum model developed was the gradient boosted model with a PPV of 67%, NPV of 87%, sensitivity of 37% and a specificity of 96% for common bile duct stones. CONCLUSION: This paper highlights the utility of machine learning in predicting CBD stones. Accuracy is limited by current data and issues do exist around both the ethics and practicality of implementation. Regardless, machine learning represents a promising new paradigm for surgical practice.

Rapid and simultaneous analysis of direct and indirect bilirubin indicators in serum through reagent-free visible-near-infrared spectroscopy combined with chemometrics.

Indirect (IBil), direct (DBil) and total (TBil) bilirubin are important clinical indicators of hepatobiliary diseases, which require rapid detection in diagnosis and treatment. IBil and DBil have a structural relationship with several macromolecules in hepatobiliary metabolism. Here, the rapid analysis models for bilirubin indicators using serum visible-near-infrared (Vis-NIR) spectroscopy were established. Norris derivative filter with optimisation was used for spectral pretreatment; the optimal parameters (derivative order, number of smoothing points, number of differential gaps) were (2, 15, 9) for IBil; (2, 13, 9) for DBil, respectively. Equidistant combination-partial least squares (EC-PLS) was used for large-scale wavelength screening. Wavelength step-by-step phase-out PLS (WSP-PLS) was used for secondary wavelength optimisation. The wavelength models of the optimal EC-WSP-PLS for IBil and DBil included 11 and 18 wavelengths, respectively. In independent validation, the root-mean-square errors and correlation coefficient for prediction (SEP, RP), and ratio of performance-to-deviation (RPD) were 0.90 µmol L-1, 0.975, and 4.4 for IBil; 0.71 µmol L-1, 0.955, and 3.3 for DBil, respectively. TBil was subjected to spectral analysis, and the summation of the prediction values of IBil and DBil was compared. The latter was obviously better, and SEP, RP, RPD were 0.82 µmol L-1, 0.990, 7.1, respectively. The results for IBil, DBil and TBil indicated high correlation, low error and good overall prediction ability and confirmed the feasibility of the simultaneous analysis of bilirubin indicators through reagent-free serum Vis-NIR spectroscopy. The proposed method is crucial for the rapid screening of large populations and the treatment of hepatobiliary diseases.

Association of Arterial Hypertension with Hepatobiliary Pathology: The Occurrence of Comorbidity and Features of Metabolic Processes.

Comorbidity of hypertension and hepatobiliary pathology has negative medical and social consequences, including an increase in the indicators of hospital admissions, disability and mortality. OBJECTIVE: The aim was to study the occurrence of hypertension combined with hepatobiliary diseases depending on social status, gender and age in 2003-2017 and their influence on indicators of metabolic processes in patients with a therapeutic profile. METHODS: A cross-sectional study using the inpatients' medical record database of the clinic of Federal Research Centre for Basic and Translational Medicine (Novosibirsk, Russia), which collects demographics, diagnoses (using ICD-10 codes), procedures and examinations of all inpatients from 2003-2017 was conducted. The incidence of comorbidity of hypertension and hepatobiliary pathology depending on age, gender and social status, based on the analysis of 13496 medical records was examined. A comparative analysis of biochemical parameters characterizing the main types of metabolism (lipid, protein, carbohydrate and purine) was carried out in 3 groups of patients: with hypertension; with hepatobiliary pathology, and with a combined pathology. RESULTS: During the years 2003-2005, there was the greatest frequency of this comorbidity in workers, in women, in the age group 60 years and older. In 2009-2017, the highest incidence was observed in the male administrative staff. In patients with this comorbidity, more pronounced changes in carbohydrate, protein, lipid and purine metabolism were found in comparison with groups of patients with isolated diseases. CONCLUSION: The results highlight the need to improve the system of prevention and treatment of comorbidity taking into account sex, age, occupation and features of metabolism.

Possible involvement of interleukin-18 in the pathology of hepatobiliary adverse effects related to treatment with ceritinib.

BACKGROUND: Ceritinib demonstrated a statistically significant effect on the progression-free survival versus chemotherapy in patients with advanced anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) as the first therapy or after previous treatment with crizotinib and one or two prior chemotherapy regimens in global phase 3 studies. However, some serious adverse effects related to ceritinib therapy were reported across these clinical studies. Among them, a grade 3 and 4 increase in hepatobiliary enzymes was one of the common adverse events related to treatment with ceritinib. However, the pathology remains unclear. Previously, increased Interleukin (IL)-18 was observed in both biliary duct disease and liver disease. Therefore, we hypothesized that IL-18 is involved in the pathology of hepatobiliary adverse effects related to treatment with ceritinib and evaluated the serum IL-18. CASE PRESENTATION: The patient was a 53-year-old Japanese woman that we previously reported as having severe hepatobiliary adverse effects related to ceritinib therapy. Laboratory data, CT and MRI were obtained at each time point. IL-18 was evaluated by ELISA method at each time point. Immunochemical staining of liver tissue was performed as a standard protocol using antibodies against IL-18. Our records showed that the levels of serum IL-18 increased from the early stage of hepatobiliary adverse effects related to the treatment with ceritinib and were became worse with an increase in hepatobiliary enzymes and the progression of imaging abnormalities in the bile duct. Furthermore, IL-18 positive cells were detected in the inflammatory sites around the interlobular bile duct of the liver tissue. CONCLUSION: Our case report shows that the increase of serum IL-18 had a positive correlation with the progression of severe hepatobiliary adverse effects related to treatment with ceritinib and the involvement of IL-18 in the hepatobiliary inflammation by pathological evaluation. These results suggest that IL-18 could be a useful surrogate marker for the hepatobiliary toxicity of ceritinib. However, this is only one case report and further prospective observations will complement our data in the future.

Potential Prediction of Acute Biliary Pancreatitis Outcome on Admission.

OBJECTIVES: This pilot study aimed to determine the feasibility of serum values of osteonectin, adiponectin, transforming growth factor beta 1, and neurotensin being used in clinical practice to predict the severity of acute pancreatitis. METHODS: Blood samples were collected from 45 consecutive newly diagnosed acute pancreatitis patients and 30 matched healthy controls. The 2 groups were matched according to age, sex, weight, height, diabetes, smoking, and alcohol consumption. The aforementioned markers were measured using enzyme-linked immunosorbent assay kits. RESULTS: Characteristics of acute pancreatitis patients and healthy controls were comparable. Osteonectin values differed significantly (P < 0.0001). Median/lower quartile/upper quartile of osteonectin levels for acute pancreatitis patients and healthy controls were 263.5/110.3/490.36 and 63.2/46.1/87.2 ng/mL, respectively. Two patients died, 1 patient underwent necrosectomy, and 4 patients had a prolonged intensive care unit/hospital stay. Acute Physiology and Chronic Health Evaluation II and Systemic Inflammatory Response Syndrome scores neither predicted serum values of any of the measured substances nor the clinical outcome (need for intervention, prolonged intensive care unit/hospital stay and mortality). Osteonectin was the only independent predictor for clinical outcome (P = 0.007). CONCLUSIONS: Serum osteonectin strongly discriminates healthy individuals from acute pancreatitis patients. Serum osteonectin shows promise in the prediction of the clinical outcome.

Primary Epidermoid Cyst of Biliary Duct Presenting as Choledochal Cyst.

Choledochal cyst is a cystic dilation of the biliary tree that can increase the risk of malignancy in bile ducts and the gallbladder. These are usually lined by bile duct epithelium, which may undergo intestinal and squamous metaplasia. This is the first report of clinically diagnosed type II choledochal cyst that is entirely lined by metaplastic stratified squamous epithelium, unlike most other cysts, which are histologically lined by bile duct epithelium. This observation can potentially explain the underlying pathogenic mechanism of rare reports of squamous cell carcinomas arising in bile duct systems.

Predicting Success in Percutaneous Transhepatic Biliary Drainage.

PURPOSE: To develop a model to predict successful bilirubin decrease following percutaneous biliary drain placement. METHODS: A total of 257 patients who were identified having undergone percutaneous transhepatic biliary drain placement (PTBD) at our institution between 2002 and 2013 had their medical records and imaging reviewed. Of those, 190 of these patients met criteria and were used in the analysis. A regression model was performed on logarithm-transformed collected variables to predict post-drainage logarithmic transformed total bilirubin levels. A stepwise variable selection method based on Schwarz Bayesian Information Criterion was used to select the most closely associated variables. The model was validated with a Monte Carlo simulation. A short program was developed to calculate the point estimate using the model developed and compared to actual values. RESULTS: The variables that best predicted bilirubin reduction were initial Tbl (PrTbl), INR and ALT. The selected model had a root mean squared error of 0.8. The model had a negative predictive value (PoTbl is below 2 mg/dL) of 83%. CONCLUSIONS: PTBD may not achieve decreasing bilirubin in patients with a malignant obstruction. This is an initial model that can help determine which patients may not benefit from PTBD placement. With more patients, the model's validity can be increased and provide useful clinical determinant to aide patient care.

Stereotactic body radiotherapy for pediatric hepatocellular carcinoma with central biliary obstruction.

Here, we present the case of a pediatric patient with newly diagnosed hepatocellular carcinoma causing central biliary obstruction and persistently elevated bilirubin of 3.0-4.3 mg/dl despite placement of bilateral internal-external biliary drains. The tumor was not resectable, and the patient was not a candidate for liver transplant due to nodal disease, for chemotherapy due to hyperbilirubinemia, or for local therapies aside from stereotactic body radiotherapy (SBRT). In this report, we discuss the successful use of SBRT in the management of this patient, and its role in allowing the patient to become a candidate for additional therapies.

Laboratory Evaluation of the Liver.

Laboratory evaluation of the hepatobiliary system has an important role in the diagnosis, monitoring, and assessment of patients with hepatobiliary diseases. Serum liver enzyme activities can be divided into markers of hepatocellular injury and cholestasis. Liver function can be assessed in several ways, including assessment of synthetic capacity, measurement of ammonia, and measurement of bile acids. It is essential to have an understanding of the performance characteristics and limitations of these tests in order to use them appropriately. This article reviews the laboratory parameters commonly used to aid diagnosing hepatobiliary disorders in dogs and cats.

Hemostatic Disorders Associated with Hepatobiliary Disease.

The liver plays a crucial role in all aspects of coagulation because most factors that regulate procoagulation, anticoagulation, and fibrinolysis are produced, cleared, and/or activated in the liver. Establishing the coagulation status of an individual patient with hepatobiliary disease can therefore be challenging. Although, classically, patients with hepatobiliary disease were thought of as potentially hypocoagulable, hypercoagulability also occurs. The article summarizes the breadth of coagulation abnormalities that have been reported in dogs and cats with hepatobiliary disease and provides strategies to respond to bleeding and thrombotic risk.

Clinical prediction rule to determine the need for repeat ERCP after endoscopic treatment of postsurgical bile leaks.

BACKGROUND AND AIMS: In patients who have undergone ERCP with biliary stenting for postsurgical bile leaks, the optimal method (ERCP or gastroscopy) and timing of stent removal is controversial. We developed a clinical prediction rule to identify cases in which a repeat ERCP is unnecessary. METHODS: Population-based study of all patients who underwent ERCP for management of surgically induced bile leaks between 2000 and 2012. Multivariate and binary recursive partitioning analyses were performed to generate a rule predicting the absence of biliary pathology on repeat endoscopic evaluation. RESULTS: A total of 259 patients were included. On multivariate analysis, postsurgical normal alkaline phosphatase (ALP; OR, 2.26; 95% CI, 1.03-4.99), time from surgery to first ERCP < 8 days (OR, 2.47; 95% CI, 1.15-5.31), and minor leak with no other pathology on initial ERCP (OR, 6.74; 95% CI, 1.75-25.89) were independently associated with the absence of persistent bile leak and other pathology on repeat ERCP. The derived rule included laparoscopic cholecystectomy, normal postsurgical ALP, minor leak with no other pathology on initial ERCP, and an interval from initial to repeat ERCP between 4 and 8 weeks. When all 4 criteria were met, the rule had a sensitivity of 94% (95% CI, 83%-99%) and a negative predictive value of 93% (95% CI, 81%-99%). Optimism-adjusted sensitivity and negative predictive value were 88% (95% CI, 76%-96%) and 86% (95% CI, 73%-96%), respectively. CONCLUSIONS: This clinical decision rule identifies patients who can have their biliary stents removed via gastroscopy, which may improve patient safety and healthcare utilization.

Change of hepatic arterial systolic/diastolic ratio predicts ischemic type biliary lesion after orthotropic liver transplantation.

BACKGROUND: We conducted this prospective nested case-control study for the hepatic artery and portal vein hemodynamic changes after orthotopic liver transplantation. METHODS: A total 128 cases of orthotropic liver transplantation were analyzed, including 25 cases of ischemic type biliary lesions (ITBL). The portal vein and hepatic artery flow velocities were detected by ultrasound on days 28, 42, and 84 after liver transplantation. In the GLM analysis of Lg(S/D), the P values of Group Effect, Time Effect, and Time×Group were 0.014, 0.376, and 0.008, respectively. CONCLUSION: Our results show a relatively reduced hepatic artery S/D in ITBL, especially in extrahepatic ITBL.

Diagnostic and prognostic roles of soluble CD22 in patients with Gram-negative bacterial sepsis.

BACKGROUND: Soluble CD22 (sCD22) is a fragment of CD22, a B cell-specific membrane protein that negatively regulates B-cell receptor signaling. To date, sCD22 has only been regarded as a tumor marker of B-cell malignancies. Its expression in infectious diseases has not yet been assessed. METHODS: Serum concentrations of sCD22, procalcitonin (PCT) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assays in patients with intra-abdominal Gram-negative bacterial infection. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic accuracy of these biomarkers in this type of infection. The correlations between biomarkers and the Acute Physiology and Chronic Health Evaluation (APACHE) II scores were also analyzed. RESULTS: Concentrations of sCD22 were significantly elevated in patients with sepsis and the elevation is correlated with the severity of sepsis. sCD22 was also slightly elevated in patients with non-infected systemic inflammatory response syndrome or local infection. The diagnostic accuracy of sCD22 for sepsis was equivalent to that of PCT or IL-6. In addition, the correlation of sCD22 with APACHE II scores was stronger than that of PCT or IL-6. CONCLUSIONS: Serum sCD22 is a novel inflammatory mediator released during infection. This soluble biomarker plays a potential role in the diagnosis of Gram-negative bacterial sepsis, with a diagnostic accuracy as efficient as that of PCT or IL-6. Furthermore, sCD22 is more valuable to predict the outcomes in patients with sepsis than PCT or IL-6. The present study suggested that sCD22 might be potentially useful in supplementing current criteria for sepsis.

A Laboratory Diagnostic Approach to Hepatobiliary Disease in Small Animals.

Routine biochemical tests generally include serum enzymes, proteins, and other markers useful for identifying hepatobiliary disease in dogs and cats. Obtaining results outside the reference intervals can occur with direct hepatocellular injury, enzyme induction by hepatocytes or biliary epithelium, or decreased hepatic function. However, detection of biochemical abnormalities does not necessarily indicate clinically significant disease. For a comprehensive approach to detection and treatment of hepatobiliary disease, the laboratory results must be correlated with the history and physical examination findings, diagnostic imaging results, and other assays.

Comparative effectiveness of pyruvate kinase M2 in bile, serum carbohydrate antigen 19-9, and biliary brushings in diagnosing malignant biliary strictures.

BACKGROUND: The role of M2-PK (pyruvate kinase) in bile has not been studied in comparison with brushings and carbohydrate antigen (CA) 19-9 in the diagnosis of malignant biliary strictures. AIM: To compare the diagnostic accuracy of biliary M2-PK with cytology and serum CA 19-9 METHODS: In this prospective cross-sectional study, bile was aspirated in 74 patients (discovery and validation cohort) undergoing endoscopic retrograde cholangiopancreatography. Levels of M2-PK were measured in bile and compared to brushings for cytology and CA 19-9. RESULTS: In the discovery cohort, the median bile M2-PK levels were significantly elevated in patients with malignant biliary strictures [187.9 U/l (interquartile range (IQR) 3.5, 3626.8)] compared to those with benign biliary conditions and primary sclerosing cholangitis [0 U/l (IQR 0, 15)] (P = 0.007). A M2-PK cutoff value of 109.1 U/l distinguished malignant from benign conditions with a sensitivity and specificity of 52.9 and 94.1 %, respectively, and area under curve (AUC) of 0.77. The sensitivity of CA 19-9 and brushings in diagnosing cancer was 52.9 % and 11.1 % and specificity 94.1 and 100 %, respectively. The presence of elevated M2-PK >109.1 U/l or CA 19-9 >33 U/ml or positive brushing was 88.2 % sensitive and 88.2 % specific, AUC of 0.89 in the diagnosis of malignancy. The diagnostic accuracy was confirmed in the validation cohort. CONCLUSIONS: As a stand-alone factor, none of the markers were able to distinguish benign from malignant biliary strictures with a high sensitivity. However, a combination was highly sensitive in diagnosing malignant biliary strictures.

Characterization of acute biliary hyperplasia in Fisher 344 rats administered the indole-3-carbinol analog, NSC-743380.

NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver-associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2 days after dosing orally for 2 consecutive days at 100mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule with a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia.

Impact of intra-operative cholangiography and parenchymal resection to donor liver function in living donor liver transplantation.

BACKGROUND: Living donor liver transplantation (LDLT) has been widely accepted over the past decade, and hepatic dysfunction often occurs in the donor in the early stage after liver donation. The present study aimed to evaluate the effect of intra-operative cholangiography (IOC) and parenchymal resection on liver function of donors in LDLT, and to assess the role of IOC in influencing the biliary complications and improving the overall outcome. METHODS: Data from 40 patients who had donated their right lobes for LDLT were analyzed. Total bilirubin (TB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) at different time points were compared, and the follow-up data and the biliary complications were also analyzed. RESULTS: The ALT and AST values were significantly increased after IOC (P<0.001) and parenchymal resection (P<0.001). However, the median values of TB, ALP and GGT were not significantly influenced by IOC (P>0.05) or parenchymal resection (P>0.05). The biochemical changes caused by IOC or parenchymal resection were not correlated with the degree of post-operative liver injury or the recovery of liver function. The liver functions of the donors after operation were stable, and none of the donors suffered from biliary stenosis or leakage during the follow-up. CONCLUSIONS: IOC and parenchymal resection may induce a transient increase in liver enzymes of donors in LDLT, but do not affect the recovery of liver function after operation. Moreover, the routine IOC is helpful to clarify the division line of the hepatic duct, thus reducing the biliary complication rate.

[Ursodeoxycholic acid-enhanced efficiency and safety of statin therapy in patients with liver, gallbladder, and/or biliary tract diseases: the RACURS study].

AIM: To evaluate the efficiency and safety of using statins in combination with ursodeoxycholic acid (UDCA) in patients with this or another liver disease at high risk for cardiovascular events (CVE). SUBJECTS AND METHODS: A register of 262 patients at high risk for CCE who needed statin therapy and have concomitant chronic liver and biliary tract diseases was created in 5 cities of the Russian Federation. RESULTS: After addition of statins or adjustment of their doses, the patients were recommended to include UDCA into their therapy. Six months after stabilization of the dose of statins, the whole group showed a significant reduction in the levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. Assessment of the laboratory parameters responsible for the safety of statin intake revealed no deterioration in the trend in the activity of alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, lactate dehydrogenase, as well as an increase in the serum level of bilirubin. The data obtained using a special questionnaire indicated that 196 patients had taken UDCA and 56 had not. The UDCA and non-UDCA subgroups did not differ in age, weight, or baseline lipid metabolic disturbances. An additional analysis showed that by the end of 6 months, the goal levels of LDL cholesterol in the UDCA and non-UDCA groups were reached in 37 and 20%, respectively (p = 0.01). CONCLUSION: UDCA added to statin therapy in patients at high risk for CVE and concurrent liver diseases contributes to an additional reduction in total cholesterol and LDL cholesterol and prevents enhanced hepatic transaminase activities.

[Blood serum cholecystokinin and clinical-functional variability of biliary pathology].

RESULTS: Basal and stimulated serum CCK concentrations were not statistically significant differences (p > 0.05) with the control group in patients studied in the whole and in patients subgroups, formed by the diagnosis of biliary pathology and the character of gallbladder emptying. Increased stimulated CCK concentration was found in patients with symptomatic variants. Reduce of serum-cholecystokinin concentration growth (ACCK) after intake of Sorbitol was revealed in subgroup of patients with low-symptom variant. Reduced sensitivity of the gallbladder to CCK was observed in subgroups of patients with gallbladder hypokinetic dyskinesia and one with symptomatic variant of biliary pathology. CONCLUSION: The sensitivity of the gallbladder neuromuscular apparatus to CCK is associated with clinical and functional variability of the biliary pathology.