Characterizing the burden of biliary tract cancers across 28 hospitals in Ontario, Canada.

BACKGROUND AND AIMS: The incidence of biliary tract cancers (BTC) appears to be increasing worldwide. We analyzed the characteristics of BTC-related hospitalizations under medical services across 28 hospitals in Ontario, Canada. METHODS: This study uses data collected by GEMINI, a hospital research data network. BTC-related hospitalizations from 2015 to 2021 under the Department of Medicine or intensive care unit were captured using the International Classification of Diseases, 10th revision, codes for intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma, and gallbladder cancers. RESULTS: A total of 4596 BTC-related hospitalizations (2720 iCCA, 1269 extrahepatic cholangiocarcinoma, 607 gallbladder cancers) were analyzed. The number of unique patients with BTC-related hospitalizations increased over time. For iCCA-related hospitalizations, the total number of hospitalizations increased (from 385 in 2016 to 420 in 2021, p = .005), the hospital length of stay decreased over the study period (mean 10 days [SD, 12] in 2016 to 9 days [SD, 8] in 2021, p = .04), and the number of in-hospital deaths was stable (from 68 [18%] in 2016 to 55 [13%] in 2021, p = .62). Other outcomes such as 30-day readmissions, medical imaging tests, intensive care unit-specific hospitalizations, and length of stay were stable over time for all cohorts. The cost of hospitalization for the BTC cohort increased from median $8203 CAD (interquartile range, 5063-15,543) in 2017 to $8507 CAD (interquartile range, 5345-14,755) in 2021. CONCLUSIONS: This real-world data analysis showed a rising number of patients with BTC-related hospitalizations and rising number of iCCA-related hospitalizations across 28 hospitals in Ontario between 2015 and 2021.

Pursuing living donor liver transplantation improves outcomes of patients with autoimmune liver diseases: An intention-to-treat analysis.

Living donor liver transplantation (LDLT) offers the opportunity to decrease waitlist time and mortality for patients with autoimmune liver disease (AILD), autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. We compared the survival of patients with a potential living donor (pLDLT) on the waitlist versus no potential living donor (pDDLT) on an intention-to-treat basis. Our retrospective cohort study investigated adults with AILD listed for a liver transplant in our program between 2000 and 2021. The pLDLT group comprised recipients with a potential living donor. Otherwise, they were included in the pDDLT group. Intention-to-treat survival was assessed from the time of listing. Of the 533 patients included, 244 (43.8%) had a potential living donor. Waitlist dropout was higher for the pDDLT groups among all AILDs (pDDLT 85 [29.4%] vs. pLDLT 9 [3.7%], p < 0.001). The 1-, 3-, and 5-year intention-to-treat survival rates were higher for pLDLT versus pDDLT among all AILDs (95.7% vs. 78.1%, 89.0% vs. 70.1%, and 87.1% vs. 65.5%, p < 0.001). After adjusting for covariates, pLDLT was associated with a 38% reduction in the risk of death among the AILD cohort (HR: 0.62, 95% CI: 0.42-0.93 [ p <0.05]), and 60% among the primary sclerosing cholangitis cohort (HR: 0.40, 95% CI: 0.22-0.74 [ p <0.05]). There were no differences in the 1-, 3-, and 5-year post-transplant survival between LDLT and DDLT (AILD: 95.6% vs. 92.1%, 89.9% vs. 89.4%, and 89.1% vs. 87.1%, p =0.41). This was consistent after adjusting for covariates (HR: 0.97, 95% CI: 0.56-1.68 [ p >0.9]). Our study suggests that having a potential living donor could decrease the risk of death in patients with primary sclerosing cholangitis on the waitlist. Importantly, the post-transplant outcomes in this population are similar between the LDLT and DDLT groups.

Factors Associated With Loss to Follow-Up in Surgical Trials: A Systematic Review and Meta-Analysis.

INTRODUCTION: Loss to follow-up (LTFU) distorts results of randomized controlled trials (RCTs). Understanding trial characteristics that contribute to LTFU may enable investigators to anticipate the extent of LTFU and plan retention strategies. The objective of this systematic review and meta-analysis was to investigate the extent of LTFU in surgical RCTs and evaluate associations between trial characteristics and LTFU. METHODS: MEDLINE, Embase, and PubMed Central were searched for surgical RCTs published between January 2002 and December 2021 in the 30 highest impact factor surgical journals. Two-hundred eligible RCTs were randomly selected. The pooled LTFU rate was estimated using random intercept Poisson regression. Associations between trial characteristics and LTFU were assessed using metaregression. RESULTS: The 200 RCTs included 37,914 participants and 1307 LTFU events. The pooled LTFU rate was 3.10 participants per 100 patient-years (95% confidence interval [CI] 1.85-5.17). Trial characteristics associated with reduced LTFU were standard-of-care outcome assessments (rate ratio [RR] 0.17; 95% CI 0.06-0.48), surgery for transplantation (RR 0.08; 95% CI 0.01-0.43), and surgery for cancer (RR 0.10; 95% CI 0.02-0.53). Increased LTFU was associated with patient-reported outcomes (RR 14.21; 95% CI 4.82-41.91) and follow-up duration ≥ three months (odds ratio 10.09; 95% CI 4.79-21.28). CONCLUSIONS: LTFU in surgical RCTs is uncommon. Participants may be at increased risk of LTFU in trials with outcomes assessed beyond the standard of care, surgical indications other than cancer or transplant, patient-reported outcomes, and longer follow-up. Investigators should consider the impact of design on LTFU and plan retention strategies accordingly.

Machine learning-based mortality prediction models using national liver transplantation registries are feasible but have limited utility across countries.

Many countries curate national registries of liver transplant (LT) data. These registries are often used to generate predictive models; however, potential performance and transferability of these models remain unclear. We used data from 3 national registries and developed machine learning algorithm (MLA)-based models to predict 90-day post-LT mortality within and across countries. Predictive performance and external validity of each model were assessed. Prospectively collected data of adult patients (aged ≥18 years) who underwent primary LTs between January 2008 and December 2018 from the Canadian Organ Replacement Registry (Canada), National Health Service Blood and Transplantation (United Kingdom), and United Network for Organ Sharing (United States) were used to develop MLA models to predict 90-day post-LT mortality. Models were developed using each registry individually (based on variables inherent to the individual databases) and using all 3 registries combined (variables in common between the registries [harmonized]). The model performance was evaluated using area under the receiver operating characteristic (AUROC) curve. The number of patients included was as follows: Canada, n = 1214; the United Kingdom, n = 5287; and the United States, n = 59,558. The best performing MLA-based model was ridge regression across both individual registries and harmonized data sets. Model performance diminished from individualized to the harmonized registries, especially in Canada (individualized ridge: AUROC, 0.74; range, 0.73-0.74; harmonized: AUROC, 0.68; range, 0.50-0.73) and US (individualized ridge: AUROC, 0.71; range, 0.70-0.71; harmonized: AUROC, 0.66; range, 0.66-0.66) data sets. External model performance across countries was poor overall. MLA-based models yield a fair discriminatory potential when used within individual databases. However, the external validity of these models is poor when applied across countries. Standardization of registry-based variables could facilitate the added value of MLA-based models in informing decision making in future LTs.

Optimizing Circulating Tumour DNA Use in the Perioperative Setting for Intrahepatic Cholangiocarcinoma: Diagnosis, Screening, Minimal Residual Disease Detection and Treatment Response Monitoring.

In this review, we present the current evidence and future perspectives on the use of circulating tumour DNA (ctDNA) in the diagnosis, management and understanding the prognosis of patients with intrahepatic cholangiocarcinoma (iCCA) undergoing surgery. Liquid biopsies or ctDNA maybe utilized to: (1) determine the molecular profile of the tumour and therefore guide the selection of molecular targeted therapy in the neoadjuvant setting, (2) form a surveillance tool for the detection of minimal residual disease or cancer recurrence after surgery, and (3) diagnose and screen for early iCCA detection in high-risk populations. The potential for ctDNA can be tumour-informed or -uninformed depending on the goals of its use. Future studies will require ctDNA extraction technique validations, with standardizations of both the platforms and the timing of ctDNA collections.

Association of Viral Hepatitis Status and Post-hepatectomy Outcomes in the Era of Direct-Acting Antivirals.

BACKGROUND: The role of viral hepatitis status in post-hepatectomy outcomes has yet to be delineated. This large, multicentred contemporary study aimed to evaluate the effect of viral hepatitis status on 30-day post-hepatectomy complications in patients treated for hepatocellular carcinoma (HCC). METHODS: Patients from the National Surgical Quality Improvement Program (NSQIP) database with known viral hepatitis status, who underwent hepatectomy for HCC between 2014 and 2018, were included. Patients were classified as HBV-only, HCV-only, HBV and HCV co-infection (HBV/HCV), or no viral hepatitis (NV). Multivariable models were used to assess outcomes of interest. The primary outcome was any 30-day post-hepatectomy complication. The secondary outcomes were major complications and post-hepatectomy liver failure (PHLF). Subgroup analyses were performed for cirrhotic and noncirrhotic patients. RESULTS: A total of 3234 patients were included. The 30-day complication rate was 207/663 (31.2%) HBV, 356/1077 (33.1%) HCV, 29/81 (35.8%) HBV/HCV, and 534/1413 (37.8%) NV (p = 0.01). On adjusted analysis, viral hepatitis status was not associated with occurrence of any 30-day post-hepatectomy complications (ref: NV, HBV odds ratio (OR) 0.89 [95% confidence interval (CI): 0.71-1.12]; HCV OR 0.91 [95% CI: 0.75-1.10]; HBV/HCV OR 1.17 [95% CI: 0.71-1.93]). Similar results were found in cirrhotic and noncirrhotic subgroups, and for secondary outcomes: occurrence of any major complications and PHLF. CONCLUSIONS: In patients with HCC managed with resection, viral hepatitis status is not associated with 30-day post-hepatectomy complications, major complications, or PHLF compared with NV. This suggests that clinical decisions and prognostication of 30-day outcomes in this population likely should not be made based on viral hepatitis status.

Systematic Review and Meta-Analysis of Prognostic Factors for Early Recurrence in Intrahepatic Cholangiocarcinoma After Curative-Intent Resection.

BACKGROUND: Recurrence rates of intrahepatic cholangiocarcinoma (iCCA) after curative hepatectomy are as high as 50% to 70%, and about half of these recurrences occur within 2 years. This systematic review aims to define prognostic factors (PFs) for early recurrence (ER, within 24 months) and 24-month disease-free survival (DFS) after curative-intent iCCA resections. METHODS: Systematic searching was performed from database inception to 14 January 2021. Duplicate independent review and data extraction were performed. Data on 13 predefined PFs were collected. Meta-analysis was performed on PFs for ER and summarized using forest plots. The Quality in Prognostic Factor Studies tool was used for risk-of-bias assessment. RESULTS: The study enrolled 10 studies comprising 4158 patients during an accrual period ranging from 1990 to 2016. In the risk-of-bias assessment of patients who experienced ER after curative-intent iCCA resection, six studies were rated as low risk and four as moderate risk (49.6%; 95% confidence interval [CI], 49.2-50.0). Nine studies were pooled for meta-analysis. Of the postoperative PFs, multiple tumors, microvascular invasion, macrovascular invasion, lymph node metastasis, and R1 resection were associated with an increased hazard for ER or a reduced 24-month DFS, and the opposite was observed for receipt of adjuvant chemo/radiation therapy. Of the preoperative factors, cirrhosis, sex, HBV status were not associated with ER or 24-month DFS. CONCLUSION: The findings from this systematic review could allow for improved surveillance, prognostication, and treatment decision-making for patients with resectable iCCAs. Further well-designed prospective studies are needed to explore prognostic factors for iCCA ER with a focus on preoperative variables.

Is it safe to administer neoadjuvant chemotherapy to patients undergoing hepatectomy for intrahepatic cholangiocarcinoma? ACS-NSQIP propensity-matched analysis.

BACKGROUND: The use of neoadjuvant chemotherapy (NAC) in patients with intrahepatic cholangiocarcinoma (iCCA) is increasing. The objective of this study was to compare the 30-day post-operative complications and length-of-stay (LOS) between patients undergoing hepatectomy for iCCA with and without NAC. METHODS: A retrospective study was conducted using the ACS-NSQIP database queried from 2014 to 2018. Patients with NAC receipt were propensity-score matched into 1:3 ratio with controls using the greedy-matching algorithm and a caliper of 0.2. Logistic and Poisson regression models were used to estimate the effect sizes. RESULTS: A total of 1508 patients who underwent hepatectomy for iCCA were included. 706 patients remained after matching and balance were achieved. The NAC group had 110 (60.1%) complications vs. 289 (55.3%) complications in the non-NAC group (p = 0.29). NAC was not associated with worse 30-day postoperative complications [OR 1.24, 95% CI: 0.87-1.76; p = 0.24]. Post-operative LOS in the NAC group was 8.56 days (mean, SD 7.4) vs. non-NAC group 9.27 days (mean, SD 8.41, p = 0.32). NAC was not associated with longer post-operative LOS [RR 0.93, 95% CI:0.80, 1.08; p = 0.32]. CONCLUSION: NAC may be safely administered without increasing the risk of 30-day complications or post-operative hospital LOS.

Clinical Outcomes of Robotic Surgery Compared to Conventional Surgical Approaches (Laparoscopic or Open): A Systematic Overview of Reviews.

OBJECTIVE: Describe clinical outcomes (eg, postoperative complications, survival) after robotic surgery compared to open or laparoscopic surgery. BACKGROUND: Robotic surgery utilization has increased over the years across a wide range of surgical procedures. However, evidence supporting improved clinical outcomes after robotic surgery is limited. METHODS: We systematically searched MEDLINE, EMBASE, and the Cochrane Central Register of systematic reviews from inception to January 2019 for systematic reviews describing postoperative outcomes after robotic surgery. We qualitatively described patient outcomes of commonly performed robotic procedures: radical prostatectomy, hysterectomy, lobectomy, thymectomy, rectal resection, partial nephrectomy, distal gastrectomy, Roux-en-Y gastric bypass, hepatectomy, distal pancreatectomy, and cholecystectomy. RESULTS: One hundred fifty-four systematic reviews included 336 studies and 18 randomized controlled trials reporting on patient outcomes after robotic compared to laparoscopic or open procedures. Data from the randomized controlled trials demonstrate that robotic-assisted radical prostatectomy offered fewer biochemical recurrence and improvement in quality of recovery and pain scores only up to 6 weeks postoperatively compared to open radical prostatectomy. When compared to laparoscopic prostatectomy, robotic surgery offered improved urinary and sexual functions. Robotic surgery for endometrial cancer had fewer conversion to open compared to laparoscopic. Otherwise, robotic surgery outcomes were similar to conventional surgical approaches for other procedures except for radical hysterectomy where minimally invasive approaches may result in patient harm compared to open approach. CONCLUSION: Robotic surgery has been widely incorporated into practise despite limited supporting evidence. More rigorous research focused on patient-important benefits is needed before further expansion of robotic surgery.

When is a Ghost Really Gone? A Systematic Review and Meta-analysis of the Accuracy of Imaging Modalities to Predict Complete Pathological Response of Colorectal Cancer Liver Metastases After Chemotherapy.

BACKGROUND: Administration of chemotherapy to patients with colorectal liver metastases may result in disappearing liver metastases (DLM). This poses a therapeutic dilemma due to the uncertainty of true complete (pathological) response. OBJECTIVE: We aimed to examine the diagnostic performance of imaging modalities in detecting true complete response in patients with DLM after chemotherapy. METHODS: We performed a systematic search for articles assessing the diagnostic performance of imaging modalities in evaluating DLM following chemotherapy. True complete response was defined as 1-year recurrence-free survival in non-resected patients or complete pathological response on histologic examination in resected patients. We calculated the negative predictive value (NPV) for detecting true complete response of each imaging modality using a random effects model. RESULTS: Thirteen studies comprising 332 patients with at least one DLM were included. The number of DLMs after chemotherapy was 955 with computed tomography (CT), 104 with positron emission tomography (PET), 50 with intraoperative ultrasound (IOUS), 585 with magnetic resonance imaging (MRI), and 175 with contrast-enhanced IOUS (CEIOUS). Substantial variation in study design, patient characteristics, and imaging features was observed. Pooled NPV was 0.79 (95% confidence interval [CI] 0.53-0.96), 0.73 (95% CI 0.58-0.85), 0.54 (95% CI 0.37-0.7), 0.47 (95% CI 0.34-0.61), and 0.22 (95% CI 0.11-0.39) for CEIOUS, MRI, IOUS, CT, and PET, respectively. CONCLUSION: After chemotherapy, MRI or CEIOUS are the most accurate imaging modalities for assessment of DLM and should be used routinely in this context. Given the high NPV of these two modalities, surgical resection of visible CRLM is warranted if technically possible, even if DLM remain.

Influence of UV Polymerization Curing Conditions on Performance of Acrylic Pressure Sensitive Adhesives.

Acrylic pressure sensitive adhesives (PSAs) were prepared by UV polymerization under varying curing conditions of both fast and slow curing, employing high- and low-intensity UV radiation, respectively. The influences of curing conditions and isobornyl acrylate (IBOA) content on PSA performance were comprehensively investigated by measurement of their rheological, thermal, and adhesive properties. In particular, rheological characterization was accomplished by several analytical methods, such as in situ UV rheology, frequency sweep, stress relaxation, and temperature ramp tests, to understand the effect of the UV curing process and IBOA content on the viscoelastic behavior of acrylic PSAs. The slow-cured samples were observed to form more tightly crosslinked networks compared to the fast-cured. On the other hand, at high loading levels of IBOA, in the case of slow curing, the sample exhibited a contrasting trend, having the shortest stress relaxation time and the highest energy dissipation; this was due to molecular chain scission occurring in the crosslinked polymer during UV polymerization. Consequently, we successfully demonstrated the influence of monomer composition of acrylic PSAs, and that of curing conditions employed in UV polymerization. This study provides valuable insights for the development of crosslinked polymer networks of acrylic PSAs for flexible display applications.

Stand-Alone Posterior Expandable Cage Technique for Adjacent Segment Degeneration with Lumbar Spinal Canal Stenosis: A Retrospective Case Series.

Background and Objectives: Symptomatic adjacent segment degeneration (ASD) with lumbar spinal canal stenosis (LSCS) is a common complication after spinal intervention, particularly interbody fusion. Stand-alone posterior expandable cages enable interbody fusion with preservation of the previous operation site, and screw-related complications are avoided. Thus, the aim of this study was to investigate the clinicoradiologic outcomes of stand-alone posterior expandable cages for ASD with LSCS. Materials and Methods: Patients with persistent neurologic symptoms and radiologically confirmed ASD with LSCS were evaluated between January 2011 and December 2016. The five-year follow-up data were used to evaluate the long-term outcomes. The radiologic parameters for sagittal balance, pain control (visual analogue scale), disability (Oswestry Disability Index), and early (peri-operative) and late (implant) complications were evaluated. Results: The data of 19 patients with stand-alone posterior expandable cages were evaluated. Local factors, such as intervertebral and foraminal heights, were significantly corrected (p < 0.01 and p < 0.01, respectively), and revision was not reported. The pain level (p < 0.01) and disability rate (p < 0.01) significantly improved, and the early complication rate was low (n = 2, 10.52%). However, lumbar lordosis (p = 0.62) and sagittal balance (p = 0.80) did not significantly improve. Furthermore, the rates of subsidence (n = 4, 21.05%) and retropulsion (n = 3, 15.79%) were high. Conclusions: A stand-alone expandable cage technique should only be considered for older adults and patients with previous extensive fusion. Although this technique is less invasive, improves the local radiologic factors, and yields favorable clinical outcomes with low revision rates, it does not improve the sagittal balance. For more widespread application, the strength of the cage material and high subsidence rates should be improved.

Low escape-rate genome safeguards with minimal molecular perturbation of Saccharomyces cerevisiae.

As the use of synthetic biology both in industry and in academia grows, there is an increasing need to ensure biocontainment. There is growing interest in engineering bacterial- and yeast-based safeguard (SG) strains. First-generation SGs were based on metabolic auxotrophy; however, the risk of cross-feeding and the cost of growth-controlling nutrients led researchers to look for other avenues. Recent strategies include bacteria engineered to be dependent on nonnatural amino acids and yeast SG strains that have both transcriptional- and recombinational-based biocontainment. We describe improving yeast Saccharomyces cerevisiae-based transcriptional SG strains, which have near-WT fitness, the lowest possible escape rate, and nanomolar ligands controlling growth. We screened a library of essential genes, as well as the best-performing promoter and terminators, yielding the best SG strains in yeast. The best constructs were fine-tuned, resulting in two tightly controlled inducible systems. In addition, for potential use in the prevention of industrial espionage, we screened an array of possible "decoy molecules" that can be used to mask any proprietary supplement to the SG strain, with minimal effect on strain fitness.

Intrinsic biocontainment: multiplex genome safeguards combine transcriptional and recombinational control of essential yeast genes.

Biocontainment may be required in a wide variety of situations such as work with pathogens, field release applications of engineered organisms, and protection of intellectual properties. Here, we describe the control of growth of the brewer's yeast, Saccharomyces cerevisiae, using both transcriptional and recombinational "safeguard" control of essential gene function. Practical biocontainment strategies dependent on the presence of small molecules require them to be active at very low concentrations, rendering them inexpensive and difficult to detect. Histone genes were controlled by an inducible promoter and controlled by 30 nM estradiol. The stability of the engineered genes was separately regulated by the expression of a site-specific recombinase. The combined frequency of generating viable derivatives when both systems were active was below detection (<10(-10)), consistent with their orthogonal nature and the individual escape frequencies of <10(-6). Evaluation of escaper mutants suggests strategies for reducing their emergence. Transcript profiling and growth test suggest high fitness of safeguarded strains, an important characteristic for wide acceptance.

Posterior Fibular Groove Deepening Procedure With Low-Profile Screw Fixation of Fibrocartilaginous Flap for Chronic Peroneal Tendon Dislocation.

Chronic peroneal tendon dislocation is an uncommon disorder that frequently presents with concomitant pathology. Posterior fibular groove deepening and retinaculum repair have been increasing in popularity for treatment of peroneal tendon dislocations. The purpose of the present study was to introduce a posterior fibular groove deepening procedure using low-profile snap-off screws to securely and simply fix the fibrocartilaginous flap to facilitate faster rehabilitation and to assess the clinical outcomes of patients with chronic peroneal tendon dislocation and associated pathologic features. In the present retrospective case series, 34 ankles in 34 patients underwent the fibular groove deepening procedure using low-profile screws with superior peroneal retinaculum repair. The clinical outcomes were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale and patient subjective satisfaction rate. The time of return to recreational and sports activities was also assessed. Weightbearing ankle radiographs were evaluated to assess the stability of the flap by checking the screws. The mean follow-up period was 47.96 (range 12 to 142) months. The mean AOFAS scale score for all patients improved from 69.96 ± 13.14 to 87.72 ± 10.13 at the last follow-up examination (p < .001). Overall, 85.3% of patients subjectively rated their operative outcomes as excellent or good. The 18 (52.9%) patients with an isolated peroneal tendon dislocation had a faster return to recreational or sports activities than the 16 (47.1%) patients with concomitant pathologic features (2.95 ± 0.19 versus 4.14 ± 1.34 months; p = .002). No patient experienced residual dislocation, screw loosening, or irritation from the screws. The fibular groove deepening procedure using low-profile screws is be a simple procedure that offers rigid fixation. This leads to relatively fast rehabilitation and resumption of recreational or sports activities.