Recurrence and tumor-related death after resection of hepatocellular carcinoma in patients with metabolic syndrome.

Background & Aims: Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed. Methods: Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events. Results: In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002). Conclusions: Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors. Impact and implications: Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

Surgical Considerations in Portal Hypertension.

This review provides an in-depth exploration of portal hypertension (PH) and its implications in various surgical procedures. The prevalence of clinically significant PH is 50% to 60% in compensated cirrhosis and 100% in decompensated cirrhosis. The feasibility and safety of hepatic and nonhepatic surgical procedures in patients with PH has been shown. Adequate preoperative risk assessment and optimization of PH are integral parts of patient assessment. The occurrence of adverse outcomes after surgery has decreased over time in this specific population, due to the development of techniques and improved perioperative multidisciplinary care.

The aim of donor safety: surgical approaches and current results.

Living liver donation (LLD) has been suggested as a potential solution to reduce the waitlist mortality for liver transplantation (LT) recipients by facilitating living donor liver transplantation (LDLT). Ensuring both donor and recipient safety is a critical aspect of LDLT. An accurate understanding of the complexity and extend of safety outcomes of the donor is imperative to maintain the high-quality standard this medical program requires. This review seeks to outline safety outcome parameters of interest for donors. Early postoperative mortality is very low with no significant differences comparing left lobe to right lobe LLD. Complications most commonly are biliary (leakage or strictures), bleeding, respiratory or pulmonary, gastrointestinal or infectious. Return to full-time work and quality of life are essential parameters in the mid and long term. As evidence continues to accumulate, outcomes may evolve with the expansion of minimal invasive surgery practice and currently laparoscopic approach is recommended in large experienced centers. By offering safer operations that require fewer incisions or liver resections, living liver donations can be further encouraged, and the perception of the procedure can be improved. Rational consideration of the safety of the donor and in-depth discussion and evaluation with the patient is of utmost importance.

Deep learning-based pathway-centric approach to characterize recurrent hepatocellular carcinoma after liver transplantation.

BACKGROUND: Liver transplantation (LT) is offered as a cure for Hepatocellular carcinoma (HCC), however 15-20% develop recurrence post-transplant which tends to be aggressive. In this study, we examined the transcriptome profiles of patients with recurrent HCC to identify differentially expressed genes (DEGs), the involved pathways, biological functions, and potential gene signatures of recurrent HCC post-transplant using deep machine learning (ML) methodology. MATERIALS AND METHODS: We analyzed the transcriptomic profiles of primary and recurrent tumor samples from 7 pairs of patients who underwent LT. Following differential gene expression analysis, we performed pathway enrichment, gene ontology (GO) analyses and protein-protein interactions (PPIs) with top 10 hub gene networks. We also predicted the landscape of infiltrating immune cells using Cibersortx. We next develop pathway and GO term-based deep learning models leveraging primary tissue gene expression data from The Cancer Genome Atlas (TCGA) to identify gene signatures in recurrent HCC. RESULTS: The PI3K/Akt signaling pathway and cytokine-mediated signaling pathway were particularly activated in HCC recurrence. The recurrent tumors exhibited upregulation of an immune-escape related gene, CD274, in the top 10 hub gene analysis. Significantly higher infiltration of monocytes and lower M1 macrophages were found in recurrent HCC tumors. Our deep learning approach identified a 20-gene signature in recurrent HCC. Amongst the 20 genes, through multiple analysis, IL6 was found to be significantly associated with HCC recurrence. CONCLUSION: Our deep learning approach identified PI3K/Akt signaling as potentially regulating cytokine-mediated functions and the expression of immune escape genes, leading to alterations in the pattern of immune cell infiltration. In conclusion, IL6 was identified to play an important role in HCC recurrence.

Neoadjuvant and adjuvant systemic therapy in HCC: Current status and the future.

Surgical therapies in patients with early-stage HCC can afford long-term survival but are often limited by the continued risk of recurrence, underscoring an interest in (neo)adjuvant strategies. Prior attempts at adjuvant therapy using tyrosine kinase inhibitors failed to yield significant improvements in recurrence-free survival or overall survival. Advances in the efficacy of systemic therapy options, including the introduction of immune checkpoint inhibitors, have fueled renewed interest in this area. Indeed, the IMBrave050 trial recently demonstrated significant improvements in recurrence-free survival with 1 year of adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing surgical resection or ablation, with several other ongoing trials in this space. There is a strong rationale for consideration of the administration of these therapies in the neoadjuvant setting, supported by early clinical data demonstrating high rates of objective responses, although larger trials examining downstream outcomes are necessary, particularly considering the possible risks of this strategy. In parallel, there has been increased interest in using systemic therapies as a bridging or downstaging strategy for liver transplantation. Current data suggest the short-term safety of this approach, with acceptable rates of rejection, so immunotherapy is not considered a contraindication to transplant; however, larger studies are needed to evaluate the incremental value of this approach over locoregional therapy. Conversely, the use of immunotherapy is currently discouraged after liver transplantation, given the high risk of graft rejection and death. The increasing complexity of HCC management and increased consideration of (neo)adjuvant strategies highlight the critical role of multidisciplinary care when making these decisions.

Disease-free survival after pancreatectomy for pancreatic neuroendocrine tumours: a 17-year single-center experience of 223 patients.

BACKGROUND: Metastasis or recurrence of pancreatic neuroendocrine tumours (pNETs) after pancreatectomy presents an important source of post-surgical morbidity. Accordingly we aim to define disease-free survival (DFS) in this population. METHODS: Patients who underwent pancreatectomy for pNETs between Jan 2005 and Jan 2022, were included. Clinicopathologic and survival data were collected and the primary endpoint was DFS. Kaplan-Meier survival analysis and Cox proportional hazards regression modelling were performed. RESULTS: Of the 223 patients, 144 (65%) distal/subtotal/partial pancreatectomies, 71 (32%) pancreaticoduodectomies, 6 (3%) total pancreatectomies, and 2 (1%) enucleations were performed. Forty-five (20%) patients had disease recurrence or metastasis after index pancreatectomy during the 17 years of the study. Non-functional pNETs (n=162, 73%) were more common than hormonally functional sub-types. The 2-year and 5-year DFS were 82% and 76%, respectively. Kaplan-Meier analysis demonstrated node positivity, size ≥4cm, lymphovascular invasion, perineural invasion, Ki-67 ≥20% and non-functional pNETs to be significantly associated with lowered DFS (p<0.05). Univariate Cox analysis identified the following predictors to be significantly associated with poorer DFS: larger tumour size (HR: 1.16 [95% CI: 1.04-1.28]), Ki-67 index ≥20% (HR: 4.93 [95% CI: 2.00-11.44]), perineural invasion (HR: 3.23 [95% CI: 1.40-7.89]), open surgery (HR: 3.34 [95% CI: 1.03-1.33]), node-positive disease (HR: 5.27 [95% CI: 2.28-13.26]) and increased BMI (HR: 1.10 [95% CI: 1.03-1.17]) (p<0.05). CONCLUSIONS: One in every five resected patients developed recurrence or metastasis after pancreatectomy. Prognostic predictors of DFS in pNETs could help optimize treatment and enhance follow-up protocols to improve quality and reduce morbidity.

Harmonizing Definitions and Perspectives in Extreme Liver Surgery: A Delphi Experts Consensus.

OBJECTIVE: To propose to our community a common language about extreme liver surgery. BACKGROUND: The lack of a clear definition of extreme liver surgery prevents convincing comparisons of results among centers. METHODS: We used a two-round Delphi methodology to quantify consensus among liver surgery experts. For inclusion in the final recommendations, we established a consensus when the positive responses (agree and totally agree) exceeded 70%. The study steering group summarized and reported the recommendations. In general, a five-point Likert scale with a neutral central value was used, and in a few cases multiple choices. Results are displayed as numbers and percentages. RESULTS: A two-round Delphi study was completed by 38 expert surgeons in complex hepatobiliary surgery. The surgeon´s median age was 58 years old (52-63) and the median years of experience was 25 years (20-31). For the proposed definitions of total vascular occlusion, hepatic flow occlusion and inferior vein occlusion, the degree of agreement was 97%, 81% and 84%, respectively. In situ approach (64%) was the preferred, followed by ante situ (22%) and ex situ (14%). Autologous or cadaveric graft for hepatic artery or hepatic vein repair were the most recommended (89%). The use of veno-venous bypass or portocaval shunt revealed the divergence depending on the case. Overall, 75% of the experts agreed with the proposed definition for extreme liver surgery. CONCLUSION: Obtaining a consensus on the definition of extreme liver surgery is essential to guarantee the correct management of patients with highly complex hepatobiliary oncological disease. The management of candidates for extreme liver surgery involves comprehensive care ranging from adequate patient selection to the appropriate surgical strategy.

Long-Term Outcomes of Recipients of Liver Transplants from Living Donors Treated with a Very Low-Calorie Diet.

The increasing prevalence of steatotic liver disease (SLD) in potential living donors is concerning, as it limits donor's availability amid rising demand. OPTIFAST very low-calorie diet (VLCD), a meal replacement product, effectively reduces weight and hepatic steatosis before transplantation. However, data on the outcomes of recipients of VLCD-treated donors are lacking. We conducted a single-center, retrospective study on 199 living donor liver transplant recipients at Toronto General Hospital, Canada, between January 2015 and January 2020. We compared the 1-year posttransplant outcomes between recipients who received organs from donors treated with VLCD (N = 34) for either weight loss or steatosis reduction, with those who did not require treatment (N = 165). Our analysis revealed no statistically significant differences in the rates of postoperative complications (23% vs 32.4%, p=0.3) or intensive care unit stays (70.9% vs 70.6%, p=1) between recipients of non-VLCD and VLCD grafts. Following adjusted multivariate logistic regression, receipt of VLCD grafts was not associated with increased hospital length of stay. In addition, one-year mortality did not differ between the two groups (4.2% non-VLCD recipients vs 2.9% VLCD recipients, p=0.6). OPTIFAST VLCD treatment for liver donors demonstrates positive and safe outcomes in recipients, expanding the pool of potential living donors for increased organ availability.

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.

Biliary complications after adult-to-adult living-donor liver transplantation: An international multicenter study of 3633 cases.

In living-donor liver transplantation, biliary complications including bile leaks and biliary anastomotic strictures remain significant challenges, with incidences varying across different centers. This multicentric retrospective study (2016-2020) included 3633 adult patients from 18 centers and aimed to identify risk factors for these biliary complications and their impact on patient survival. Incidences of bile leaks and biliary strictures were 11.4% and 20.6%, respectively. Key risk factors for bile leaks included multiple bile duct anastomoses (odds ratio, [OR] 1.8), Roux-en-Y hepaticojejunostomy (OR, 1.4), and a history of major abdominal surgery (OR, 1.4). For biliary anastomotic strictures, risk factors were ABO incompatibility (OR, 1.4), blood loss >1 L (OR, 1.4), and previous abdominal surgery (OR, 1.7). Patients experiencing biliary complications had extended hospital stays, increased incidence of major complications, and higher comprehensive complication index scores. The impact on graft survival became evident after accounting for immortal time bias using time-dependent covariate survival analysis. Bile leaks and biliary anastomotic strictures were associated with adjusted hazard ratios of 1.7 and 1.8 for graft survival, respectively. The study underscores the importance of minimizing these risks through careful donor selection and preoperative planning, as biliary complications significantly affect graft survival, despite the availability of effective treatments.

Transplant oncology - Current indications and strategies to advance the field.

Liver transplantation (LT) was originally described by Starzl as a promising strategy to treat primary malignancies of the liver. Confronted with high recurrence rates, indications drifted towards non-oncologic liver diseases with LT finally evolving from a high-risk surgery to an almost routine surgical procedure. Continuously improving outcomes following LT and evolving oncological treatment strategies have driven renewed interest in transplant oncology. This is not only reflected by constant refinements to the criteria for LT in patients with HCC, but especially by efforts to expand indications to other primary and secondary liver malignancies. With new patient-centred oncological treatments on the rise and new technologies to expand the donor pool, the field has the chance to come full circle. In this review, we focus on the concept of transplant oncology, current indications, as well as technical and ethical aspects in the context of donor organs as precious resources.

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.

Is Repeat Resection for Recurrent Intrahepatic Cholangiocarcinoma Warranted? Outcomes of an International Analysis.

BACKGROUND: Recurrence of intrahepatic cholangiocarcinoma (ICC) after liver resection (LR) remains high, and optimal therapy for recurrent ICC is challenging. Herein, we assess the outcomes of patients undergoing repeat resection for recurrent ICC in a large, international multicenter cohort. PATIENTS AND METHODS: Outcomes of adults from six large hepatobiliary centers in North America, Europe, and Asia with recurrent ICC following primary LR between 2001 and 2015 were analyzed. Cox models determined predictors of post-recurrence survival. RESULTS: Of patients undergoing LR for ICC, 499 developed recurrence. The median time to recurrence was 10 months, and 47% were intrahepatic. Overall 3-year post-recurrence survival rate was 28.6%. In total, 121 patients (25%) underwent repeat resection, including 74 (61%) repeat LRs. Surgically treated patients were more likely to have solitary intrahepatic recurrences and significantly prolonged survival compared with those receiving locoregional or systemic therapy alone with a 3-year post-recurrence survival rate of 47%. Independent predictors of post-recurrence death included time to recurrence < 1 year [HR 1.66 (1.32-2.10), p < 0.001], site of recurrence [HR 1.74 (1.28-2.38), p < 0.001], macrovascular invasion [HR 1.43 (1.05-1.95), p = 0.024], and size of recurrence > 3 cm [HR 1.68 (1.24-2.29), p = 0.001]. Repeat resection was independently associated with decreased post-recurrence death [HR 0.58 0.43-0.78), p < 0.001]. CONCLUSIONS: Repeat resection for recurrent ICC in select patients can result in extended survival. Thus, challenging the paradigm of offering these patients locoregional or chemo/palliative therapy alone as the mainstay of treatment.

Liver transplantation for intrahepatic cholangiocarcinoma: who, when and how.

PURPOSE OF REVIEW: Using transplant oncology principles, selected patients with intrahepatic cholangiocarcinoma (iCCA) may achieve long-term survival after liver transplantation. Strategies for identifying and managing these patients are discussed in this review. RECENT FINDINGS: Unlike initial reports, several modern series have reported positive outcomes after liver transplantation for iCCA. The main challenges are in identifying the appropriate candidates and graft scarcity. Tumor burden and response to neoadjuvant therapies have been successfully used to identify favorable biology in unresectable cases. New molecular biomarkers will probably predict this response in the future. Also, new technologies and better strategies have been used to increase graft availability for these patients without affecting the liver waitlist. SUMMARY: Liver transplantation for the management of patients with unresectable iCCA is currently a reality under strict research protocols. Who is a candidate for transplantation, when to use neoadjuvant and locoregional therapies, and how to increase graft availability are the main topics of this review.

Living Donor Liver Transplantation for Hepatocellular Carcinoma Within and Outside Traditional Selection Criteria: A Multicentric North American Experience.

OBJECTIVE: To evaluate long-term oncologic outcomes of patients post-living donor liver transplantation (LDLT) within and outside standard transplantation selection criteria and the added value of the incorporation of the New York-California (NYCA) score. BACKGROUND: LDLT offers an opportunity to decrease the liver transplantation waitlist, reduce waitlist mortality, and expand selection criteria for patients with hepatocellular carcinoma (HCC). METHODS: Primary adult LDLT recipients between October 1999 and August 2019 were identified from a multicenter cohort of 12 North American centers. Posttransplantation and recurrence-free survival were evaluated using the Kaplan-Meier method. RESULTS: Three hundred sixty LDLTs were identified. Patients within Milan criteria (MC) at transplantation had a 1, 5, and 10-year posttransplantation survival of 90.9%, 78.5%, and 64.1% versus outside MC 90.4%, 68.6%, and 57.7% ( P = 0.20), respectively. For patients within the University of California San Francisco (UCSF) criteria, respective posttransplantation survival was 90.6%, 77.8%, and 65.0%, versus outside UCSF 92.1%, 63.8%, and 45.8% ( P = 0.08). Fifty-three (83%) patients classified as outside MC at transplantation would have been classified as either low or acceptable risk with the NYCA score. These patients had a 5-year overall survival of 72.2%. Similarly, 28(80%) patients classified as outside UCSF at transplantation would have been classified as a low or acceptable risk with a 5-year overall survival of 65.3%. CONCLUSIONS: Long-term survival is excellent for patients with HCC undergoing LDLT within and outside selection criteria, exceeding the minimum recommended 5-year rate of 60% proposed by consensus guidelines. The NYCA categorization offers insight into identifying a substantial proportion of patients with HCC outside the MC and the UCSF criteria who still achieve similar post-LDLT outcomes as patients within the criteria.

Trajectories of patients relisted for liver transplantation.

INTRODUCTION AND OBJECTIVES: Recurrent cirrhosis complicates 10-30% of Liver transplants (LT) and can lead to consideration for re-transplantation. We evaluated the trajectories of relisted versus primary listed patients on the waitlist using a competing risk framework. MATERIALS AND METHODS: We retrospectively examined 1,912 patients listed for LT at our centre between from 2012 to 2020. Cox proportional hazard models were used to assess overall survival (OS) by listing type and competing risk analysis Fine-Gray models were used to assess cumulative incidence of transplant by listing type. RESULTS: 1,731 patients were included (104 relisted). 44.2% of relisted patients received exception points vs. 19.8% of primary listed patients (p<0.001). Patients relisted without exceptions, representing those with graft cirrhosis, had the worst OS (HR: 4.17, 95%CI 2.63 - 6.67, p=<0.0001) and lowest instantaneous rate of transplant (HR: 0.56, 95%CI 0.38 - 0.83, p=0.006) than primary listed with exception points. On multivariate analysis listing type, height, bilirubin and INR were associated with cumulative incidence of transplant, while listing type, bilirubin, INR, sodium, creatinine were associated with OS. Within relisted patients, there was a trend towards higher mortality (HR: 1.79, 95%CI 0.91 - 3.52, p=0.08) and low transplant incidence (HR: 0.51, 95%CI 0.22 - 1.15, p=0.07) for graft cirrhosis vs other relisting indications. CONCLUSIONS: Patients relisted for LT are carefully curated and comprise a minority of the waitlist population. Despite their younger age, they have worse liver/kidney function, poor waitlist survival, and decreased transplant incidence suggesting the need for early relisting, while considering standardized exception points.

Update to 'A Contemporary Systematic Review on Liver Transplantation for Unresectable Liver Metastasis of Colorectal Cancer'.

Colorectal cancer is the second most common cause of cancer-related death worldwide, and half of patients present with colorectal liver metastasis (CRLM). Liver transplant (LT) has emerged as a treatment modality for otherwise unresectable CRLM. Since the publication of the Lebeck-Lee systematic review in 2022, additional evidence has come to light supporting LT for CRLM in highly selected patients. This includes reports of >10-year follow-up with over 80% survival rates in low-risk patients. As these updated reports have significantly changed our collective knowledge, this article is intended to serve as an update to the 2022 systematic review to include the most up-to-date evidence on the subject.