Search Results (76)

Immune checkpoint blockade has changed the management of several digestive system cancers, but its impact is highly context dependent. This review evaluates evidence for esophageal, gastric and gastroesophageal junction, colorectal, hepatocellular, biliary tract and gallbladder, and pancreatic cancers. Randomized phase III trials have established chemoimmunotherapy or dual-checkpoint strategies in advanced esophageal cancer, biomarker- and regimen-dependent first-line therapy in gastric cancer, PD-1-based therapy for MSI-H/dMMR colorectal cancer, atezolizumab–bevacizumab and STRIDE for unresectable hepatocellular carcinoma, and chemoimmunotherapy for advanced biliary tract cancer. Recent results also expand perioperative treatment: neoadjuvant checkpoint blockade produces high pathological response rates in dMMR colon cancer, adjuvant atezolizumab plus mFOLFOX6 improves disease-free survival in stage III dMMR colon cancer, and perioperative serplulimab improves event-free survival in PD-L1-positive resectable gastric cancer. These advances coexist with important negative findings. Pembrolizumab-containing therapy did not meet superiority end points in KEYNOTE-062, the initial adjuvant signal in IMbrave050 was not sustained, and unselected pancreatic ductal adenocarcinoma remains largely resistant to checkpoint blockade. Early vaccine, cellular, TIGIT, radiomics, spatial, and multi-omics studies remain hypothesis-generating and require external or randomized validation. Clinical interpretation should integrate evidence maturity, biomarker validity, immune-related toxicity, patient-reported outcomes, cost, access, and manufacturing demands rather than response rate alone. Full article

The liver is an immunologically distinctive organ. Portal blood continuously delivers gut-derived antigens and microbial products, requiring hepatic immunity to balance surveillance with restraint. In hepatocellular carcinoma (HCC), this physiology is commonly overlaid by chronic injury, inflammation, and fibrosis, so the background liver forms part of the disease context in which the tumor microenvironment (TME) develops. This review synthesizes how cellular architecture, tumor-intrinsic programs, and structural, metabolic, and microbial conditions interact to shape immune evasion and heterogeneity. HCC provides the principal evidence base, with intrahepatic cholangiocarcinoma (iCCA) used as a structured, biologically distinct comparator. We organize therapies by the microenvironmental barriers they are intended to modify and distinguish established clinical efficacy from evidence that the proposed mechanisms mediate treatment benefit. Single-cell and spatial studies have resolved cellular states and spatial arrangements, including onco-fetal endothelial–myeloid neighborhoods and a macrophage–fibroblast boundary band separating lymphocyte-rich stroma from malignant tissue. These patterns operate within fibrotic and metabolically altered tissue and vary by etiology, spatial context, and tumor type. Vascular endothelial growth factor blockade with immune checkpoint inhibition and dual checkpoint blockade are established first-line options in advanced HCC. Chemo-immunotherapy is established in biliary tract cancer, and IDH1 inhibition has established efficacy in IDH1-mutant cholangiocarcinoma. Myeloid- and stroma-directed strategies, natural-product approaches, and engineered-cell therapies remain preclinical or early clinical. None of the pivotal trials tested whether the proposed microenvironmental mechanism mediated treatment benefit. The liver TME informs treatment selection without yet determining it. Full article

Immune checkpoint inhibitor (ICI)-based combinations have become central systemic treatment options for advanced hepatocellular carcinoma (HCC) and are now being integrated into selected intermediate-stage settings. As tumor responses have improved, some patients who were not initially candidates for curative-intent treatment may later become candidates for resection, ablation, or liver transplantation. However, radiographic response alone does not define curative-intent candidacy, and no shared framework currently guides how post-immunotherapy response should be translated into a treatment decision. Terminology also differs regionally: Asian literature frames a resection-anchored paradigm, whereas Western practice uses transplant-anchored downstaging. This narrative review proposes a multidisciplinary framework for immunotherapy-based conversion to curative-intent treatment in HCC. We first clarify the lexicon of conversion, downstaging, bridging, neoadjuvant therapy, post-ICI transplantation, and drug-free or treatment-free status. We then summarize conversion-relevant evidence across key clinical decision settings, including transarterial chemoembolization (TACE)-unsuitable intermediate-stage disease, portal vein tumor thrombus or macrovascular invasion, borderline-resectable or locally advanced disease, and transplant downstaging or bridging. The central framework defines curative-intent transition through the intersection of three domains: technical suitability, oncologic suitability, and physiologic or liver-reserve suitability. Biomarkers, imaging response, tumor-marker kinetics, liver function, and treatment-related toxicity are discussed as inputs into candidacy rather than as response measures alone. Finally, we propose a multidisciplinary workflow and highlight lessons from pancreatic cancer, biliary tract cancer, and colorectal liver metastases. As an expert-opinion-based framework, this approach should structure multidisciplinary discussion rather than serve as validated selection criteria; harmonized terminology, prospective conversion registries, and conversion-specific endpoints are needed for prospective validation. Full article

Biliary tract cancers (BTCs) comprise a heterogeneous group of malignancies arising from the biliary tree, including cholangiocarcinomas and gallbladder carcinomas. Although their incidence is rising globally in Western countries, these cancers are rare and most often diagnosed at advanced stages. Their molecular heterogeneity and frequent resistance to therapy further contribute to their dismal prognosis. In recent years, molecular profiling studies have led to a better understanding of BTC biology and have opened new therapeutic opportunities, particularly for patients with advanced or metastatic disease. Alterations in DNA damage repair (DDR) genes have been identified in a substantial proportion of BTC cases, with some cohorts observing frequencies approaching ~70%. These genetic alterations play a critical role in tumorigenesis and disease progression and may contribute to treatment resistance. In this article, we discuss the current knowledge on: (1) the main DDR signaling pathways; (2) the prevalence of DDR gene alterations across BTC subtypes; (3) the potential of DDR gene alterations as prognostic and/or predictive biomarkers of treatment response; and (4) the latest advances in DDR-based targeted therapies and ongoing clinical trials in BTC. Full article

Background: Biliary tract cancers (BTCs), encompassing cholangiocarcinoma and gallbladder carcinoma, are aggressive malignancies with poor prognosis and increasing incidence in selected regions worldwide. Advances in imaging, biomarker profiling, immunotherapy, and targeted therapies have improved treatment options but have also increased the economic pressure on health systems. Understanding the economic evidence on BTC is therefore important for resource allocation and health technology assessment. Methods: We systematically searched PubMed/MEDLINE, Embase, Scopus, and Web of Science for peer-reviewed economic studies of BTC published from January 2010 to March 2025. Eligible studies included cost-effectiveness, cost–utility, cost–benefit, cost-of-illness, and resource-use analyses. The review followed PRISMA reporting principles. Reporting completeness was assessed using CHEERS 2022, and methodological credibility was appraised using the Drummond framework. Results: Twenty studies were included: 13 cost-effectiveness or cost–utility analyses and seven cost-of-illness or resource-use studies. Conventional chemotherapy strategies, including gemcitabine plus cisplatin in some settings and other cytotoxic combinations in selected jurisdictions, generally produced more favorable economic results than newer systemic therapies, although findings varied by country, threshold, comparator, and price assumptions. First-line immunotherapy combinations and biomarker-directed targeted therapies frequently produced ICERs above jurisdiction-specific willingness-to-pay thresholds at current prices, often requiring substantial price reductions to approach cost-effectiveness. Real-world studies showed high resource use and costs, particularly with hospitalizations and later treatment lines. Evidence on screening and prevention was limited, with one study suggesting that ultrasound surveillance may be cost-effective in a liver fluke-endemic region of Thailand. Discussion: The available economic evidence suggests that affordability and jurisdiction-specific value assessment are central to BTC policy decisions. Current prices for several immunotherapy and targeted agents limit cost-effectiveness in published models, while evidence on prevention, early detection, and care-pathway interventions remains sparse and context-specific. Full article

In the hepatobiliary system, the majority of neoplasms grow within the hepatic parenchyma; however, some arise, grow, and/or spread within the lumen of the intrahepatic large bile ducts and the perihilar/distal bile ducts (collectively referred to as large bile ducts), representing specialized ductal organs associated with unique peribiliary glands and being distinct from the intrahepatic small bile ducts and bile ductules embedded within the hepatic parenchyma. Precursors of cholangiocarcinoma (CCA) arising within the lumen of large bile ducts have recently been proposed. Neoplasms growing and spreading within the lumen of large bile ducts have been categorized into four groups and are discussed here in light of updated pathological findings. (i) Precursor(s) of CCA arising in the large bile ducts (large-duct-type intrahepatic CCA and perihilar/distal CCA): These precursors include high-grade biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile duct (IPNB), and intraductal oncocytic papillary neoplasm (IOPN). High-grade BilIN presents as a flat, microscopic lesion with dysplastic cytoarchitectural alterations and grows along the luminal surface of large bile ducts, whereas the latter two present as grossly visible polypoid or tumorous lesions composed of papillary, villous, or tubular proliferation of neoplastic epithelium with delicate fibrovascular cores. These lesions may eventually progress to invasive CCA. Intraductal tubulopapillary neoplasm of the bile duct (ITPN), previously categorized as another precursor of CCA arising in large bile ducts, appears to represent a heterogeneous group of neoplasms with respect to progression and presumed cell of origin. Some ITPNs are frequently associated with nodular invasive carcinoma resembling small-duct-type intrahepatic CCA (SD-iCCA) and share genetic alterations with SD-iCCA; such cases may arise in association with small bile ducts or bile ductules. In contrast, other ITPNs exhibit cystic changes with tubulopapillary features and may arise in association with peribiliary glands or cysts. (ii) Secondary growth and spread of biliary neoplasms: This category comprises several patterns. First, intraepithelial neoplastic spread directly and continuously from the primary neoplastic lesion is observed in almost all cases of high-grade BilIN, IPNB, and IOPN; it spreads laterally along the luminal surface of the proximal and distal bile ducts and extends vertically into the adjacent peribiliary glands. Intraluminal cast-like spread in the bile ducts adjacent to the primary neoplastic lesion also occurs in some precursor lesions, particularly in ITPN. Implantation of a biliary neoplasm from one part of the biliary tract to another results in discontinuous, multifocal biliary neoplasms, particularly in IPNB, and occurs mainly in the distal bile ducts relative to the main tumor. Multicentric tumorigenesis may contribute to the multifocal development of precursors and CCA in the bile ducts. The accumulation of additional genetic alterations, beyond the common mutations detected in primary tumors, may contribute to metachronous recurrence of CCA after curative resection of the primary biliary tumor. Cancerization of the duct (COD) by CCA may also contribute to secondary growth and spread within the bile duct lumen. Specifically, flat-type cancerization of pre-existing non-neoplastic bile ducts, resembling high-grade BilIN, occurs in approximately one-third of hilar CCA cases. Intraductal polypoid, cast-like cancerization within the lumen of adjacent bile ducts, resembling polypoid precursors of CCA, can also occur in approximately one-tenth of SD-iCCA. (iii) Prominent intraductal polypoid growth of invasive CCA: Invasive CCA rarely presents with predominant intraductal polypoid carcinoma that is continuous with periductal infiltrating CCA; this pattern can be referred to as polypoid invasive CCA. (iv) Nonbiliary neoplasms presenting bile duct tumor thrombus (BDTT): BDTT associated with hepatocellular carcinoma and with extrahepatic malignancies extending into the bile duct lumen can mimic the intraluminal growth and spread patterns of the above-mentioned biliary neoplasms. In conclusion, intraluminally growing biliary neoplasms in the large bile ducts comprise a heterogeneous group that can be reasonably classified into four categories. This categorization may facilitate understanding of these intrabiliary growing neoplasms. Full article

Currently, there are very few efficient treatment options for hepatobiliary pancreatic cancer (HPC), which comprises pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC), and hepatocellular carcinoma (HCC). The HPC tumors are the most lethal malignant tumors in the world. Traditional chemotherapy offers little survival benefit and is associated with notable systemic toxicity, which has made antibody–drug conjugates (ADCs) a hopeful treatment option. Strong cytotoxic drugs combine with monoclonal antibodies to attack tumor-associated antigens. This review discusses the benefits and current developments of Antibody–Drug Conjugates (ADCs) in treating HPC. It also covers their mechanisms of action, ongoing clinical trials, and the challenges of targeting specific antigens like B7-H3, c-MET, and Trop-2. ADCs deliver chemotherapy directly to cancer cells while protecting healthy tissues. It also addresses the favorable outcomes of several preclinical and clinical studies and highlights future paths to enhance ADC efficacy, including addressing tumor heterogeneity, overcoming resistance, and optimizing drug-delivery techniques. This approach has the possibility to further increase patient survival and minimize side effects in HPC patients. To the best of our knowledge and based on the available literature, we have made every effort to include all relevant publications; any inadvertent omissions are entirely unintentional. Full article

Mucosal-associated invariant T (MAIT) cells are abundant innate-like T lymphocytes in the human liver which can provide antimicrobial defense, amplify inflammatory processes and mediate tissue repair and fibrosis depending on microenvironmental cues. Chronic liver diseases of diverse etiologies, including viral hepatitis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, biliary tract disease, autoimmune hepatitis and hepatocellular carcinoma are accompanied by numerical and functional adjustments in the MAIT cell population. In this review, we integrate existing data on MAIT cell markers and functions in diverse liver diseases, comparing how these cells are similarly or differentially shaped by distinct pathogenic contexts. Finally, we propose a spatially anchored conceptual and technical framework to study MAIT cell biology in liver disease. Full article

Background/Objectives: The anti-PD-L1 antibody has been applied for use in first-line advanced biliary duct cancer patients. However, clinical evidence of toripalimab in combination with biweekly 5-fluorouracil (5-FU) is limited and predictive biomarkers of treatment benefits remain unclear. Methods: This prospective study enrolled patients with unresectable or metastatic BTC who received toripalimab in combination with gemcitabine and biweekly 5-FU. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). Secondary endpoints included overall survival (OS) and safety. Exploratory analyses evaluated associations between programmed cell death-ligand 1 (PD-L1) expression or tumor mutational burden (TMB) and clinical outcomes. Results: A total of 30 patients were enrolled, with a median follow-up duration of 16.0 months. The ORR was 13.0%. The median PFS and OS were 5.3 months (95% CI: 3.59–7.01) and 11.7 months (95% CI: 6.07–17.33), respectively. Subgroup analyses revealed no significant association between PD-L1 status or TMB level and improved PFS. All patients experienced adverse events (AEs), while grade 3–4 AEs occurred in eight patients (26.7%), most commonly anemia (20.0%), leukocytopenia (13.3%), and nausea (6.6%). No grade 5 AEs were observed, and the safety profile was considered manageable. Conclusions: Toripalimab in combination with gemcitabine and 5-fluorouracil showed promising efficacy and was well-tolerated as a first-line therapy in advanced biliary duct cancer patients. Although PD-L1 expression and TMB did not predict treatment benefit, larger studies are needed to validate potential biomarkers and further optimize immunochemotherapy strategies for BTC. Full article

Background: Ampullary cancer is a rare biliary tract cancer arising from one of the three epithelial tissues in the region. Leveraging a large patient-level genomic database, this study aims to identify, explore, and describe the genetic landscape of ampullary carcinoma and its implications. Methods: A retrospective analysis of ampullary cancer samples was conducted using the AACR Project GENIE database. Analysis of recurrent somatic mutations at large and between patient populations, and co-occurrence and mutual exclusivity of mutations was conducted, with a p-value < 0.05. Results: The most frequent mutations were identified as TP53 (53.2%), KRAS (46.6%), and SMAD4 (16.6%). Mutational differences were noted between sexes, White vs. Non-white groups, and histopathological subtypes. Significant mutual exclusivity was found between KRAS and ERBB2. Co-occurrence was observed in the ARID1A mutation with KMT2D, ERBB2, and PIK3CA; CDKN2A with the SMAD4 and KRAS mutations; TP53 mutation with the CTNNB1 mutation; and KRAS co-occurred with an APC mutation. Reduced survival rates were seen in populations with the TP53 or KRAS mutation. Conclusions: This study provides a detailed descriptive genomic landscape of ampullary carcinoma, highlighting frequent mutations between patient groups and the mutational burden of the DNA damage response pathway in ampullary cancer, laying important groundwork for the development of therapeutic targets and more individualized treatment regimens. Full article

Biliary tract carcinoma (BTC) is a group of highly heterogeneous malignancies arising from the biliary epithelium. Anatomically, BTC is categorized into gallbladder cancer (GBC) and cholangiocarcinoma (CCA), with the latter further subdivided into intrahepatic (iCCA), perihilar (pCCA), and distal cholangiocarcinoma (dCCA). Epidemiological studies reveal a dismal five-year survival rate of less than 20% for BTC patients, with limited responses to current chemotherapy regimens, underscoring the urgent need to unravel its complex molecular pathogenesis. Recent research has increasingly focused on the regulatory networks of post-translational modifications, particularly the ubiquitin-proteasome system (UPS), in tumorigenesis. As the largest subfamily of deubiquitinating enzymes (DUBs), ubiquitin-specific proteases (USPs) regulate the stability of key oncoproteins such as phosphatase and tensin homolog (PTEN) and c-Myc, playing pivotal roles in tumor cell proliferation, apoptosis evasion, invasion, and metastasis. This review systematically summarizes the differential expression profiles of USP family members (e.g., USP1, USP3, USP7, USP8, USP9X, USP21, and USP22) in BTC and their clinical significance, with a focus on elucidating how specific USPs regulate tumor progression through key substrates, including poly(ADP-ribose) polymerase 1 (PARP1), dynamin-1-like protein (DNM1L), and O-GlcNAc transferase (OGT). Furthermore, based on recent advances, we discuss the therapeutic potential of small-molecule USP inhibitors in BTC targeted therapy, providing a theoretical foundation for developing novel precision treatment strategies. Full article

Background/Objectives: The TOPAZ-1 phase III trial reported a survival benefit of using durvalumab, an anti-programmed death ligand 1 (anti-PD-L1) antibody, in combination with gemcitabine and cisplatin (GCD) treatment in patients with advanced biliary tract cancer. This retrospective study investigated the efficacy and safety of GCD treatment for advanced biliary tract cancer in real-world conditions. Methods: The study subjects were 52 patients with biliary tract cancer who received GCD therapy between January 2023 and May 2024. The observation parameters included the modified Glasgow Prognostic Score (mGPS), neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), tumor markers (CEA, CA19-9), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: The cohort included 36 men and 16 women, with a median age of 73.0 years. There were 36 cases of cholangiocarcinoma (distal: 10, perihilar: 19, intrahepatic: 7), 13 cases of gallbladder cancer, and 3 cases of ampullary carcinoma. The stages were locally advanced in 30 cases and metastatic in 22 cases. Biliary drainage was performed in 30 cases. There were 38 cases receiving first-line therapy and 14 cases receiving second-line or later treatments. The median values at the start of GCD therapy were ALB 3.7 g/dL, CRP 0.39 mg/dL, NLR 2.4, PLR 162.5, CEA 4.8 ng/mL, and CA19-9 255.9 U/mL. The mGPS distribution was 0:23 cases, 1:18 cases, and 2:11 cases. The treatment outcomes were ORR 25.0% (CR 2 cases, PR 11 cases), DCR 78.8% (SD 28 cases, PD 10 cases, NE 1 case), median PFS 8.6 months, and median OS 13.9 months. The PLR was suggested to be useful for predicting PFS. A decrease in CEA at six weeks after the start of treatment was a significant predictor of PFS and OS. Gallbladder cancer had a significantly poorer prognosis compared to other cancers. The immune-related adverse events included hypothyroidism in two cases, cholangitis in one case, and colitis in one case. Conclusions: The ORR, DCR, and PFS were comparable to those in the TOPAZ-1 trial. Although limited by its retrospective design and small sample size, this study suggests that GCD therapy is an effective treatment regimen for unresectable biliary tract cancer in real-world clinical practice. Full article

Immunotherapy has emerged as a transformative approach in gastrointestinal (GI) cancers, addressing historically poor survival rates in advanced-stage disease. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis demonstrate remarkable efficacy in colorectal cancer with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), exemplified by trials like NICHE-2 achieving exceptional pathological response rates. However, significant limitations persist, including resistance in some dMMR/MSI-H tumors, minimal efficacy in proficient mismatch repair (pMMR) tumors, and low overall response rates across most GI malignancies due to tumor heterogeneity and immune evasion mechanisms. Predictive biomarkers such as tumor mutational burden (TMB) and PD-L1 expression are crucial for optimizing patient selection, while hypermutated pMMR tumors with POLE mutations represent emerging therapeutic opportunities. In pancreatic adenocarcinoma, where survival remains dismal, combination strategies with chemotherapy and novel approaches like cancer vaccines show promise but lack transformative breakthroughs. Esophagogastric cancers benefit from ICIs combined with chemotherapy, particularly in MSI-H and HER2-positive tumors, while hepatocellular carcinoma has achieved significant progress with combinations like atezolizumab–bevacizumab and durvalumab–tremelimumab surpassing traditional therapies. Biliary tract cancers show modest improvements with durvalumab–chemotherapy combinations. Despite these advances, immunotherapy faces substantial challenges including immune-related adverse events, acquired resistance through cancer immunoediting, and the need for biomarker-driven approaches to overcome tumor microenvironment barriers. This review discusses key clinical trials, therapeutic progress, and emerging modalities including CAR T-cell therapies and combination strategies, emphasizing the critical need to address resistance mechanisms and refine precision medicine approaches to fully realize immunotherapy’s potential in GI malignancies. Full article

The 26th annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Saskatoon, Saskatchewan, on 17–18 October 2024. The WCGCCC is an interactive multidisciplinary conference that was attended by healthcare professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with hepatocellular and biliary tract cancers. Specialists from the fields of medical and radiation oncology, interventional radiology, pathology and laboratory medicine, and general and hepatobiliary surgery participated in presentations and discussions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of hepatocellular and biliary tract cancers. Full article

Gallbladder carcinoma (GBC) is one of the most aggressive malignancies of the biliary tract, often originating from chronic inflammation associated with gallstones and cholecystitis. Persistent inflammation plays a pivotal role in the development of preneoplastic changes, such as metaplasia, which may progress to malignancy. Despite its relatively low incidence, GBC is characterized by a poor prognosis due to late-stage diagnosis, highlighting the urgent need for improved early detection strategies. This study aimed to assess the diagnostic and prognostic significance of CA 19-9 and CEA levels in patients with gallbladder lesions, while also evaluating systemic inflammation and hemostatic dysregulation. A retrospective analysis was conducted on patients diagnosed with gallbladder lesions, with histopathological confirmation of adenocarcinoma and metaplasia. Laboratory assessments included serum levels of tumour markers, inflammatory markers such as CRP, and key hemostatic parameters, including thrombocyte count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen levels. A predictive scoring model was developed using the cutoff values of CA 19-9 and CEA to assess their combined diagnostic potential. Among the patients studied, 48.9% had an initial diagnosis of chronic cholecystitis, while 32.2% presented with acute cholecystitis. Adenocarcinoma was identified in 6.7% of cases after histopathological examination, predominantly in females over 65 years old with acute cholecystitis. Metaplasia was detected in 7.8% of cases, primarily in elderly females with chronic cholecystitis. Laboratory findings revealed significantly elevated levels of CA 19-9, CEA, AFP, and CA-125 in patients with adenocarcinoma. Additionally, abnormalities in hemostatic parameters, including increased fibrinogen levels and alterations in thrombocyte count, were observed in patients with malignancy. A combined predictive score using CA 19-9 and CEA demonstrated strong potential for detecting adenocarcinoma and metaplasia, improving diagnostic accuracy. Our findings emphasize the clinical importance of integrating tumour markers, inflammatory biomarkers, and hemostatic parameters in the evaluation of gallbladder lesions associated with chronic inflammation. The combined assessment of these factors enhances early detection, facilitates malignancy risk stratification, and improves prognostic evaluation, particularly in patients with metabolic and cardiovascular comorbidities. Full article