Glucagon-like peptide-1 receptor agonist use is associated with a lower risk of major adverse liver-related outcomes: a meta-analysis of observational cohort studies

Background
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promising effects on liver histology in phase 2 trials enrolling patients with metabolic dysfunction-associated steatotic liver disease. However, the impact of GLP-1RAs on the long-term risk of major adverse liver-related outcomes (MALOs) remains uncertain.

Objective
We performed a meta-analysis of observational cohort studies to quantify the magnitude and direction of the association between GLP-1RA use and MALOs in people with type 2 diabetes (T2D).

Design
We systematically searched eligible cohort studies comparing GLP-1RA new users versus users of other glucose-lowering medications. The primary outcome was the cumulative incidence rates of MALOs. Secondary outcomes included hepatic decompensation events, hepatocellular carcinoma (HCC) and liver-related mortality. Random-effects models were used to calculate incidence rate ratios (IRRs).

Results
11 retrospective cohort studies with aggregate data on 1 467 220 patients with T2D (647 903 GLP-1RA new users, 819 317 non-users) were included. GLP-1RA use was significantly associated with a lower risk of MALOs (IRR 0.71, 95% CI 0.57 to 0.88) and hepatic decompensation (IRR 0.70, 95% CI 0.52 to 0.94). Association with reduced risk of HCC was also observed (IRR 0.82, 95% CI 0.61 to 1.11). Compared with other antidiabetic medications, GLP-1RAs showed superior effectiveness versus SGLT2 inhibitors in preventing MALOs (IRR 0.93, 95% CI 0.87 to 0.99), versus DPP-4 inhibitors in preventing hepatic decompensation (IRR 0.74, 95% CI 0.66 to 0.83) and versus insulin therapy in preventing HCC (IRR 0.32, 95% CI 0.13 to 0.80).

Conclusions
GLP-1RA use is associated with a lower risk of liver-related complications and hepatic decompensation in people with T2D. These findings suggest a role of GLP-1RAs in preventing liver-related complications beyond their beneficial cardiometabolic effects.

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Mutational signatures define immune and Wnt-associated subtypes of ampullary carcinoma

Background and objective
Ampullary carcinoma (AMPAC) taxonomy is based on morphology and immunohistochemistry. This classification lacks prognostic reliability and unique genetic associations. We applied an approach of integrative genomics characterising patients with AMPAC exploring molecular subtypes that may guide personalised treatments.

Design
We analysed the mutational landscapes of 170 patients with AMPAC. The discovery included 110 tumour/normal pairs and the validation comprised 60 patients. In a tumour subset, we interrogated the transcriptomes and DNA methylomes. Patients were stratified based on mutational signatures and associated with molecular and clinical features. To evaluate tumour and immune cellularity, 22 tumours were independently assessed histomorphologically and by digital pathology.

Results
We defined three patient clusters by mutational signatures independent of histomorphology. Cluster 1 (C1) was defined by spontaneous deamination of DNA 5-methylcytosine and defective mismatch repair. C2 and C3 were related to the activity of transcription-coupled nucleotide excision repair but C3 was further defined by the polymerase eta mutational process. C1–2 showed enrichment of Wnt pathway alterations, aberrant DNA methylation profiles, immune cell exclusion and patients with poor prognosis. These features were associated with a hypermutator phenotype caused by C >T alterations at CpGs. C3 patients with improved overall survival were associated with activation of immune-related pathways, immune infiltration and elevated expression of immunoinhibitory checkpoint genes.

Conclusion
Immunogenicity and Wnt pathway associations, emphasised by the mutational signatures, defined patients with prospective sensitivity to either immunotherapy or Wnt pathway inhibitors. This emphasises a novel mutational signature-based AMPAC classification with prognostic potential, suggesting prospective implications for subgroup-specific management of patients with AMPAC.

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Necessity of Surgery for Low-Risk Ductal Carcinoma In Situ of the Breast

Ductal carcinoma in situ (DCIS) is defined as “a neoplastic proliferation of cells within the ductal-lobular structures of the breast that has not penetrated the myoepithelial basement membrane interface.” DCIS is considered to be a nonobligate precursor to invasive cancer, such that the purpose of therapy is primarily to avoid the occurrence of invasive cancer. To achieve this end, DCIS has historically been treated in the same way as invasive breast cancer: surgery, often followed by radiation and antiestrogen therapy (if the DCIS is hormone receptor positive). Advances in mammography and the increasing use of magnetic resonance imaging for breast cancer screening have led to the detection of smaller, low-risk lesions. Growing evidence suggests that low-risk DCIS is unlikely to develop into invasive cancer, leading to a question of whether DCIS can be managed with active surveillance alone, thereby avoiding treatment-associated morbidity.

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Is It Time to Abandon Surgery for Low-Risk DCIS?

Ductal carcinoma in situ (DCIS) is considered a nonobligate precursor of invasive breast cancer. Surgery is thought to reduce this risk, as evidenced by studies demonstrating cause-specific survival of 97% to 98% after treatment with mastectomy or lumpectomy with or without radiotherapy. Invasive cancer is found at surgical excision in 26% of all women diagnosed with DCIS by core biopsy and in 20% of those with low- to intermediate-grade DCIS or lesions of 2 cm or smaller on mammography. Despite the apparent success of surgery, significant concerns about overtreatment of DCIS have been raised. The substantial increase in the detection of DCIS between 1992 and 2011 that coincided with the widespread adoption of screening mammography did not result in parallel reductions in invasive cancer detection or breast cancer mortality, suggesting that a proportion of the DCIS being identified would have never progressed to invasive cancer. The very high cause-specific survival after surgery and the limited knowledge of the evolution of untreated DCIS raises the possibility that similar excellent outcomes might be obtained with a less aggressive approach such as active monitoring, with surgery reserved for patients showing evidence of progression to invasive cancer; however, the safety of this approach is uncertain. Ideally, a subset of DCIS patients at low risk of progression to invasive cancer could be identified by molecular profiling, but at present, this goal remains aspirational.

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