Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities.

BACKGROUND: Combined small-cell lung cancer (C-SCLC) is composed of SCLC admixed with a non-small-cell cancer component. They currently receive the same treatment as SCLC. The recent evidence that SCLC may belong to either of two lineages, neuroendocrine (NE) or non-NE, with different vulnerability to specific cell death pathways such as ferroptosis, opens new therapeutic opportunities also for C-SCLC. MATERIALS AND METHODS: Thirteen C-SCLCs, including five with adenocarcinoma (CoADC), five with large-cell neuroendocrine carcinoma (CoLCNEC) and three with squamous cell carcinoma (CoSQC) components, were assessed for alterations in 409 genes and transcriptomic profiling of 20 815 genes. RESULTS: All 13 cases harbored TP53 (12 cases) and/or RB1 (7 cases) inactivation, which was accompanied by mutated KRAS in 4 and PTEN in 3 cases. Potentially targetable alterations included two KRAS G12C, two PIK3CA and one EGFR mutations. Comparison of C-SCLC transcriptomes with those of 57 pure histology lung cancers (17 ADCs, 20 SQCs, 11 LCNECs, 9 SCLCs) showed that CoLCNEC and CoADC constituted a standalone group of NE tumors, while CoSQC transcriptional setup was overlapping that of pure SQC. Using transcriptional signatures of NE versus non-NE SCLC as classifier, CoLCNEC was clearly NE while CoSQC was strongly non-NE and CoADC exhibited a heterogeneous phenotype. Similarly, using ferroptosis sensitivity/resistance markers, CoSQC was classified as sensitive (as expected for non-NE), CoLCNEC as resistant (as expected for NE) and CoADC showed a heterogeneous pattern. CONCLUSIONS: These data support routine molecular profiling of C-SCLC to search for targetable driver alterations and to precisely classify them according to therapeutically relevant subgroups (e.g. NE versus non-NE).

[Dyspepsia and Helicobacter pylori]. / Dispepsia ed Helicobacter pylori.

Since Helicobacter pylori (Hp) was first isolated in 1983, much work has been carried out on the pathogenic effects of this organism. Hp infection is common in humans and currently is the most important etiologic agent in the development of chronic active gastritis, gastric and duodenal ulcers, carcinoma and Malt-lymphoma of the stomach. Moreover Hp infection has also been associated with various extradigestive diseases. At present, a role of Hp infection in dyspepsia is discussed. Dyspepsia is defined by persistence of pain, burning or discomfort localised to the upper abdomen; some authors include in dyspepsia symptoms such as belching, bloating, alitosis, nausea, postprandial repletion, vomiting and regurgitation. In absence of any underlying pathologies, such as peptic ulcer, gastroesophageal reflux, pancreatitis, biliary tract disease or others, dyspepsia is defined as functional or idiopathic dyspepsia. Functional dyspepsia may be distinct in ulcer, reflux or dysmotility-like dyspepsia and unspecified dyspepsia. Hp infection is common in dyspeptic patients and a role of this bacterium has been postulated mostly in ulcer-like dyspepsia. Mechanisms by when Hp induces dyspeptic symptoms are uncertain; bacterial cytotoxins, phlogosis mediators, activity of chronic gastritis Helicobacter-related and host immune response probably play an important role in pathogenesis of functional dyspepsia. However, dyspepsia is not present only in infected patients; therefore other pathogenic factors may be implicated in expression of dyspeptic symptoms in uninfected subjects, such as gastric dysmotility, modifications of gastric output or altered visceral sensibility, psychological factors, gastroesophageal reflux and irritable bowel.