Immunophenotypes of pancreatic ductal adenocarcinoma: Meta-analysis of transcriptional subtypes.

Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and has one of the highest mortality rates of any cancer type with a 5-year survival rate of <5%. Recent studies of PDAC have provided several transcriptomic classifications based on separate analyses of individual patient cohorts. There is a need to provide a unified transcriptomic PDAC classification driven by therapeutically relevant biologic rationale to inform future treatment strategies. Here, we used an integrative meta-analysis of 353 patients from four different studies to derive a PDAC classification based on immunologic parameters. This consensus clustering approach indicated transcriptomic signatures based on immune infiltrate classified as adaptive, innate and immune-exclusion subtypes. This reveals the existence of microenvironmental interpatient heterogeneity within PDAC and could serve to drive novel therapeutic strategies in PDAC including immune modulation approaches to treating this disease.This study was supported by the NIHR Oxford Biomedical Research Centre. CY is supported by a UK Medical Research Council Research Grant (MR/P02646X/1). MLD is funded by Wellcome Trust grant 100262Z/12/Z. SS is funded by a NIHR Academic Clinical Lecturership

Treatment and overall survival of four types of non-metastatic periampullary cancer:nationwide population-based cohort study

Background: Periampullary adenocarcinoma consists of pancreatic adenocarcinoma (PDAC), distal cholangiocarcinoma (DC), ampullary cancer (AC), and duodenal adenocarcinoma (DA). The aim of this study was to assess treatment modalities and overall survival by tumor origin. Methods: Patients diagnosed with non-metastatic periampullary cancer in 2012–2018 were identified from the Netherlands Cancer Registry. OS was studied with Kaplan–Meier analysis and multivariable Cox regression analyses, stratified by origin. Results: Among the 8758 patients included, 68% had PDAC, 13% DC, 12% AC, and 7% DA. Resection was performed in 35% of PDAC, 56% of DC, 70% of AC, and 59% of DA. Neoadjuvant and/or adjuvant therapy was administered in 22% of PDAC, 7% of DC, 7% of AC, and 12% of DA. Three-year OS was highest for AC (37%) and DA (34%), followed by DC (21%) and PDAC (11%). Adjuvant therapy was associated with improved OS among PDAC (HR = 0.62; 95% CI 0.55–0.69) and DC (HR = 0.69; 95% CI 0.48–0.98), but not AC (HR = 0.87; 95% CI 0.62–1.22) and DA (HR = 0.85; 95% CI 0.48–1.50). Conclusion: This retrospective study identified considerable differences in treatment modalities and OS between the four periampullary cancer origins in daily clinical practice. An improved OS after adjuvant chemotherapy could not be demonstrated in patients with AC and DA

Prophylactic Intra-Uterine β-Cyclodextrin Administration during Intra-Uterine Ureaplasma parvum Infection Partly Prevents Liver Inflammation without Interfering with the Enterohepatic Circulation of the Fetal Sheep

Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in β-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of β-sitosterol and campesterol dissolved in β-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + β-cyclodextrin, or β-cyclodextrin alone. In addition, IA administration of β-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier β-cyclodextrin did not have additional effects

Clinical-grade Detection of Microsatellite Instability in Colorectal Tumors by Deep Learning

Background and Aims: Microsatellite instability (MSI) and mismatch-repair deficiency (dMMR) in colorectal tumors are used to select treatment for patients. Deep learning can detect MSI and dMMR in tumor samples on routine histology slides faster and cheaper than molecular assays. But clinical application of this technology requires high performance and multisite validation, which have not yet been performed. Methods: We collected hematoxylin and eosin-stained slides, and findings from molecular analyses for MSI and dMMR, from 8836 colorectal tumors (of all stages) included in the MSIDETECT consortium study, from Germany, the Netherlands, the United Kingdom, and the United States. Specimens with dMMR were identified by immunohistochemistry analyses of tissue microarrays for loss of MLH1, MSH2, MSH6, and/or PMS2. Specimens with MSI were identified by genetic analyses. We trained a deep-learning detector to identify samples with MSI from these slides; performance was assessed by cross-validation (n=6406 specimens) and validated in an external cohort (n=771 specimens). Prespecified endpoints were area under the receiver operating characteristic (AUROC) curve and area under the precision-recall curve (AUPRC). Results: The deep-learning detector identified specimens with dMMR or MSI with a mean AUROC curve of 0.92 (lower bound 0.91, upper bound 0.93) and an AUPRC of 0.63 (range, 0.59–0.65), or 67% specificity and 95% sensitivity, in the cross-validation development cohort. In the validation cohort, the classifier identified samples with dMMR with an AUROC curve of 0.95 (range, 0.92–0.96) without image-preprocessing and an AUROC curve of 0.96 (range, 0.93–0.98) after color normalization. Conclusions: We developed a deep-learning system that detects colorectal cancer specimens with dMMR or MSI using hematoxylin and eosin-stained slides; it detected tissues with dMMR with an AUROC of 0.96 in a large, international validation cohort. This system might be used for high-throughput, low-cost evaluation of colorectal tissue specimens

The role of re-resection in recurrent hepatocellular carcinoma

PURPOSE: While liver resection is a well-established treatment for primary HCC, surgical treatment for recurrent HCC (rHCC) remains the topic of an ongoing debate. Thus, we investigated perioperative and long-term outcome in patients undergoing re-resection for rHCC in comparative analysis to patients with primary HCC treated by resection. METHODS: A monocentric cohort of 212 patients undergoing curative-intent liver resection for HCC between 2010 and 2020 in a large German hepatobiliary center were eligible for analysis. Patients with primary HCC (n = 189) were compared to individuals with rHCC (n = 23) regarding perioperative results by statistical group comparisons and oncological outcome using Kaplan-Meier analysis. RESULTS: Comparative analysis showed no statistical difference between the resection and re-resection group in terms of age (p = 0.204), gender (p = 0.180), ASA category (p = 0.346) as well as main preoperative tumor characteristics, liver function parameters, operative variables, and postoperative complications (p = 0.851). The perioperative morbidity (Clavien-Dindo ≥ 3a) and mortality were 21.7% (5/23) and 8.7% (2/23) in rHCC, while 25.4% (48/189) and 5.8% (11/189) in primary HCC, respectively (p = 0.851). The median overall survival (OS) and recurrence-free survival (RFS) in the resection group were 40 months and 26 months, while median OS and RFS were 41 months and 29 months in the re-resection group, respectively (p = 0.933; p = 0.607; log rank). CONCLUSION: Re-resection is technically feasible and safe in patients with rHCC. Further, comparative analysis displayed similar oncological outcome in patients with primary and rHCC treated by liver resection. Re-resection should therefore be considered in European patients diagnosed with rHCC

The role of re-resection in recurrent hepatocellular carcinoma

PURPOSE: While liver resection is a well-established treatment for primary HCC, surgical treatment for recurrent HCC (rHCC) remains the topic of an ongoing debate. Thus, we investigated perioperative and long-term outcome in patients undergoing re-resection for rHCC in comparative analysis to patients with primary HCC treated by resection. METHODS: A monocentric cohort of 212 patients undergoing curative-intent liver resection for HCC between 2010 and 2020 in a large German hepatobiliary center were eligible for analysis. Patients with primary HCC (n = 189) were compared to individuals with rHCC (n = 23) regarding perioperative results by statistical group comparisons and oncological outcome using Kaplan–Meier analysis. RESULTS: Comparative analysis showed no statistical difference between the resection and re-resection group in terms of age (p = 0.204), gender (p = 0.180), ASA category (p = 0.346) as well as main preoperative tumor characteristics, liver function parameters, operative variables, and postoperative complications (p = 0.851). The perioperative morbidity (Clavien-Dindo ≥ 3a) and mortality were 21.7% (5/23) and 8.7% (2/23) in rHCC, while 25.4% (48/189) and 5.8% (11/189) in primary HCC, respectively (p = 0.851). The median overall survival (OS) and recurrence-free survival (RFS) in the resection group were 40 months and 26 months, while median OS and RFS were 41 months and 29 months in the re-resection group, respectively (p = 0.933; p = 0.607; log rank). CONCLUSION: Re-resection is technically feasible and safe in patients with rHCC. Further, comparative analysis displayed similar oncological outcome in patients with primary and rHCC treated by liver resection. Re-resection should therefore be considered in European patients diagnosed with rHCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00423-022-02545-1

The prognostic role of in-hospital transfusion of fresh frozen plasma in patients with cholangiocarcinoma undergoing curative-intent liver surgery

INTRODUCTION: Major hepatectomy for perihilar and intrahepatic cholangiocarcinoma (CCA) is often associated with a significant intraoperative blood loss and the requirement for perioperative transfusion of blood products. The aim of this study was to investigate the oncological impact of fresh frozen plasma (FFP) transfusion during hospitalization in patients undergoing hepatectomy for CCA as adverse effects have been described in other malignancies. MATERIAL AND METHODS: Patients undergoing hepatectomy for CCA from 2010 to 2019 at a single institution were eligible for this study. Survival analysis was carried out according to Kaplan-Meier and the associations of cancer-specific (CSS) and recurrence-free survival (RFS) with in-hospital application of FFP and other clinico-pathological characteristics were assessed using Cox regression models. Perioperatively deceased patients were excluded from the analysis. RESULTS: A total of 219 CCA patients were included in this survival analysis of which 53.0% (116/219) received FFP during hospitalization. Patients receiving in-hospital FFP showed a median CCS of 33 months (3-year-CSS = 46%, 5-year-CSS = 29%) compared to 83 months (3-year-CSS = 55%, 5-year-CSS = 53%) in patients who did not receive in-hospital FFP (p = 0.006 log rank). Further, in-hospital FFP was identified as an independent predictor of oncological outcome in multivariable analysis (CSS: HR = 1.71, p = 0.016; RFS: HR = 1.89, p = 0.003). CONCLUSION: In a large European cohort of patients, in-hospital transfusion of FFP was identified as a novel independent prognostic marker in CCA patients undergoing curative-intent liver surgery. A restrictive transfusion policy is therefore recommended to improve long-term outcome in these patients

Erratum to: ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density

Albert Dahan, Ann Dunne, Maarten Swartjes, Paolo L Proto, Lara Heij, Oscar Vogels, Monique van Velzen, Elise Sarton, Marieke Niesters, Martijn R Tannemaat, Anthony Cerami, and Michael Brines. (2013) ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density. Mol. Med. 19:334–45

Predicting Mutational Status of Driver and Suppressor Genes Directly from Histopathology With Deep Learning:A Systematic Study Across 23 Solid Tumor Types

In the last four years, advances in Deep Learning technology have enabled the inference of selected mutational alterations directly from routine histopathology slides. In particular, recent studies have shown that genetic changes in clinically relevant driver genes are reflected in the histological phenotype of solid tumors and can be inferred by analysing routine Haematoxylin and Eosin (H&E) stained tissue sections with Deep Learning. However, these studies mostly focused on selected individual genes in selected tumor types. In addition, genetic changes in solid tumors primarily act by changing signaling pathways that regulate cell behaviour. In this study, we hypothesized that Deep Learning networks can be trained to directly predict alterations of genes and pathways across a spectrum of solid tumors. We manually outlined tumor tissue in H&E-stained tissue sections from 7,829 patients with 23 different tumor types from The Cancer Genome Atlas. We then trained convolutional neural networks in an end-to-end way to detect alterations in the most clinically relevant pathways or genes, directly from histology images. Using this automatic approach, we found that alterations in 12 out of 14 clinically relevant pathways and numerous single gene alterations appear to be detectable in tissue sections, many of which have not been reported before. Interestingly, we show that the prediction performance for single gene alterations is better than that for pathway alterations. Collectively, these data demonstrate the predictability of genetic alterations directly from routine cancer histology images and show that individual genes leave a stronger morphological signature than genetic pathways