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Multiple Endocrine Neoplasia type 1 (MEN1) Clinical Practice Guidelines (2012) are predominantly based on expert opinion due to limited available evidence at the time, leaving room for interpretation and variation in practices. Evidence on the natural course of MEN1-related neuroendocrine tumours (NET) and the value of screening programs has increased and new imaging techniques have emerged. The aim of this study is to provide insight in the current practices of screening and surveillance for MEN1-related NETs in ENETS Centers of Excellence (CoEs). A clinical practice questionnaire was distributed among all 65 ENETS CoEs. Response rate was 91% (59/65). In 14% of CoEs <10 patients, in 50% 10-49, in 31% 50-100 and in 3 centres (5%) >100 patients with MEN1 are seen. Practices with regard to screening and surveillance of NETs were markedly heterogeneous. Differences between countries were noted in the use of gut hormones for biochemical screening and the choice for imaging modality for screening/surveillance of pancreatic NETs (PanNETs). Magnetic resonance imaging (MRI) is the preferred modality for screening and surveillance of PanNETs, whereas this is computed tomography (CT) for thoracic NETs. Practices regarding screening for thoracic NETs were more homogeneous among larger volume CoEs, with longer screening intervals. The majority of CoEs tailored the surveillance of small pancreatic and lung NETs to observed growth rate. 68% of CoEs advise patients with clinical MEN1 with negative genetic testing to undergo periodic screening like mutation-positive patients. In conclusion, there is still marked heterogeneity in practice, although there are also common trends. Differences were sometimes associated with volume or country, but often no association was found. This underscores the need for clear and evidence-based practice recommendations., (© 2024 The Author(s). Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Many pancreatic neuroendocrine tumors (PanNETs) fall into 2 major prognostic subtypes based on DAXX/ATRX-induced alternative lengthening of telomerase phenotype and alpha- and beta-cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well-characterized in terms of their histologic and hormonal phenotypes. We aimed to identify new subgroups of PanNETs by extending the currently used transcription factor signatures and investigating their correlation with histologic, hormonal, molecular, and prognostic findings. One hundred eighty-five PanNETs (nonfunctioning 165 and functioning 20), resected between 1996 and 2023, were classified into 5 subgroups (A1, A2, B, C, and D) by cluster analysis based on ARX, PDX1, islet-1 (ISL1), and CDX2 expressions and correlated with trabecular vs solid histology, expression of insulin, glucagon, polypeptide (PP), somatostatin, serotonin, gastrin, calcitonin, adrenocorticotropic hormone (ACTH), DAXX/ATRX, MEN1, and alternative lengthening of telomerase status by fluorescence in situ hybridization, and disease-free survival. A1 (46%, ARX+/ISL1+/PDX1-/CDX2-) and A2 (15%, ARX+/ISL1+/PDX1+/CDX2-) showed trabecular histology and glucagon/PP expression, with A2 also showing gastrin expression. B (18%, PDX1+/ISL1+/ARX-/CDX2-) showed solid histology, insulin, and somatostatin expression (P < .001). It included all insulinomas and had the best outcome (P < .01). C (15%, ARX-/PDX1-/ISL1-/CDX2-) showed solid histology and frequent expression of serotonin, calcitonin, and ACTH. D (5%, PDX1+/CDX2+/ISL1-/ARX-) showed solid histology, expressed ACTH/serotonin, and was an independent poor prognosticator (P < .01). Differential expressions of ARX, PDX1, ISL1, and CDX2 stratified PanNETs into 5 subgroups with different histologies, hormone expressions, and outcomes. Subgroups A1 and A2 resembled the alpha-cell-like type, and subgroup B, the beta-cell-like type. Subgroup C with almost no transcription factor signature was unclear in cell lineage, whereas the PDX+/CDX2+ signature of subgroup D suggested a pancreatic/intestinal cell lineage. Assigning PanNETs to the subgroups may help establish the diagnosis, predict the outcome, and guide the treatment., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy., (© 2024 The Author(s). Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is considered a low-immunogenic (LI) tumor with a "cold" tumor microenvironment and is mostly unresponsive to immune checkpoint blockade therapies. In this study, we decipher the impact of intratumoral heterogeneity of immune determinants on antitumor responses., Experimental Design: We performed spatial proteomic and transcriptomic analyses and multiplex immunofluorescence on multiple tumor regions, including tumor center (TC) and invasive front (IF), from 220 patients with PDAC, classified according to their transcriptomic immune signaling into high-immunogenic PDAC (HI-PDAC, n = 54) and LI PDAC (LI-PDAC, n = 166). Spatial compartments (tumor: pancytokeratin+/CD45- and leukocytes: pancytokeratin-/CD45+) were defined by fluorescence imaging., Results: HI-PDAC exhibited higher densities of cytotoxic T lymphocytes with upregulation of T-cell priming-associated immune determinants, including CD40, ITGAM, glucocorticoid-induced TNF-related receptor, CXCL10, granzyme B, IFNG, and HLA-DR, which were significantly more prominent at the IF than at the TC. In contrast, LI-PDAC exhibited immune-evasive tumor microenvironments with downregulation of immune determinants and a negative gradient from TC to IF. Patients with HI-PDAC had significantly better outcomes but showed more frequently exhausted immune phenotypes., Conclusions: Our results indicate strategic differences in the regulation of immune determinants, leading to different levels of effectiveness of antitumor responses between HI and LI tumors and dynamic spatial changes, which affect the evolution of immune evasion and patient outcomes. This finding supports the coevolution of tumor and immune cells and may help define therapeutic vulnerabilities to improve antitumor immunity and harness the responsiveness to immune checkpoint inhibitors in patients with PDAC., (©2024 American Association for Cancer Research.)

Background: Chemotherapy has limited efficacy in advanced digestive high-grade neuroendocrine neoplasms (HG-NEN) and prognosis is dismal. Predictive markers for palliative chemotherapy are lacking, and prognostic markers are limited., Methods: Digestive HG-NEN patients (n = 229) were prospectively included 2013-2017. Pathological re-assessment revealed 188 neuroendocrine carcinomas (NEC) and 41 neuroendocrine tumours (NET G3). Tumour-DNA was sequenced across 360 cancer-related genes, assessing mutations (mut) and copy number alterations. We linked sequencing results to clinical information and explored potential markers for first-line chemotherapy efficacy and survival., Results: In NEC given cis/carboplatin and etoposide (PE), TP53mut predicted inferior response rate in multivariate analyses (p = 0.009) and no BRAFmut NEC showed response. In overall assessment of PE-treated NEC, no genetic alterations were prognostic for OS. For small-cell NEC, TP53mut were associated with longer OS (p = 0.011) and RB1 deletions predicted lack of immediate-progression (p = 0.003). In non-small cell NEC, APC mut were associated with immediate-progression and shorter PFS (p = 0.008/p = 0.004). For NET G3, ATRXmut, ARID1A- and ERS1 deletions were associated with shorter PFS., Conclusion: Correlations between genetic alterations and response/immediate-progression to PE were frequent in NEC but affected PFS or OS only when subdividing for cell-type. The classification of digestive NEC into large- and small-cell seems therefore molecularly and clinically relevant., (© 2024. The Author(s).)

Histological analysis is the core of follicular thyroid carcinoma (FTC) classification. The histopathological criteria of capsular and vascular invasion define malignancy and aggressiveness of FTC. Analysis of multiple sections is cumbersome and as only a minute tissue fraction is analyzed during histopathology, under-sampling remains a problem. Application of an efficient tool for complete tissue imaging in 3D would speed-up diagnosis and increase accuracy. We show that X-ray propagation-based imaging (XPBI) of paraffin-embedded tissue blocks is a valuable complementary method for follicular thyroid carcinoma diagnosis and assessment. It enables a fast, non-destructive and accurate 3D virtual histology of the FTC resection specimen. We demonstrate that XPBI virtual slices can reliably evaluate capsular invasions. Then we discuss the accessible morphological information from XPBI and their significance for vascular invasion diagnosis. We show 3D morphological information that allow to discern vascular invasions. The results are validated by comparing XPBI images with clinically accepted histology slides revised by and under supervision of two experienced endocrine pathologists.

Traditionally considered non-functional low proliferative benign neuroendocrine proliferations measuring less than 5 mm, pancreatic (neuro)endocrine microadenomas are now classified as pancreatic neuroendocrine microtumors in the 2022 WHO classification of endocrine and neuroendocrine tumors. This case report discussed the features of an incidentally identified 4.7-mm glucagon-expressing pancreatic neuroendocrine microtumor with MEN1 mutation only, chromosomally stable and an epigenetic alpha-like phenotype. The tumor was associated with an unexplained increased proliferation rate in Ki-67 of 15%. There was no associated DAXX/ATRX deficiency. The presented case challenges the conventional thought of a low proliferative disease of the so-called "pancreatic neuroendocrine microadenomas" and provides additional support to the 2022 WHO classification that also requires grading of these neoplasms. Despite exhibiting molecular features of less aggressive behavior, the case also underscores the biological complexity of pancreatic neuroendocrine microtumors. By recognizing the heterogenous spectrum of neuroendocrine neoplasms, the current case also contributes to ongoing discussions on how to optimize the clinical management of such tumors., (© 2024. The Author(s).)

Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed "primary hyperplasia". Whether these tumors represent a multi-glandular clonal disease or hyperplasia has not been robustly proven so far. Loss of Menin protein expression is associated with inactivation of both alleles and a good surrogate for a MEN1 gene mutation. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene is mutated in MEN4 and encodes for protein p27 whose expression is poorly studied in the syndromic MEN1 setting.Here, we analyzed histomorphology and protein expression of Menin and p27 in parathyroid adenomas of 25 patients of two independent, well-characterized MEN1 cohorts. The pattern of loss of heterozygosity (LOH) was assessed by fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Further, next-generation sequencing (NGS) was performed on eleven nodules of four MEN1 patients.Morphologically, the majority of MEN1 adenomas consisted of multiple distinct nodules, in which Menin expression was mostly lost and p27 protein expression reduced. FISH analysis revealed that most nodules exhibited MEN1 loss, with or without the loss of centromere 11. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors.Syndromic MEN1 parathyroid adenomas therefore consist of multiple clones with subclones, which supports the current concept of the novel WHO classification of parathyroid tumors (2022). p27 expression was lost in a large fraction of MEN1 parathyroids and must therefore be used with caution in suggesting MEN4., (© 2024. The Author(s).)

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients' clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses.PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5 A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN., (© 2024. The Author(s).)

Background and Aim: The coronavirus disease 2019 (COVID-19) outbreak deeply affected intensive care units (ICUs). We aimed to explore the main changes in the distribution and characteristics of Swiss ICU patients during the first two COVID-19 waves and to relate these figures with those of the preceding two years., Methods: Using the national ICU registry, we conducted an exploratory study to assess the number of ICU admissions in Switzerland and their changes over time, characteristics of the admissions, the length of stay (LOS) and its trend over time, ICU mortality and changes in therapeutic nursing workload and hospital resources in 2020 and compare them with the average figures in 2018 and 2019., Results: After analysing 242,935 patient records from all 84 certified Swiss ICUs, we found a significant decrease in admissions (-9.6%, corresponding to -8005 patients) in 2020 compared to 2018/2019, with an increase in the proportion of men admitted (61.3% vs 59.6%; p <0.001). This reduction occurred in all Swiss regions except Ticino. Planned admissions decreased from 25,020 to 22,021 in 2020 and mainly affected the neurological/neurosurgical (-14.9%), gastrointestinal (-13.9%) and cardiovascular (-9.3%) pathologies. Unplanned admissions due to respiratory diagnoses increased by 1971 (+25.2%), and those of patients with acute respiratory distress syndrome (ARDS) requiring isolation reached 9973 (+109.9%). The LOS increased by 20.8% from 2.55 ± 4.92 days (median 1.05) in 2018/2019 to 3.08 ± 5.87 days (median 1.11 days; p <0.001), resulting in an additional 19,753 inpatient days. The nine equivalents of nursing manpower use score (NEMS) of the first nursing shift (21.6 ± 9.0 vs 20.8 ± 9.4; p <0.001), the total NEMS per patient (251.0 ± 526.8 vs 198.9 ± 413.8; p <0.01) and mortality (5.7% vs 4.7%; p <0.001) increased in 2020. The number of ICU beds increased from 979 to 1012 (+3.4%), as did the number of beds equipped with mechanical ventilators (from 773 to 821; +6.2%)., Conclusions: Based on a comprehensive national data set, our report describes the profound changes triggered by COVID-19 over one year in Swiss ICUs. We observed an overall decrease in admissions and a shift in admission types, with fewer planned hospitalisations, suggesting the loss of approximately 3000 elective interventions. We found a substantial increase in unplanned admissions due to respiratory diagnoses, a doubling of ARDS cases requiring isolation, an increase in ICU LOS associated with substantial nationwide growth in ICU days, an augmented need for life-sustaining therapies and specific therapeutic resources and worse outcomes.

Pancreatic neuroendocrine neoplasms (PanNEN) are rather rare entities. Morphology, combined with immunohistochemistry, allows typing and grading, thereby leading therapeutic decisions. Depending on tumor stage and differential diagnosis, a broad diagnostic panel may be required. The present work summarizes the minimal diagnostic, prognostic, and predictive markers in PanNEN.Markers of choice for defining a neuroendocrine phenotype are synaptophysin, chromogranin A, and INSM1. The proliferation fraction Ki67 is indispensable for grading, while p53 and Rb1 can help in the differentiation from neuroendocrine carcinoma (NEC). Transcription factors, such as cdx2, TTF‑1, and Islet‑1, can indicate the site of a primary tumor in the setting of a cancer of unknown primary (CUP). DAXX/ATRX immunohistochemistry has mainly prognostic value. Molecular pathology studies currently have little practical value in the diagnosis of PanNEN.An important pitfall in routine diagnostics is the wide spectrum of differential diagnoses mimicking neuroendocrine neoplasms. An expanded immunohistochemical panel is strongly recommended in case of doubt., (© 2024. The Author(s).)

The tall cell subtype (TC-PTC) is an aggressive subtype of papillary thyroid carcinoma (PTC). The TC-PTC is defined as a PTC comprising at least 30% epithelial cells that are three times as tall as they are wide. In practice, this definition is difficult to adhere to, resulting in high inter-observer variability. In this multicenter study, we validated a previously trained deep learning (DL)-based algorithm for detection of tall cells on 160 externally collected hematoxylin and eosin (HE)-stained PTC whole-slide images. In a test set of 360 manual annotations of regions of interest from 18 separate tissue sections in the external dataset, the DL-based algorithm detected TCs with a sensitivity of 90.6% and a specificity of 88.5%. The DL algorithm detected non-TC areas with a sensitivity of 81.6% and a specificity of 92.9%. In the validation datasets, 20% and 30% TC thresholds correlated with a significantly shorter relapse-free survival. In conclusion, the DL algorithm detected TCs in unseen, external scanned HE tissue slides with high sensitivity and specificity without any retraining., Competing Interests: Johan Lundin is a co-founder and board member, and Mikael Lundin is a co-founder and director of concept design at Aiforia Technologies Oy, Helsinki Finland., (© 2024 The Authors.)

Synoptic reporting increases completeness and standardization of surgical pathology reports and thereby contributes to an increased quality of clinical cancer care. Nevertheless, its widespread practical implementation remains a challenge, which is in part related to the effort required for setup and maintenance of database structures. This prompted us to assess the effect of a simple template-based, database-free system for synoptic reporting on completeness of surgical pathology reports. For this purpose, we analyzed 200 synoptic reports (100 colon and 100 lung cancer resections each) for completeness as required by the pertinent College of American Pathologists (CAP) protocols and compared these to a control dataset of 200 narrative reports. Introduction of template-based synoptic reporting resulted in improved completeness (98% of mandatory data elements) as compared to narrative reports (77%). Narrative reports showed a high degree of completeness for data elements covered by previously existing dictation templates. In conclusion, template-based synoptic reporting without underlying database structure can be a useful transitory phase in the implementation of synoptic reporting. It can result in a similar degree of completeness as reported in the literature for database solutions and provides other benefits of synoptic reporting while facilitating its implementation., (© 2023. The Author(s).)

This ENETS guidance paper for well-differentiated nonfunctioning pancreatic neuroendocrine tumours (NF-Pan-NET) has been developed by a multidisciplinary working group, and provides up-to-date and practical advice on the management of these tumours. Using the extensive experience of centres treating patients with NF-Pan-NEN, the authors of this guidance paper discuss 10 troublesome questions in everyday clinical practice. Our many years of experience in this field are still being verified in the light of the results of new clinical, which set new ways of proceeding in NEN. The treatment of NF-Pan-NEN still requires a decision of a multidisciplinary team of specialists in the field of neuroendocrine neoplasms., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Background: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients., Methods: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m 2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed., Results: For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment., Conclusion: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL., Clinical Trial Registration: ClinicalTrials.gov (NTC02248012)., (© 2023. The Author(s).)

Tumor cell fraction (TCF) estimation is a common clinical task with well-established large interobserver variability. It thus provides an ideal test bed to evaluate potential impacts of employing a tumor cell fraction computer-aided diagnostic (TCFCAD) tool to support pathologists' evaluation. During a National Slide Seminar event, pathologists (n = 69) were asked to visually estimate TCF in 10 regions of interest (ROIs) from hematoxylin and eosin colorectal cancer images intentionally curated for diverse tissue compositions, cellularity, and stain intensities. Next, they re-evaluated the same ROIs while being provided a TCFCAD-created overlay highlighting predicted tumor vs nontumor cells, together with the corresponding TCF percentage. Participants also reported confidence levels in their assessments using a 5-tier scale, indicating no confidence to high confidence, respectively. The TCF ground truth (GT) was defined by manual cell-counting by experts. When assisted, interobserver variability significantly decreased, showing estimates converging to the GT. This improvement remained even when TCFCAD predictions deviated slightly from the GT. The standard deviation (SD) of the estimated TCF to the GT across ROIs was 9.9% vs 5.8% with TCFCAD (P < .0001). The intraclass correlation coefficient increased from 0.8 to 0.93 (95% CI, 0.65-0.93 vs 0.86-0.98), and pathologists stated feeling more confident when aided (3.67 ± 0.81 vs 4.17 ± 0.82 with the computer-aided diagnostic [CAD] tool). TCFCAD estimation support demonstrated improved scoring accuracy, interpathologist agreement, and scoring confidence. Interestingly, pathologists also expressed more willingness to use such a CAD tool at the end of the survey, highlighting the importance of training/education to increase adoption of CAD systems., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Polarimetry is an optical characterization technique capable of analyzing the polarization state of light reflected by materials and biological samples. In this study, we investigate the potential of Müller matrix polarimetry (MMP) to analyze fresh pancreatic tissue samples. Due to its highly heterogeneous appearance, pancreatic tissue type differentiation is a complex task. Furthermore, its challenging location in the body makes creating direct imaging difficult. However, accurate and reliable methods for diagnosing pancreatic diseases are critical for improving patient outcomes. To this end, we measured the Müller matrices of ex-vivo unfixed human pancreatic tissue and leverage the feature-learning capabilities of a machine-learning model to derive an optimized data representation that minimizes normal-abnormal classification error. We show experimentally that our approach accurately differentiates between normal and abnormal pancreatic tissue. This is, to our knowledge, the first study to use ex-vivo unfixed human pancreatic tissue combined with feature-learning from raw Müller matrix readings for this purpose., (© 2023. Springer Nature Limited.)

A 44-year-old female patient with a familial adenomatous polyposis (FAP) was diagnosed with a cribriform morular thyroid carcinoma (CMTC). We observed within the very necrotic tumor a small but distinct poorly differentiated carcinomatous component. As expected, next generation sequencing of both components revealed a homozygous APC mutation and in addition, a TERT promoter mutation. A TP53 mutation was found exclusively in the CMTC part, while the poorly differentiated component showed a clonal evolution, harboring an activating PIK3CA mutation and copy number gains of BRCA2, FGF23, FGFR1, and PIK3CB-alterations which are typically seen in squamous cell carcinoma. The mutational burden in both components was low, and there was no evidence for microsatellite instability. No mutations involving the mitogen-activated protein kinase (MAPK) pathway, typically seen in papillary thyroid carcinomas, were detected. Immunohistochemically, all tumor parts were negative for thyroglobulin, providing further evidence that this entity does not belong to the follicular epithelial cell-derived thyroid carcinoma group. CD5 was negative in the poorly differentiated component, making a relation to intrathyroidal thymic carcinoma rather unlikely. However, since this marker was seen in the morules, a loss in the poorly differentiated component and a relation to the ultimobranchial body cannot be excluded either. After total thyroidectomy and radioiodine ablation, the patient was disease-free with no residual tumor burden on 2-year follow-up., (© 2023. The Author(s).)

High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.

Objective: Most patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence., Design: PDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung (n=49/17%), local (n=31/11%), peritoneal (n=38/13%) and no-recurrence (n=73/26%). Spatial compartments were identified by fluorescent imaging as: pancytokeratin (PanCK) + CD45 - (tumour cells); CD45 + PanCK - (leucocytes) and PanCK - CD45 - (stromal cells), followed by transcriptomic (72 genes) and proteomic analysis (51 proteins) for immune pathway targets. Results from next-generation sequencing (n=194) were integrated. Finally, 10 tumours from each group underwent immunophenotypic analysis by multiplex immunofluorescence. A validation cohort (n=109) was examined in parallel., Results: No-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin + fibroblasts. PDACs with liver and/or peritoneal recurrences display low immunogenicity, stemness phenotype and innate immune responses, whereas those with peritoneal metastases are additionally rich in FAP + fibroblasts. PDACs with local and/or lung recurrences display interferon-gamma signalling and mixed adaptive and innate immune responses, but with different leading immune cell population. Tumours with local recurrences overexpress dendritic cell markers whereas those with lung recurrences neutrophilic markers. Except the exclusive presence of RNF43 mutations in the no-recurrence group, no genetic differences were seen. The no-recurrence group exhibited the best, whereas liver and peritoneal recurrences the poorest prognosis., Conclusions: Our findings demonstrate distinct inflammatory/stromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvant/neoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

This ENETS guidance paper aims to provide practical advice to clinicians for the diagnosis, treatment and follow-up of functioning syndromes in pancreatic neuroendocrine tumours (NET). A NET-associated functioning syndrome is defined by the presence of a clinical syndrome combined with biochemical evidence of inappropriately elevated hormonal levels. Different hormonal syndromes can be encountered in pancreatic NET patients, including insulinoma, gastrinoma as well as the rare glucagonoma, VIPoma, ACTHoma, PTHrPoma, carcinoid syndrome, calcitoninoma, GHRHoma and somatostatinoma. The recommendations provided in this paper focus on the biochemical, genetic and imaging work-up as well as therapeutic management of the individual hormonal syndromes in well-differentiated, grade 1-3, functioning NET with the primary tumour originating in the pancreas, and for specific subtypes also in the duodenum., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Endogenous hyperinsulinemic hypoglycemia (EHH) is a rare condition with an incidence of approximately 4-6 per million person-years and comprises a group of disorders causing hyperinsulinemic hypoglycemia without exogenous administration of insulin or its secretagogues. In adults, most cases (approximately 90%) are secondary to a single insulinoma. Other causes include insulinoma in the context of multiple endocrine neoplasia type 1 (approximately 5% of cases) and non-insulinoma pancreatogenous hypoglycemia syndrome, which is estimated to account for 0.5-5% of all cases. Recently, an entity called insulinomatosis has been described as a novel cause of EHH in adults. The characteristic feature of insulinomatosis is the synchronous or metachronous occurrence of multiple pancreatic neuroendocrine tumors expressing exclusively insulin. While most cases arise sporadically, there is recent evidence that autosomal dominant inheritance of mutations in the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) gene can cause a familial form of insulinomatosis. In these families, EHH is paradoxically associated with the occurrence of diabetes mellitus within the same family. This review summarizes the current clinical, biochemical, imaging and genetic knowledge of this disease.

Background: In patients with neuroendocrine liver metastasis (NELM), liver transplantation (LT) is an alternative to liver resection (LR), although the choice of therapy remains controversial. In this multicenter study, we aim to provide novel insight in this dispute., Methods: Following a systematic literature search, 15 large international centers were contacted to provide comprehensive data on their patients after LR or LT for NELM. Survival analyses were performed with the Kaplan-Meier method, while multivariable Cox regression served to identify factors influencing survival after either transplantation or resection. Inverse probability weighting and propensity score matching was used for analyses with balanced and equalized baseline characteristics., Results: Overall, 455 patients were analyzed, including 230 after LR and 225 after LT, with a median follow-up of 97 months [95% confidence interval (CI): 85-110 months]. Multivariable analysis revealed G3 grading as a negative prognostic factor for LR [hazard ratio (HR)=2.22, 95% CI: 1.04-4.77, P =0.040], while G2 grading (HR=2.52, 95% CI: 1.15-5.52, P =0.021) and LT outside Milan criteria (HR=2.40, 95% CI: 1.16-4.92, P =0.018) were negative prognostic factors in transplanted patients. Inverse probability-weighted multivariate analyses revealed a distinct survival benefit after LT. Matched patients presented a median overall survival (OS) of 197 months (95% CI: 143-not reached) and a 73% 5-year OS after LT, and 119 months (95% CI: 74-133 months) and a 52.8% 5-year OS after LR (HR=0.59, 95% CI: 0.3-0.9, P =0.022). However, the survival benefit after LT was lost if patients were transplanted outside Milan criteria., Conclusions: This multicentric study in patients with NELM demonstrates a survival benefit of LT over LR. This benefit depends on adherence to selection criteria, in particular low-grade tumor biology and Milan criteria, and must be balanced against potential risks of LT., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objectives: Contribution margin per hour (CMH) has been proposed in healthcare systems to increase the profitability of operating suites. The aim of our study is to propose a simple and reproducible model to calculate CMH and to increase cost-effectiveness., Methods: For the ten most commonly performed surgical procedures at our Institution, we prospectively collected their diagnosis-related group (DRG) reimbursement, variable costs and mean procedural time. We quantified the portion of total staffed operating room time to be reallocated with a minimal risk of overrun. Moreover, we calculated the total CMH with a random reallocation on a first come-first served basis. Finally, prioritizing procedures with higher CMH, we ran a simulation by calculating the total CMH., Results: Over a two-months period, we identified 14.5 hours of unutilized operating room to reallocate. In the case of a random "first come-first serve" basis, the total earnings were 87,117 United States dollars (USD). Conversely, with a reallocation which prioritized procedures with a high CMH, it was possible to earn 140,444 USD (p < 0.001)., Conclusion: Surgical activity may be one of the most profitable activities for hospitals, but a cost-effective management requires a comprehension of its cost profile. Reallocation of unused operating room time according to CMH may represent a simple, reproducible and reliable tool for elective cases on a waiting list. In our experience, it helped improving the operating suite cost-effectiveness., (Copyright © 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier España, S.L.U. All rights reserved.)

Screening of lymph node metastases in colorectal cancer (CRC) can be a cumbersome task, but it is amenable to artificial intelligence (AI)-assisted diagnostic solution. Here, we propose a deep learning-based workflow for the evaluation of CRC lymph node metastases from digitized hematoxylin and eosin-stained sections. A segmentation model was trained on 100 whole-slide images (WSIs). It achieved a Matthews correlation coefficient of 0.86 (±0.154) and an acceptable Hausdorff distance of 135.59 μm (±72.14 μm), indicating a high congruence with the ground truth. For metastasis detection, 2 models (Xception and Vision Transformer) were independently trained first on a patch-based breast cancer lymph node data set and were then fine-tuned using the CRC data set. After fine-tuning, the ensemble model showed significant improvements in the F1 score (0.797-0.949; P <.00001) and the area under the receiver operating characteristic curve (0.959-0.978; P <.00001). Four independent cohorts (3 internal and 1 external) of CRC lymph nodes were used for validation in cascading segmentation and metastasis detection models. Our approach showed excellent performance, with high sensitivity (0.995, 1.0) and specificity (0.967, 1.0) in 2 validation cohorts of adenocarcinoma cases (n = 3836 slides) when comparing slide-level labels with the ground truth (pathologist reports). Similarly, an acceptable performance was achieved in a validation cohort (n = 172 slides) with mucinous and signet-ring cell histology (sensitivity, 0.872; specificity, 0.936). The patch-based classification confidence was aggregated to overlay the potential metastatic regions within each lymph node slide for visualization. We also applied our method to a consecutive case series of lymph nodes obtained over the past 6 months at our institution (n = 217 slides). The overlays of prediction within lymph node regions matched 100% when compared with a microscope evaluation by an expert pathologist. Our results provide the basis for a computer-assisted diagnostic tool for easy and efficient lymph node screening in patients with CRC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Lipid metabolism plays an important role in liver pathophysiology. The liver lobule asymmetrically distributes oxygen and nutrition, resulting in heterogeneous metabolic functions. Periportal and pericentral hepatocytes have different metabolic functions, which lead to generating liver zonation. We developed spatial metabolic imaging using desorption electrospray ionisation mass spectrometry to investigate lipid distribution across liver zonation with high reproducibility and accuracy., Methods: Fresh frozen livers from healthy mice with control diet were analysed using desorption electrospray ionisation mass spectrometry imaging. Imaging was performed at 50 μm × 50 μm pixel size. Regions of interest (ROIs) were manually created by co-registering with histological data to determine the spatial hepatic lipids across liver zonation. The ROIs were confirmed by double immunofluorescence. The mass list of specific ROIs was automatically created, and univariate and multivariate statistical analysis were performed to identify statistically significant lipids across liver zonation., Results: A wide range of lipid species was identified, including fatty acids, phospholipids, triacylglycerols, diacylglycerols, ceramides, and sphingolipids. We characterised hepatic lipid signatures in three different liver zones (periportal zone, midzone, and pericentral zone) and validated the reproducibility of our method for measuring a wide range of lipids. Fatty acids were predominantly detected in the periportal region, whereas phospholipids were distributed in both the periportal and pericentral zones. Interestingly, phosphatidylinositols, PI(36:2), PI(36:3), PI(36:4), PI(38:5), and PI(40:6) were located predominantly in the midzone (zone 2). Triacylglycerols and diacylglycerols were detected mainly in the pericentral region. De novo triacylglycerol biosynthesis appeared to be the most influenced pathway across the three zones., Conclusions: The ability to accurately assess zone-specific hepatic lipid distribution in the liver could lead to a better understanding of lipid metabolism during the progression of liver disease., Impact and Implications: Zone-specific hepatic lipid metabolism could play an important role in lipid homoeostasis during disease progression. Herein, we defined the zone-specific references of hepatic lipid species in the three liver zones using molecular imaging. The de novo triacylglycerol biosynthesis was highlighted as the most influenced pathway across the three zones., Competing Interests: EC is an employee of Waters Corporation. The remaining authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

The incidence of well-differentiated non-functioning pancreatic neuroendocrine tumors (NF-PanNET) increased during the last decades. The risk of relapse after curative surgery, albeit low, is not negligible; moreover, adjuvant treatment is currently not an option and a reliable predictive model based on prognostic characteristics is urgently needed for tailoring a follow-up strategy. The histological classification of PanNET now relies only on the proliferative activity (mitosis and Ki67) and staging. In contrast to other endocrine neoplasms, the role of infiltrative growth pattern in NF-PanNET is not taken into consideration at present. In the current study, 247 consecutive patients who underwent surgical resection for a NF-PanNET were examined for the histological growth pattern of the tumor. Two distinct patterns (non-infiltrative vs. infiltrative) were described with the latter being further subclassified according to the type of structures invaded by the tumor (non-infiltrative: pattern 1; infiltration of adjacent pancreatic parenchyma and/or peripancreatic soft tissue: pattern 2; invasion of nearby organs and/or major vessels: pattern 3). The infiltrative growth resulted to be strongly associated with a poorer survival compared to a non-infiltrative growth (p < 0.001). In particular, the distinction between pancreatic parenchyma and/or peripancreatic soft tissue invasion versus adjacent organs and/or major vessels invasion was the most powerful predictor of recurrence after surgery at multivariate analysis (pattern 2 vs. pattern 1: HR 10.136, p = 0.028; pattern 3 vs. pattern 1: HR 15.775, p = 0.015). The infiltrative growth pattern could therefore provide additional prognostic information implementing the current grading and staging system., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The standardized preanalytical code (SPREC) aggregates warm ischemia (WIT), cold ischemia (CIT), and fixation times (FIT) in a precise format. Despite its growing importance underpinned by the European in vitro diagnostics regulation or broad preanalytical programs by the National Institutes of Health, little is known about its empirical occurrence in biobanked surgical specimen. In several steps, the Tissue Bank Bern achieved a fully informative SPREC code with insights from 10,555 CIT, 4,740 WIT, and 3,121 FIT values. During process optimization according to LEAN six sigma principles, we identified a dual role of the SPREC code as a sample characteristic and a traceable process parameter. With this preanalytical study, we outlined real-life data in a variety of organs with specific differences in WIT, CIT, and FIT values. Furthermore, our FIT data indicate the potential to adapt the SPREC fixation toward concrete paraffin-embedding time points and to extend its categories beyond 72 h due to weekend delays. Additionally, we identified dependencies of preanalytical variables from workload, daytime, and clinics that were actionable with LEAN process management. Thus, streamlined biobanking workflows during the day were significantly resilient to workload peaks, diminishing the turnaround times of native tissue processing (i.e. CIT) from 74.6 to 46.1 min under heavily stressed conditions. In conclusion, there are surgery-specific preanalytics that are surgico-pathologically limited even under process optimization, which might affect biomarker transfer from one entity to another. Beyond sample characteristics, SPREC coding is highly beneficial for tissue banks and Institutes of Pathology to track WIT, CIT, and FIT for process optimization and monitoring measurements., (© 2022 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Purpose: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC., Materials and Methods: We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days., Results: We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in liquid biopsies. In exploratory subgroup assessments, concordance was higher in patients with liver metastases ( P = 1.5 × 10 -5 ) and increasing with level of liver involvement ( P = 1.2 × 10 -4 ). The concordance was similar between GEP-NEC with different primary sites, except being lower in esophageal cases ( P = .001). Concordance was not associated with tumor mutation burden. Tumor tissue mutations also detected in liquid biopsies was lower for MSI (40%) versus MSS tumors (70%; P = 7.8 × 10 -4 ). We identified potentially targetable mutations in plasma of 26 (52%) of patients with GEP-NEC; nine patients (18%) had potentially targetable mutation detected only in liquid biopsies., Conclusion: Liquid biopsy analyses may be an applicable alternative to solid biopsies in GEP-NEC. Liquid biopsies may add additional mutations compared with tumor biopsies alone and could be useful for biomarker assessment in clinical trials for these patients.

Background: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy., Methods: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693., Findings: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71)., Interpretation: This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort., Funding: Swiss Cancer Research foundation., Competing Interests: Declaration of interests MBe reports funding from Novartis, Pfizer, and Ipsen; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Pfizer, Ipsen, and Advanced Accelerator Applications (AAA); support for attending meetings or travel from Novartis, Pfizer, and Ipsen; and participation on data safety monitoring board or advisory boards from Pfizer and AAA. IB reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Bristol Myers Squibb (BMS) and Bayer Vital and support for attending meetings or travel for European Musculo-Skeletal Oncology Society 2022 conference from PharmaMar. RG-C reports funding of investigator-initiated clinical trials from Pfizer, BMS, and MSD, and an real-world data project from Servier; consulting fees from AAA/Novartis, Advanz Pharma, Amgen, Bayer, BMS, Boehringer (Ingelheim), Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, PharmaMar, and Pierre Fabre; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Roche. GC reports grants or contracts from AAA; consulting fees from AAA; payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AAA, Ipsen, and Keocyt; and support for attending meetings or travel from AAA, Ipsen, and Keocyt. MPa reports payments for advisory boards or lectures from AAA and Novartis; payments for advisory boards, consultancy, or lectures from Ipsen; payment for lectures from Boehringer Ingelheim, MSD, Lilly, and Recordati; payment for advisory boards from Riemser; payment for services (radiological review of phase 3 study) from Hutchmed; payment for travel for participation in study steering committee meeting from Rayzebio; payment to institution from Crinetics and AAA; and unpaid roles as ENETS vice president, European Society for Medical Oncology (ESMO) Education Committee, ESMO scientific steering committee NET track, advisor on the International Neuroendocrine Cancer Alliance board, and advisor for German patient support group. GR reports payments for speaker bureaus from AAA. AR reports being an ENETS Advisory Board member. TV reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Ipsen; support for attending meetings or travel from Ipsen; and an unpaid position as secretary in the Dutch Belgian Neuroendocrine Tumor Society. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Pancreatic neuroendocrine neoplasms (PanNENs) are the second most common malignancy of the pancreas. Surgery remains the only curative treatment for localized disease. For patients with inoperable advanced or metastatic disease, few targeted therapies are available, but their efficacy is unpredictable and variable. Exploiting prior knowledge on pathogenetic processes involved in PanNEN tumorigenesis, we tested buparlisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor), as single agents or in combination, in different preclinical models. First, we used cell lines representative of well-differentiated (INS-1E, NT-3) and poorly differentiated (BON-1) PanNENs. The combination of buparlisib with ribociclib reduced the proliferation of 2D and 3D spheroid cultures more potently than the individual drugs. Buparlisib, but not ribociclib, induced apoptosis. The anti-proliferative activity of the drugs correlated with downstream target inhibition at mRNA and protein levels. We then tested the drugs on primary islet microtissues from a genetic PanNET animal model ( Men1 -defective mice) and from wild-type mice: the drug combination was effective against the former without altering islet cell physiology. Finally, we treated PanNET patient-derived islet-like 3D tumoroids: the combination of buparlisib with ribociclib was effective in three out of four samples. Combined targeting of PI3K and CDK4/6 is a promising strategy for PanNENs spanning various molecular and histo-pathological features.

Serotonin producing pancreatic neuroendocrine tumors (SP-PanNET) account for 0.58-1.4% of all pancreatic neuroendocrine tumors (PanNET). They may present with atypical symptoms, such as acute pancreatitis and are often radiologically characterized by main pancreatic duct dilatation. SP-PanNET are well differentiated neuroendocrine tumors (NET) distinct from classical PanNET by atypical serotonin secretion and abundant dense stroma deposition, like serotonin producing ileal NET leading in some cases to difficulties to reliably distinguish SP-PanNET from ileal NET metastases. The biology and molecular profile of SP-PanNET remain poorly characterized and the cell of origin within the pancreas is unclear. To address these questions, we analyzed a large cohort of SP-PanNET by immunohistochemistry (n = 29; ATRX, DAXX, MENIN, Islet1, PAX6, PDX1, ARX, CDX2), whole genome copy number array (Oncoscan™) and a large NGS panel (NovoPM™) (n = 10), FISH (n = 13) and RNA sequencing (n = 24) together with 21 ileal NET and 29 nonfunctioning PanNET (NF-PanNET). These analyses revealed a unique genomic profile with frequent isolated loss of chromosome 1 (14 cases-61%) and few pathogenic mutations (KMT2C in 2 cases, ARID1A in 1 case). Unsupervised RNAseq-based clustering showed that SP-PanNET were closer to NF-PanNET than ileal NET with an exclusive beta cell-like signature. SP-PanNET showed TGF-β pathway activation signatures associated with extracellular matrix remodeling and similar signature were reproduced in vitro when pancreatic stellate cells were exposed to serotonin. SP-PanNET immunohistochemical profile resemble that of ileal NET except for PDX1 and PAX6 expression to a lesser extend suggesting that these two markers may be useful to diagnose SP-PanNET. Taken together, this suggests that SP-PanNET are a very specific PanNET entity with a peculiar biology leading to the characteristic fibrotic aspect., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Precision medicine is entering a new era of digital diagnostics; the availability of integrated digital pathology (DP) and structured clinical datasets has the potential to become a key catalyst for biomedical research, education and business development. In Europe, national programs for sharing of this data will be crucial for the development, testing, and validation of machine learning-enabled tools supporting clinical decision-making. Here, the Swiss Digital Pathology Consortium (SDiPath) discusses the creation of a Swiss Digital Pathology Infrastructure (SDPI), which aims to develop a unified national DP network bringing together the Swiss Personalized Health Network (SPHN) with Swiss university hospitals and subsequent inclusion of cantonal and private institutions. This effort builds on existing developments for the national implementation of structured pathology reporting. Opening this national infrastructure and data to international researchers in a sequential rollout phase can enable the large-scale integration of health data and pooling of resources for research purposes and clinical trials. Therefore, the concept of a SDPI directly synergizes with the priorities of the European Commission communication on the digital transformation of healthcare on an international level, and with the aims of the Swiss State Secretariat for Economic Affairs (SECO) for advancing research and innovation in the digitalization domain. SDPI directly addresses the needs of existing national and international research programs in neoplastic and non-neoplastic diseases by providing unprecedented access to well-curated clinicopathological datasets for the development and implementation of novel integrative methods for analysis of clinical outcomes and treatment response. In conclusion, a SDPI would facilitate and strengthen inter-institutional collaboration in technology, clinical development, business and research at a national and international scale, promoting improved patient care via precision medicine., (© 2022. The Author(s).)

Background: Hypervascularization is a typical feature of pancreatic neuroendocrine tumors, and it frequently allows their recognition at imaging studies. However, the density of microvessels in pancreatic neuroendocrine tumors changes according to their biological behavior, and a low microvessel density is associated with higher disease aggressiveness. The primary aim was to investigate the relationship between microvessel density and aggressiveness of nonfunctioning pancreatic neuroendocrine tumors. The secondary aim was to evaluate the ability of contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound in predicting tumor microvessel density., Methods: The patients who underwent surgery for nonfunctioning pancreatic neuroendocrine tumors (n = 66) with an available preoperative contrast-enhanced computed tomography (n = 39) and/or contrast-enhanced endoscopic ultrasound (n = 37) performed at San Raffaele Hospital (2016-2020) were included. The tumor vascularization was assessed by CD-34 staining, contrast-enhanced computed tomography, and contrast-enhanced endoscopic ultrasound. Median microvessel density (165 microvessels/mm 2 ) was chosen as the cutoff to define low microvessel density and high microvessel density., Results: The patients with a low microvessel density showed a significantly higher frequency of nodal metastases (P = .026), G2-G3 tumors (P = .022), and death domain-associated protein/α-thalassemia/mental retardation syndrome X-linked loss (P = .011) compared to patients with high microvessel density. The contrast-enhanced computed tomography tumor density in the arterial phase was significantly higher in patients with high microvessel density compared to those with low microvessel density (P = .016). The patients with a low microvessel density showed a significantly higher frequency of contrast-enhanced endoscopic ultrasound arterial hypoenhancement (P = .042) and late washout (P = .034). Contrast-enhanced computed tomography arterial hypoenhancement (P = .007) and contrast-enhanced endoscopic ultrasound late washout (P = .048) independently predicted a low microvessel density in the patients who underwent contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound, respectively., Conclusion: A low microvessel density represents a marker of aggressiveness in the patients with nonfunctioning pancreatic neuroendocrine tumors. Contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound are reliable and easily available tools for preoperative assessment of microvessel density., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Neuroendocrine neoplasms (NENs) present with advanced disease at diagnosis in up to 28% of cases, precluding the possibility of curative-intent surgery. Histopathological heterogeneity of this disease can be observed inter-individually as well as intra-individually during disease course. The present study aimed to assess the frequency of Ki-67 change after radical surgery, in a series of patients with radically resected entero-pancreatic neuroendocrine tumors (EP-NETs). We present the analysis of a multicenter, retrospective, series of EP-NETs G1-G2 recurring after radical resection and with histological re-evaluation at disease recurrence (DR). The primary endpoint was the description of Ki-67 change at DR compared to time of surgery. The secondary endpoint was assessment of recurrence-free survival (RFS) rates. In total, 47 patients had a second histological evaluation and could be included in the present study. Median Ki-67 at surgery was 3% (range 1-15%) but, at DR, a significant increase in the value was observed (7%, range 1-30%; p < .01) and involved 66.0% of cases, with a corresponding increase in tumor grading in 34.0% (p = .05). Median RFS of the overall population was 40 months, and was worse when Ki-67 increased at DR vs. stable Ki-67 value (36 vs. 61 months, respectively; p = .02). In conclusion, in more than half of the cases with relapse after radical surgery, a higher proliferative index with a potentially more aggressive potential was observed. Therefore, histological reassessment should be considered on DR because tailored therapeutic strategies may be required for these patients., (© 2022 British Society for Neuroendocrinology.)

Background: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date., Objective: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence., Patients and Methods: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model., Results: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01)., Conclusions: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs., (© 2022. Society of Surgical Oncology.)

Aim: This systematic review aimed to investigate the drugs used and their potential effect on noninvasive ventilation (NIV)., Background: NIV is used increasingly in acute respiratory failure (ARF). Sedation and analgesia are potentially beneficial in NIV, but they can have a deleterious impact. Proper guidelines to specifically address this issue and the recommendations for or against it are scarce in the literature. In the most recent guidelines published in 2017 by the European Respiratory Society/American Thoracic Society (ERS/ATS) relating to NIV use in patients having ARF, the well-defined recommendation on the selective use of sedation and analgesia is missing. Nevertheless, some national guidelines suggested using sedation for agitation., Methods: Electronic databases (PubMed/Medline, Google Scholar, and Cochrane library) from January 1999 to December 2019 were searched systematically for research articles related to sedation and analgosedation in NIV. A brief review of the existing literature related to sedation and analgesia was also done., Review Results: Sixteen articles (five randomized trials) were analyzed. Other trials, guidelines, and reviews published over the last two decades were also discussed. The present review analysis suggests dexmedetomidine as the emerging sedative agent of choice based on the most recent trials because of better efficacy with an improved and predictable cardiorespiratory profile., Conclusion: Current evidence suggests that sedation has a potentially beneficial role in patients at risk of NIV failure due to interface intolerance, anxiety, and pain. However, more randomized controlled trials are needed to comment on this issue and formulate strong evidence-based recommendations., How to Cite This Article: Karim HMR, Šarc I, Calandra C, Spadaro S, Mina B, Ciobanu LD, et al. Role of Sedation and Analgesia during Noninvasive Ventilation: Systematic Review of Recent Evidence and Recommendations. Indian J Crit Care Med 2022;26(8):938-948., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2022; Jaypee Brothers Medical Publishers (P) Ltd.)

Aim: Tumor mutational burden (TMB: somatic mutations per megabase, mut/Mb) predicts the efficacy of immunotherapy. Here, we link TMB levels with the activation of immune pathways and intratumoral immune responses in pancreatic adenocarcinoma (PDAC) to explore immunoarchitectural patterns associated with high TMB., Methods: We assessed TMB in 161 resected, microsatellite stable (MSS) PDACs, including 41 long-term survivors (LTS). Five microsatellite instable (MSI-high) cases were also assessed. Cases were classified into TMB-high (≥10 mut/Mb), TMB-intermediate (>5 < 10 mut/Mb), and TMB-low (≤5 mut/Mb) categories. Tumors additionally underwent mRNA in situ hybridization for immune pathway genes and were immunoprofiled by multiplex immunofluorescence followed by automated image analysis., Results: We detected 12 TMB-high, 28 TMB-intermediate, and 121 TMB-low cases. TMB-high tumors comprised ten LTSs (10/41; 24%) and two conventional PDACs (2/120; 1.7%). They exhibited the highest T cell density with significantly increased CD3 + CD4 + T helper and CD208 + dendritic cell (DC) counts, compared to all other cases. CD3 + CD8 + cytotoxic T cells were significantly closer to tumor cells and T helper cells closer to DCs in TMB-high PDACs. Immune pathways involved in T cell activation, immune cell adhesion/migration, antigen presentation, and cytokine signaling were upregulated in most TMB-high and many TMB-intermediate tumors. ARID1A and ERBB4 alterations were more frequent in TMB-high PDACs. All MSI-high PDACs were TMB-high., Conclusions: TMB-high cases frequently belong to specific PDAC subsets with prolonged survival such as LTSs and MSI-high PDACs. They display strong anti-tumor immune responses fueled by a T helper cell/DC-mediated priming of the cytotoxic T cells. Moreover, they frequently harbor further actionable alterations., Competing Interests: Conflict of interest statement All authors of this manuscript declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Adrenarche is an early event in sexual maturation in prepubertal children and corresponds to the postnatal development of the adrenocortical zona reticularis (zR). However, the molecular mechanisms that govern the onset and maturation of zR remain unknown. Using tissue laser microdissection combined with transcript quantification and immunodetection, we showed that the human zR receives low levels of cholesterol in comparison with other adrenal layers. To model this metabolic condition, we challenged adrenal cells in vitro using cholesterol deprivation. This resulted in reprogramming the steroidogenic pathway toward inactivation of 3-beta-hydroxysteroid dehydrogenase type 2 (HSD3B2), increased CYB5A expression, and increased biosynthesis of dehydroepiandrosterone (DHEA), 3 key features of zR maturation during adrenarche. Finally, we found that cholesterol deprivation leads to decreased transcriptional activity of POU3F2, which normally stimulates the expression of HSD3B2 by directly binding to its promoter. These findings demonstrate that cholesterol deprivation can account, at least in part, for the acquisition of a zR-like androgenic program in humans., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patient blood management (PBM) promotes the routine detection and treatment of anaemia before surgery, optimising the management of bleeding disorders, thus minimising iatrogenic blood loss and pre-empting allogeneic blood utilisation. PBM programmes have expanded from the elective surgical setting to nonsurgical patients, including those in intensive care units (ICUs), but their dissemination in a whole country is unknown., Methods: We performed a cross-sectional, anonymous survey (10 October 2018 to 13 March 2019) of all ordinary medical members of the Swiss Society of Intensive Care Medicine and the registered ICU nurses from the 77 certified adult Swiss ICUs. We analysed PBM-related interventions adopted in Swiss ICUs and related them to the spread of PBM in Swiss hospitals. We explored blood test ordering policies, blood-sparing strategies and red blood cell-related transfusion practices in ICUs., Results: A total of 115 medical doctors and 624 nurses (response rates 27% and 30%, respectively) completed the surveys. Hospitals had implemented a PBM programme according to 42% of physicians, more commonly in Switzerland's German-speaking regions (Odds Ratio [OR] 3.39, 95% confidence interval [CI] 1.23-9.35; p = 0.018) and in hospitals with more than 500 beds (OR 3.91, 95% CI 1.48-10.4; p = 0.006). The PBM programmes targeted the detection and correction of anaemia before surgery (79%), minimising perioperative blood loss (94%) and optimising anaemia tolerance (98%). Laboratory tests were ordered in 70.4% by the intensivist during morning rounds; the nurses performed arterial blood gas analyses autonomously in 48.4%. Blood-sparing techniques were used by only 42.1% of nurses (263 of 624, missing: 6) and 47.0% of physicians (54 of 115). Approximately 60% of respondents used an ICU-specific transfusion guideline. The reported haemoglobin threshold for the nonbleeding ICU population was 70 g/l and, therefore, was at the lower limit of current guidelines., Conclusions: Based on this survey, the estimated proportion of the intensivists working in hospitals with a PBM initiative is 42%, with significant variability between regions and hospitals of various sizes. The risk of iatrogenic anaemia is relevant due to liberal blood sample collection practices and the underuse of blood-sparing techniques. The reported transfusion threshold suggests excellent adherence to current international ICU-specific transfusion guidelines.

The 2022 WHO classification reflects increases in the knowledge of the underlying pathogenesis of parathyroid disease. In addition to the classic characteristic features of parathyroid neoplasms, subtleties in histologic features which may indicate an underlying genetic abnormality reflect increased understanding of the clinical manifestations, histologic, and genetic correlation in parathyroid disease. The importance of underlying genetic aberrancies is emphasized due to their significance to the care of the patient. Traditionally, the term "parathyroid hyperplasia" has been applied to multiglandular parathyroid disease; however, the concept of hyperplasia is generally no longer supported in the context of primary hyperparathyroidism since affected glands are usually composed of multiple "clonal" neoplastic proliferations. In light of these findings and management implications for patient care, the 2022 WHO classification endorses primary hyperparathyroidism-related multiglandular parathyroid disease (multiglandular multiple parathyroid adenomas) as a germline susceptibility-driven multiglandular parathyroid neoplasia. From such a perspective, pathologists can provide additional value to genetic triaging by recognizing morphological and immunohistochemical harbingers of MEN1, CDKN1B, MAX, and CDC73-related manifestations. In the current WHO classification, the term "parathyroid hyperplasia" is now used primarily in the setting of secondary hyperplasia which is most often caused by chronic renal failure. In addition to expansion in the histological features, including those that may be suggestive of an underlying genetic abnormality, there are additional nomenclature changes in the 2022 WHO classification reflecting increased understanding of the underlying pathogenesis of parathyroid disease. The new classification no longer endorses the use of "atypical parathyroid adenoma". This entity is now being replaced with the term of "atypical parathyroid tumor" to reflect a parathyroid neoplasm of uncertain malignant potential. The differential diagnoses of atypical parathyroid tumor are discussed along with the details of worrisome clinical and laboratory findings, and also features that define atypical histological and immunohistochemical findings to qualify for this diagnosis. The histological definition of parathyroid carcinoma still requires one of the following findings: (i) angioinvasion (vascular invasion) characterized by tumor invading through a vessel wall and associated thrombus, or intravascular tumor cells admixed with thrombus, (ii) lymphatic invasion, (iii) perineural (intraneural) invasion, (iv) local malignant invasion into adjacent anatomic structures, or (v) histologically/cytologically documented metastatic disease. In parathyroid carcinomas, the documentation of mitotic activity (e.g., mitoses per 10mm 2 ) and Ki67 labeling index is recommended. Furthermore, the importance of complete submission of parathyroidectomy specimens for microscopic examination, and the crucial role of multiple levels along with ancillary biomarkers have expanded the diagnostic workup of atypical parathyroid tumors and parathyroid carcinoma to ensure accurate characterization of parathyroid neoplasms. The concept of parafibromin deficiency has been expanded upon and term "parafibromin deficient parathyroid neoplasm" is applied to a parathyroid neoplasm showing complete absence of nuclear parafibromin immunoreactivity. Nucleolar loss is considered as abnormal finding that requires further molecular testing to confirm its biological significance. The 2022 WHO classification emphasizes the role of molecular immunohistochemistry in parathyroid disease. By adopting a question-answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the understanding of the underlying pathogenesis of parathyroid disease that are now reflected in the updated classification and new entities in the 2022 WHO classification., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This review of the familial tumor syndromes involving the endocrine organs is focused on discussing the main updates on the upcoming fifth edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. This review emphasizes updates on histopathological and molecular genetics aspects of the most important syndromes involving the endocrine organs. We describe the newly defined Familial Cancer Syndromes as MAFA-related, MEN4, and MEN5 as well as the newly reported pathological findings in DICER1 syndrome. We also describe the updates done at the new WHO on the syndromic and non-syndromic familial thyroid diseases. We emphasize the problem of diagnostic criteria, mention the new genes that are possibly involved in this group, and at the same time, touching upon the role of some immunohistochemical studies that could support the diagnosis of some of these conditions. As pathologists play an important role in identifying tumors within a familial cancer syndrome, we highlight the most important clues for raising the suspicious of a syndrome. Finally, we highlight the challenges in defining these entities as well as determining their clinical outcome in comparison with sporadic tumors. Instead of the usual subject review, we present the highlights of the updates on familial cancer syndromes by answering select questions relevant to practicing pathologists., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent years the WHO classification of neuroendocrine neoplasms (NEN) has evolved. Nomenclature as well as thresholds for grading have changed leading to potential confusion and lack of comparability of tumour reports. Therefore, the European Neuroendocrine Tumour Society (ENETS) has set-up an interdisciplinary working group to develop templates for a pathology data set for standardised reporting of NEN. Experts of various disciplines, members of the ENETS Advisory Board, formed a taskforce that discussed and decided on the structure, content and the number of templates needed for reporting the most common NEN. The selection of the required items was based on the WHO classification of digestive system tumours, the WHO classification of tumours of the lung and mediastinum and on "ENETS standard of care" reports. The final proposal of the working group was approved by the ENETS Advisory Board. Templates for synoptic reporting were created for the seven most common NEN primary sites, that is, stomach, duodenum, jejunum-ileum, appendix, colon-rectum, pancreas, lung and mediastinum. In addition, a general template for reporting biopsies was designed. The templates allow the recording of the essential items on differentiation, proliferation (Ki-67 and mitosis), neuroendocrine features (positivity for chromogranin A and synaptophysin) and stage as well as several optional markers especially helpful for the distinction of neuroendocrine tumours (NET) from neuroendocrine carcinomas (NEC). In summary, this paper presents the content and development of synoptic reports for most sites of NEN by a multidisciplinary team of international experts in the field, which could help to improve unambiguous reporting of NEN., (© 2022 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Background: Pancreatic neuroendocrine neoplasms (PanNENs) fall into two subclasses: the well-differentiated, low- to high-grade pancreatic neuroendocrine tumors (PanNETs), and the poorly-differentiated, high-grade pancreatic neuroendocrine carcinomas (PanNECs). While recent studies suggest an endocrine descent of PanNETs, the origin of PanNECs remains unknown., Methods: We performed DNA methylation analysis for 57 PanNEN samples and found that distinct methylation profiles separated PanNENs into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA alterations and immunohistochemistry of cell-type markers PDX1, ARX, and SOX9 were utilized to further characterize PanNECs and their cell of origin in the pancreas., Results: Phylo-epigenetic and cell-type signature features derived from alpha, beta, acinar, and ductal adult cells suggest an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin., Conclusions: Our study provides a robust and clinically applicable method to clearly distinguish PanNECs from G3 PanNETs, improving patient stratification., (© 2022. The Author(s).)

Immunotherapy, including PD-1/PD-L1 agonists, has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). We examined the PD-1/PD-L1 expression and immunoarchitectural features by automated morphometric analysis using multiplex immunofluorescence and 118 microsatellite-stable, treatment-naïve, surgically resected PDACs (study cohort). Five microsatellite-instable cases were stained in parallel (MSI cohort). Molecular analysis was additionally performed. An independent PDAC cohort ( n = 226) was immunostained for PD-L1 and used as a validation cohort. PD-L1 expression on tumor cells (TC) and/or immune cells (IC) was present in 32% and 30% of the study and validation cohorts, respectively, and assigned into one of four patterns: "adaptive-1" (TC: 0, IC > 1%), "adaptive-2" (TC > 1% to < 25%, IC > 1%), "constitutive" (TC ≥ 25%, IC: 0), and "combined" (TC ≥ 25%, IC > 1%). "Constitutive" tumors were characterized by reduced numbers of all ICs and poor outcome. In contrast, "adaptive-1" tumors exhibited abundant T cells, including high counts of cytotoxic CD3 + CD8 + and PD-1 + CD3 + CD8 + cells, but low counts of PD-L1 + CD3 + CD8 + cells and associated with the best outcome. "Adaptive-2" tumors displayed higher proportions of PD-L1 + CD3 + CD8 + T cells and tumor-associated macrophages (CD68 + and CD68 + CD206 + ) compared with "adaptive-1" tumors. In the "combined" pattern, extensive PD-L1 expression on TCs was accompanied by increased numbers of T cells and improved overall survival. ICs were closer to PD-L1 - than to PD-L1 + PDAC cells. TP53 and PIK3CA alterations tended to be more frequent in PD-L1 + tumors. The 5 MSI cases were PD-L1 - The distinct PD-1/PD-L1-associated immunoarchitectural patterns underpin the heterogeneity of the immunologic responses and might be used to inform patient outcomes and therapeutic decisions in pancreatic cancer., (©2021 American Association for Cancer Research.)

High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.

High-flow nasal cannula oxygen therapy (HFNCOT) system consists of an air/oxygen supply system capable of delivering up to 100% humidified and heated oxygen at a flow rate of up to 80 L/min. The system includes a blender, active humidifier, single heated tube, and nasal cannula. HFNCOT has many physiological advantages compared with other standard oxygen therapies, such as anatomical dead space washout, more constant fraction of inspired oxygen, positive end-expiratory (PEEP) effect, supplement of adequate humidification and maintenance of muco-ciliary function. HFNCOT is mostly used for hypoxemic acute respiratory failure, although it also has other indications. HFNCOT is a common choice of physicians as its technology makes it more silent and comfortable. Though HFNCOT is used in many clinical settings, there is a lack of publications addressing devices and initial settings. We present a review on HFNCOT, with focus on device and application methodology.