Publications by authors named "Claudio Luchini"

118 Publications

Platinum-Based Treatment for Well- and Poorly Differentiated Pancreatic Neuroendocrine Neoplasms.

Pancreas 2021 Feb;50(2):138-146

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Objectives: Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation.

Methods: Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation.

Results: Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2).

Conclusions: Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.
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http://dx.doi.org/10.1097/MPA.0000000000001740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880539PMC
February 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 Feb 3;4(1):155. Epub 2021 Feb 3.

ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, 37134, Italy.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility.

Int J Cancer 2021 Feb 3. Epub 2021 Feb 3.

Department of Biology, University of Pisa, Pisa, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.
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http://dx.doi.org/10.1002/ijc.33475DOI Listing
February 2021

Simple mucinous cyst: another potential cancer precursor in the pancreas? Case report with molecular characterization and systematic review of the literature.

Virchows Arch 2021 Jan 28. Epub 2021 Jan 28.

Clinica Chirurgica 1 - Pancreatic and Endocrine Digestive Surgical Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, via Giustiniani, 2, 35128, Padua, Italy.

Cystic lesions of the pancreas may range from benign to precursors of pancreatic cancer. Simple mucinous cyst (SMC) is larger than 1 cm, has a gastric-type flat mucinous lining, and minimal atypia without ovarian-type stroma. We report a new case of pancreatic SMC, coupling a systematic review of the English literature mainly focused on their clinic-pathological features. We reviewed 103 cases of SMC in adults (73 women), averaging 57 (range, 26-70) years. The SMCs were located in the body-tail region of the pancreas in 60 (58%) cases, presenting as single cystic lesions in 94% of cases; 43% of patients were asymptomatic. A preoperative fine-needle aspiration of the cyst fluid detected amylase and carcinoembryonic antigen positivity in 71% and 76% of cases, respectively. Patients underwent surgery mostly for suspected malignancy; in 83% of cases, a standard pancreatic resection was performed. Mean SMC size was 4.9 (range, 1.5-12.0) cm. Mucins MUC5AC and MUC6 resulted positive in 77% and 81% of cases performed, respectively, whereas MUC2 was negative in all but one patient. The SMC from our institution was characterized by a KRAS somatic mutation. The diagnosis of SMC should be considered when a solitary pancreatic cyst larger than 1 cm is detected in asymptomatic patients. To establish a correct diagnosis, an extensive histologic/immunohistochemical analysis is essential. The presence of a KRAS mutation highlights that SMC may represent another potential pancreatic cancer precursor.
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http://dx.doi.org/10.1007/s00428-021-03029-1DOI Listing
January 2021

Microsatellite instability/mismatch repair deficiency in pancreatic cancers: the same or different?

Gut 2021 Jan 19. Epub 2021 Jan 19.

Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1136/gutjnl-2020-323805DOI Listing
January 2021

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells: a challenging cancer with new horizons?

Authors:
Claudio Luchini

Virchows Arch 2021 Jan 14. Epub 2021 Jan 14.

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134, Verona, Italy.

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http://dx.doi.org/10.1007/s00428-021-03021-9DOI Listing
January 2021

Stem cells for treatment of cardiovascular diseases: An umbrella review of randomized controlled trials.

Ageing Res Rev 2021 Jan 9;67:101257. Epub 2021 Jan 9.

Geriatric Unit, Department of Internal Medicine and Geriatrics, University of Palermo, Palermo, Italy.

Aims: Stem cells are a promising therapy for various medical conditions. The literature regarding their adoption for the clinical care of cardiovascular diseases (CVD) is still conflicting. Therefore, our aim is to assess the strength and credibility of the evidence on clinical outcomes and application of stem cells derived from systematic reviews and meta-analyses of intervention studies in CVD.

Methods And Results: Umbrella review of systematic reviews with meta-analyses of randomized controlled trials (RCTs) using placebo/no intervention as control group. For meta-analyses of RCTs, outcomes with a random-effect p-value <0.05, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) assessment was used, classifying the evidence from very low to high. From 184 abstracts initially identified, 11 meta-analyses (for a total of 34 outcomes) were included. Half of the outcomes were statistically significant (p < 0.05), indicating that stem cells are more useful than placebo. High certainty of evidence supports the associations of the use of stem cells with a better left ventricular end systolic volume and left ventricular ejection fraction (LVEF) in acute myocardial infarction; improved exercise time in refractory angina; a significant lower risk of amputation rate in critical limb ischemia; a higher successful rate in complete healing in case of lower extremities ulcer; and better values of LVEF in systolic heart failure, as compared to placebo.

Conclusion And Relevance: The adoption of stem cells in clinical practice is supported by a high certainty of strength in different CVD, with the highest strength in acute myocardial infarction and refractory angina.
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http://dx.doi.org/10.1016/j.arr.2021.101257DOI Listing
January 2021

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology.

Int J Mol Sci 2020 Nov 22;21(22). Epub 2020 Nov 22.

Division of Oncology, University of Verona, 37126 Verona, Italy.

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (, , , ). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.
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http://dx.doi.org/10.3390/ijms21228841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700259PMC
November 2020

Current prognostic and predictive biomarkers for gastrointestinal tumors in clinical practice.

Pathologica 2020 Sep;112(3):248-259

Anatomic Pathology, San Martino IRCCS Hospital,, Genova, Italy.

The pathologist emerged in the personalized medicine era as a central actor in the definition of the most adequate diagnostic and therapeutic algorithms. In the last decade, gastrointestinal oncology has seen a significantly increased clinical request for the integration of novel prognostic and predictive biomarkers in histopathological reports. This request couples with the significant contraction of invasive sampling of the disease, thus conferring to the pathologist the role of governor for both proper pathologic characterization and customized processing of the biospecimens. This overview will focus on the most commonly adopted immunohistochemical and molecular biomarkers in the routine clinical characterization of gastrointestinal neoplasms referring to the most recent published recommendations, guidelines and expert opinions.
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http://dx.doi.org/10.32074/1591-951X-158DOI Listing
September 2020

Malignant epithelial/exocrine tumors of the pancreas.

Pathologica 2020 Sep;112(3):210-226

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.

Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.
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http://dx.doi.org/10.32074/1591-951X-167DOI Listing
September 2020

Inflammatory and tumor-like lesions of the pancreas.

Pathologica 2020 Sep;112(3):197-209

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.

Inflammatory/tumor-like lesions of the pancreas represent a heterogeneous group of diseases that can variably involve the pancreatic gland determining different signs and symptoms. In the category of inflammatory/tumor-like lesions of the pancreas, the most important entities are represented by chronic pancreatitis, which includes alcoholic, obstructive and hereditary pancreatitis, paraduodenal (groove) pancreatitis, autoimmune pancreatitis, lymphoepithelial cyst, pancreatic hamartoma and intrapancreatic accessory spleen. An in-depth knowledge of such diseases is essential, since they can cause severe morbidity and may represent a potential life-threatening risk for patients. Furthermore, in some cases the differential diagnosis with malignant tumors may be challenging. Herein we provide a general overview of all these categories, with the specific aim of highlighting their most important clinic-pathological hallmarks to be used in routine diagnostic activities and clinical practice.
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http://dx.doi.org/10.32074/1591-951X-168DOI Listing
September 2020

Reassessment of the Optimal Number of Examined Lymph Nodes in Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma.

Ann Surg 2020 Nov 9. Epub 2020 Nov 9.

Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy.

Objective: To reappraise the optimal number of examined lymph nodes (ELN) in pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC).

Summary Background Data: The well-established threshold of 15 ELN in PD for PDAC is optimized for detecting one positive node (PLN) per the previous 7 edition of the AJCC staging manual. In the framework of the 8 edition, where at least four PLN are needed for an N2 diagnosis, this threshold may be inadequate for accurate staging.

Methods: Patients who underwent upfront PD at two academic institutions between 2000 and 2016 were analyzed. The optimal ELN threshold was defined as the cut-point associated with a 95% probability of identifying at least 4 PLN in N2 patients. The results were validated addressing the N-status distribution and stage migration.

Results: Overall, 1218 patients were included. The median number of ELN was 26 (IQR 17-37). ELN was independently associated with N2-status (OR 1.27, p < 0.001). The estimated optimal threshold of ELN was 28. This cut-point enabled improved detection of N2 patients and stage III disease (58% versus 37%, p = 0.001). The median survival was 28.6 months. There was an improved survival in N0/N1 patients when ELN exceeded 28, suggesting a stage migration effect (47 versus 29 months, adjusted HR 0.649, p < 0.001). In N2 patients, this threshold was not associated with survival on multivariable analysis.

Conclusion: Examining at least 28 LN in PD for PDAC ensures optimal staging through improved detection of N2/stage III disease. This may have relevant implications for benchmarking processes and quality implementation.
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http://dx.doi.org/10.1097/SLA.0000000000004552DOI Listing
November 2020

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities.

J Exp Clin Cancer Res 2020 Oct 28;39(1):227. Epub 2020 Oct 28.

Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases.The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.
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http://dx.doi.org/10.1186/s13046-020-01732-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594413PMC
October 2020

Epithelial Nr5a2 heterozygosity cooperates with mutant Kras in the development of pancreatic cystic lesions.

J Pathol 2021 Feb 24;253(2):174-185. Epub 2020 Nov 24.

Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre - CNIO, Madrid, Spain.

Cystic neoplasms of the pancreas are an increasingly important public health problem. The majority of these lesions are benign but some progress to invasive pancreatic ductal adenocarcinoma (PDAC). There is a dearth of mouse models of these conditions. The orphan nuclear receptor NR5A2 regulates development, differentiation, and inflammation. Germline Nr5a2 heterozygosity sensitizes mice to the oncogenic effects of mutant Kras in the pancreas. Here, we show that - unlike constitutive Nr5a2 mice - conditional Nr5a2 heterozygosity in pancreatic epithelial cells, combined with mutant Kras (KPN ), leads to a dramatic replacement of the pancreatic parenchyma with cystic structures and an accelerated development of high-grade PanINs and PDAC. Timed histopathological analyses indicated that in KPN mice PanINs precede the formation of cystic lesions and the latter precede PDAC. A single episode of acute caerulein pancreatitis is sufficient to accelerate the development of cystic lesions in KPN mice. Epithelial cells of cystic lesions of KPN mice express MUC1, MUC5AC, and MUC6, but lack expression of MUC2, CDX2, and acinar markers, indicative of a pancreato-biliary/gastric phenotype. In accordance with this, in human samples we found a non-significantly decreased expression of NR5A2 in mucinous tumours, compared with conventional PDAC. These results highlight that the effects of loss of one Nr5a2 allele are time- and cell context-dependent. KPN mice represent a new model to study the formation of cystic pancreatic lesions and their relationship with PanINs and classical PDAC. Our findings suggest that pancreatitis could also contribute to acceleration of cystic tumour progression in patients. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5570DOI Listing
February 2021

Amsterdam International Consensus Meeting: tumor response scoring in the pathology assessment of resected pancreatic cancer after neoadjuvant therapy.

Mod Pathol 2021 01 12;34(1):4-12. Epub 2020 Oct 12.

Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including "minimal" or "extensive" with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the "Materials and methods" section.
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http://dx.doi.org/10.1038/s41379-020-00683-9DOI Listing
January 2021

Assessing the quality of studies in meta-research: Review/guidelines on the most important quality assessment tools.

Pharm Stat 2021 Jan 15;20(1):185-195. Epub 2020 Sep 15.

Department of Neurosciences, University of Padova, Padova, Italy.

Systematic reviews and meta-analyses pool data from individual studies to generate a higher level of evidence to be evaluated by guidelines. These reviews ultimately guide clinicians and stakeholders in health-related decisions. However, the informativeness and quality of evidence synthesis inherently depend on the quality of what has been pooled into meta-research projects. Moreover, beyond the quality of included individual studies, only a methodologically correct process, in relation to systematic reviews and meta-analyses themselves, can produce a reliable and valid evidence synthesis. Hence, quality of meta-research projects also affects evidence synthesis reliability. In this overview, the authors provide a synthesis of advantages and disadvantages and main characteristics of some of the most frequently used tools to assess quality of individual studies, systematic reviews, and meta-analyses. Specifically, the tools considered in this work are the Newcastle-Ottawa scale (NOS) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) for observational studies, the Consolidated Standards of Reporting Trials (CONSORT), the Jadad scale, the Cochrane risk of bias tool 2 (RoB2) for randomized controlled trials, the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and the Assessment of Multiple Systematic Reviews 2 (AMSTAR2), and AMSTAR-PLUS for meta-analyses. WHAT IS ALREADY KNOWN?: The informativeness and quality of evidence synthesis inherently depend on the quality of what has been pooled into meta-research projects. Beyond the quality of included individual studies, only a methodologically correct process, in relation to systematic reviews and meta-analyses themselves, can produce a reliable and valid evidence synthesis. WHAT IS NEW?: In this overview, the authors provide a synthesis of advantages and disadvantages and main characteristics of some of the most frequently used tools to assess quality of individual studies, systematic reviews, and meta-analyses. POTENTIAL IMPACT: This overview serves as a starting point and a brief guide to identify and understand the main and most frequently used tools for assessing the quality of studies included in meta-research. The authors here share their experience in publishing several meta-research-related articles covering different areas of medical sciences.
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http://dx.doi.org/10.1002/pst.2068DOI Listing
January 2021

Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours.

Gut 2020 Sep 3. Epub 2020 Sep 3.

Division of Molecular Pathology, Institute of Cancer Research, London, UK

Objective: A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease.

Design: Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence.

Results: The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%-31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype.

Conclusion: This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond.
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http://dx.doi.org/10.1136/gutjnl-2020-321016DOI Listing
September 2020

CD117 Is a Specific Marker of Intraductal Papillary Mucinous Neoplasms (IPMN) of the Pancreas, Oncocytic Subtype.

Int J Mol Sci 2020 Aug 12;21(16). Epub 2020 Aug 12.

Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy.

The intraductal oncocytic papillary neoplasm (IOPN) of the pancreas has been recognized by WHO classification as a unique intraductal papillary mucinous neoplasm (IPMN) category. IOPN is composed of oxyphil cells, usually expressing MUC5AC, MUC6, and Hep Par-1, and harboring / fusion genes as their genetic hallmark. Although IOPNs are associated with an infiltrative adenocarcinoma in up to 30% of cases, the survival rate after surgical resection approaches 100%. This highlights the importance of the correct IOPN diagnosis, above all in cases with an associated invasive component. In this study, the immunohistochemical expression of CD117 was investigated in 111 IPMNs, including 17 oncocytic, 45 gastric, 20 pancreatico-biliary, and 29 intestinal IPMNs. We also tested the expression of MUC5AC, MUC6, and Hep Par-1 in the IOPN cohort. CD117 positivity was significantly more frequent in IOPNs compared to the other IPMN subtypes ( < 0.0001). Furthermore, within IOPN, a lower or absent CD117, MUC5AC, MUC6, and Hep Par-1 expression tended to be associated with the presence of an infiltrative component. Our findings shed light into the biology of these complex lesions, which are confirmed to be a distinctive IPMN subtype; notably, CD117 emerged as a potential, additional tool in the differential diagnosis of IPMNs.
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http://dx.doi.org/10.3390/ijms21165794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461050PMC
August 2020

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Nat Commun 2020 08 14;11(1):4085. Epub 2020 Aug 14.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
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http://dx.doi.org/10.1038/s41467-020-17917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428044PMC
August 2020

Epithelial-mesenchymal transition in undifferentiated carcinoma of the pancreas with and without osteoclast-like giant cells.

Virchows Arch 2020 Jul 13. Epub 2020 Jul 13.

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134, Verona, Italy.

Undifferentiated carcinoma (UC) and undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) are peculiar variants of pancreatic ductal adenocarcinoma (PDAC), characterized by hypercellularity and absence of glandular patterns. The inflammatory microenvironment is peculiar in UCOGC, since it is dominated by macrophages and osteoclast-like giant cells. However, from a molecular point of view, both UC and UCOGC are very similar to conventional PDAC, sharing alterations of the most common genetic drivers. Clinically, UC usually show a worse prognosis, whereas UCOGC may show a better prognosis if it is not associated with a PDAC component. To highlight potential biological differences between these entities, we investigated the role of the epithelial to mesenchymal transition (EMT) in UC and UCOGC. Specifically, we analyzed the immunohistochemical expression of three well-known EMT markers, namely Twist1, Snai2, and E-cadherin, in 16 cases of UCOGC and 10 cases of UC. We found that EMT is more frequently activated in UC (10/10 cases) than in UCOGC (8/16 cases; p = 0.05). Furthermore, in UCOGC, EMT was activated with a higher frequency in cases with an associated PDAC component. Snai2 was the most frequently and strongly expressed marker in both tumor types (10/10 UC, 8/16 UCOGC), and its expression was higher in UC than in UCOGC (mean immunohistochemical score: 4.8 in UC vs. 2.1 in UCOGC, p < 0.01). Our results shed new light on the biology of UC and UCOGC: EMT appeared as a more important process in UC, and Snai2 emerged as a central EMT effector in this setting.
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http://dx.doi.org/10.1007/s00428-020-02889-3DOI Listing
July 2020

Medullary Pancreatic Carcinoma Due to Somatic POLE Mutation: A Distinctive Pancreatic Carcinoma With Marked Long-Term Survival.

Pancreas 2020 08;49(7):999-1003

From the Department of Pathology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen.

Medullary pancreatic carcinoma (MPC) is a rare histological variant of pancreatic ductal adenocarcinoma (PDAC). Because of its rarity, data on the molecular background of MPC are limited. Previous studies have shown that a subset of MPCs is microsatellite instable due to mismatch repair deficiency. Here, we present a unique case of a female patient in her 60s who is a long-term survivor after surgery for pancreatic cancer. The patient had a microsatellite stable MPC with a somatic mutation of the polymerase epsilon gene (POLE). Both microsatellite instable and POLE-mutated cancers are usually associated with high tumor mutational burden and antigen load, resulting in a prominent antitumor immune response and overall better survival. The current case illustrates that, in addition to mismatch repair deficiency, MPC can develop because of a somatic POLE mutation, resulting in a tumor with a high tumor mutational burden and leading to a better prognosis compared with conventional PDAC. This new finding may have important implications in the management of patients with MPC and calls for further studies on the role of POLE in PDAC.
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http://dx.doi.org/10.1097/MPA.0000000000001588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368848PMC
August 2020

Digital pathology for second opinion consultation and donor assessment during organ procurement: Review of the literature and guidance for deployment in transplant practice.

Transplant Rev (Orlando) 2020 10 13;34(4):100562. Epub 2020 Jun 13.

Department of Pathology, UPMC Shadyside Hospital, University of Pittsburgh, Pittsburgh, PA, USA.

Telepathology has been an important application for second opinion consultation ever since the introduction of digital pathology. However, little is known regarding teleconsultation for second opinion in transplantation. There is also limited literature on telepathology during organ donor procurement, typically utilized when general pathologists on-call request back-up to help assess donor biopsies for organ suitability or to diagnose newly discovered tumors with urgent time constraints. In this review, we searched Pubmed/Embase and websites of transplant organizations to collect and analyze published evidence on teleconsultation for donor evaluation and organ procurement. Of 2725 records retrieved using the key terms 'telepathology', 'second opinion' and 'transplantation', 26 suitable studies were included. Most records were from North America and included validation studies of telepathology being used for remote frozen section interpretation of donor biopsies with whole slide imaging. The data from these published studies supports the transition towards digital teleconsultation in transplant settings where consultations among pathologists are still handled by pathologists being called on site, via telephone and/or email.
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http://dx.doi.org/10.1016/j.trre.2020.100562DOI Listing
October 2020

Molecular Tumor Boards in Clinical Practice.

Trends Cancer 2020 09 6;6(9):738-744. Epub 2020 Jun 6.

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy.

Next-generation sequencing (NGS) application in clinical practice requires the implementation of molecular tumor boards (MTBs). Starting from a systematic review of literature, we discuss the MTB-related key points: MTB aims and composition, types of tumors to discuss, types of molecular analyses, methods for classifying actionability, appropriate turnaround time, and cost management.
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http://dx.doi.org/10.1016/j.trecan.2020.05.008DOI Listing
September 2020

Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club.

Pancreatology 2020 Jun 29;20(4):586-593. Epub 2020 Apr 29.

Department of Pathology, Royal Liverpool University Hospital, Liverpool, UK. Electronic address:

Background: Chronic pancreatitis is a complex multifactorial fibro-inflammatory disease. Consensus guidelines are needed for the histopathological evaluation of non-autoimmune chronic pancreatitis (CP).

Methods: An international working group with experts on the histopathology of CP evaluated 15 statements generated from evidence on seven key clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the statements for strength of agreement, using a nine-point Likert scale, and Cronbach's alpha reliability coefficients were calculated.

Results: Strong consensus was obtained for 12 statements relating to all seven key questions including that: the cardinal features of CP are the triad of fibrosis, loss of acinar tissue and duct changes; there are no unique histopathological features that distinguish the different aetiologies of CP; clinical history and laboratory investigations, including genetic testing, are important in establishing the aetiology of CP; there is no reproducible and universally accepted histological grading system for assessing severity of CP, although classification as "mild", "moderate" and "severe" is usually applied; scoring systems for fibrosis are not validated for clinical use; asymptomatic fibrosis is a common finding associated with ageing, and not necessarily evidence of CP; there are no obvious diagnostic macroscopic features of early CP; histopathology is not the gold standard for the diagnosis of CP; and cytology alone is not a reliable method for the diagnosis of CP.

Conclusions: Cardinal histopathological features of CP are well-defined and internationally accepted and pathological assessment is relevant for the purpose of differential diagnosis with other pancreatic diseases, especially cancer. However, a reliable diagnosis of CP requires integration of clinical, laboratory and imaging features and cannot be made by histology alone.
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http://dx.doi.org/10.1016/j.pan.2020.04.009DOI Listing
June 2020

Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome.

Cancer Res 2020 07 6;80(13):2804-2817. Epub 2020 May 6.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene (or its signaling partner ). Reexpression of SMAD4 abrogated the collective invasion phenotype in -mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged -mutant PDAC organoids required exogenous TGFβ, suggesting that invasion in -mutant organoids is mediated through noncanonical TGFβ signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFβ-stimulated invasion in -mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in -mutant and wild-type tumors are different in both morphology and molecular mechanism.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335355PMC
July 2020

Exosomal miRNA signatures of pancreatic lesions.

BMC Gastroenterol 2020 May 6;20(1):137. Epub 2020 May 6.

ARC-NET Research Centre, University of Verona, Verona, Italy.

Background: Pancreatic and peri-pancreatic neoplasms encompass a variety of histotypes characterized by a heterogeneous prognostic impact. miRNAs are considered efficient candidate biomarkers due to their high stability in tissues and body fluids. We applied Nanostring profiling of circulating exosomal miRNAs to distinct pancreatic lesions in order to establish a source for biomarker development.

Methods: A series of 140 plasma samples obtained from patients affected by pancreatic ductal adenocarcinoma (PDAC, n = 58), pancreatic neuroendocrine tumors (PanNET, n = 42), intraductal papillary mucinous neoplasms (IPMN, n = 20), and ampulla of Vater carcinomas (AVC, n = 20) were analyzed. Comprehensive miRNA profiling was performed on plasma-derived exosomes. Relevant miRNAs were validated by qRT-PCR and in situ hybridization (ISH).

Results: Lesion specific miRNAs were identified through multiple disease comparisons. Selected miRNAs were validated in the plasma by qRT-PCR and at tissue level by ISH. We leveraged the presence of clinical subtypes with each disease cohort to identify miRNAs that are differentially enriched in aggressive phenotypes.

Conclusions: This study shows that pancreatic lesions are characterized by specific exosomal-miRNA signatures. We also provide the basis for further explorations in order to better understand the relevance of these signatures in pancreatic neoplasms.
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http://dx.doi.org/10.1186/s12876-020-01287-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204029PMC
May 2020

Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications.

Gut 2021 Jan 29;70(1):148-156. Epub 2020 Apr 29.

ARC-Net Research Center and Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.

Objective: Recently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC).

Design: PubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project).

Results: Overall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%-2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a / wild-type molecular background (p<0.01), with more common genes mutations. Data on survival are still unclear.

Conclusion: PDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.
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http://dx.doi.org/10.1136/gutjnl-2020-320726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211065PMC
January 2021

Reappraisal of nodal staging and study of lymph node station involvement in distal pancreatectomy for body-tail pancreatic ductal adenocarcinoma.

Eur J Surg Oncol 2020 09 13;46(9):1734-1741. Epub 2020 Apr 13.

Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy.

Background: The pattern of nodal spread in body-tail pancreatic ductal adenocarcinoma (PDAC) has been poorly investigated. This study analyzed the characteristics of lymph node (LN) involvement and the prognostic role of nodal metastases stratified by LN stations.

Methods: All upfront distal pancreatectomies (DPs) for PDAC (2000-2017) with complete information on station 8,10,11, and 18 were included. Clinico-pathological correlates and survival were investigated using uni- and multivariable analyses.

Results: Among 100 included patients, 28 were N0, 42 N1 and 30 N2. The median number of examined LN was 32 (IQR 26-44). Tumor size at preoperative imaging increased across N-classes. Preoperative size >27.5 mm was associated with N2 status. The frequency of nodal metastases at stations 8, 9, 10, 11, and 18 was 12.0%, 10.9%, 3.0%, 71.0%, and 19%, respectively. The pattern of LN spread was independent from primary tumor location (with tail tumors metastasizing to station 8/9 and body tumors to station 10), while it was highly associated with N-class. At multivariable analysis, tumor grading, adjuvant treatment, station 9 and 10 metastases were independent prognostic factors in node-positive patients.

Conclusions: In patients undergoing upfront DP for PDAC preoperative tumor size is associated with the degree of nodal spread. While station 11 was the most frequently involved, only station-9 and 10 metastases were independent prognostic factors. The site of nodal metastases was somewhat unpredictable based on tumor location. This data has potential implications for allocating patients to neoadjuvant treatment and supports the performance of routine splenectomy during DP for PDAC.
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http://dx.doi.org/10.1016/j.ejso.2020.04.006DOI Listing
September 2020

Does Site Matter? Impact of Tumor Location on Pathologic Characteristics, Recurrence, and Survival of Resected Pancreatic Ductal Adenocarcinoma.

Ann Surg Oncol 2020 Oct 19;27(10):3898-3912. Epub 2020 Apr 19.

Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy.

Background: The authors hypothesized that in resected pancreatic adenocarcinoma (PDAC), pathologic characteristics, oncologic outcomes, prognostic factors, and the accuracy of the American Joint Committee on Cancer (AJCC) staging system might differ based on tumor location.

Methods: Patients undergoing pancreatectomy for PDAC at two academic institutions from 2000 to 2015 were retrieved. A comparative analysis between head (H-PDAC) and body-tail (BT-PDAC) tumors was performed using uni- and multivariable models. The accuracy of the eighth AJCC staging system was analyzed using C-statistics.

Results: Among 1466 patients, 264 (18%) had BT-PDAC, which displayed greater tumor size but significantly lower rates of perineural invasion and G3/4 grading. Furthermore, BT-PDAC was associated with a lower frequency of nodal involvement and a greater representation of earlier stages. The recurrence-free survival and disease-specific survival times were longer for BT-PDAC (16 vs 14 months [p = 0.020] and 33 vs 26 months [p = 0.026], respectively), but tumor location was not an independent predictor of recurrence or survival in the multivariable analyses. The recurrence patterns did not differ. Certain prognostic factors (i.e., CA 19.9, grading, R-status, and adjuvant treatment) were common, whereas others were site-specific (i.e., preoperative pain, diabetes, and multivisceral resection). The performances of the AJCC staging system were similar (C-statistics of 0.573 for H-PDAC and 0.597 for BT-PDAC, respectively).

Conclusions: Despite differences in pathologic profile found to be in favor of BT-PDAC, tumor location was not an independent predictor of recurrence or survival after pancreatectomy. An array of site-specific prognostic factors was identified, but the AJCC staging system displayed similar prognostic power regardless of primary tumor location.
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http://dx.doi.org/10.1245/s10434-020-08354-4DOI Listing
October 2020

Endoscopic ultrasound guided fine needle biopsy samples to drive personalized medicine: A proof of concept study.

Pancreatology 2020 06 17;20(4):778-780. Epub 2020 Mar 17.

ARC-Net Research Centre and Department of Diagnostics and Public Health, University of Verona, Verona, Italy; Department of Diagnostics and Public Health, University of Verona, Verona, Italy.

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http://dx.doi.org/10.1016/j.pan.2020.03.005DOI Listing
June 2020