Publications by authors named "Irene Esposito"

214 Publications

Invasive Breast Carcinoma with Neuroendocrine Differentiation: A Single-Center Analysis of Clinical Features and Prognosis.

Geburtshilfe Frauenheilkd 2022 Jan 18;82(1):68-84. Epub 2021 Nov 18.

Department of Obstetrics and Gynaecology, University of Düsseldorf, Düsseldorf, Germany.

Invasive breast cancer with neuroendocrine differentiation is a rare subtype of breast malignancy. Due to frequent changes in the definition of these lesions, the correct diagnosis, estimation of exact prevalence, and clinical behaviour of this entity may be challenging. The aim of this study was to evaluate the prevalence, clinical features, and outcomes in a large cohort of patients with breast cancer with neuroendocrine differentiation. Twenty-seven cases of breast cancer with neuroendocrine differentiation have been included in this analysis. Twenty-one cases were identified by systematic immunohistochemical re-evaluation of 465 breast cancer specimens using the neuroendocrine markers chromogranin A and synaptophysin, resulting in a prevalence of 4.5%. A further six cases were identified by a review of clinical records. Median age at the time of diagnosis was 61 years. 70% of patients had T2 - 4 tumors and 37% were node-positive. The most common immunohistochemical subtype was HR-positive/HER2-negative (85%). 93% were positive for synaptophysin and 48% for chromogranin A. Somatostatin receptor type 2A status was positive in 12 of 24 analyzed tumors (50%). Neuroendocrine-specific treatment with somatostatin analogues was administered in two patients. The 5-year survival rate was 70%. Breast cancer with neuroendocrine differentiation is mostly HR-positive/HER2-negative and the diagnosis is made at a higher TNM stage than in patients with conventional invasive breast carcinoma. Moreover, breast cancer with neuroendocrine differentiation was found to be associated with impaired prognosis in several retrospective trials. Due to somatostatin receptor 2A expression, somatostatin receptor-based imaging can be used and somatostatin receptor-targeted therapy can be offered in selected cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1557-1280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8747900PMC
January 2022

Neoadjuvant Treatment Lowers the Risk of Mesopancreatic Fat Infiltration and Local Recurrence in Patients with Pancreatic Cancer.

Cancers (Basel) 2021 Dec 23;14(1). Epub 2021 Dec 23.

Department of General, Visceral, Thoracic and Pediatric Surgery (A), Medical Faculty, Heinrich-Heine-University, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.

Background: Survival following surgical treatment of ductal adenocarcinoma of the pancreas (PDAC) remains poor. The recent implementation of the circumferential resection margin (CRM) into standard histopathological evaluation lead to a significant reduction in R0 rates. Mesopancreatic fat infiltration is present in ~80% of PDAC patients at the time of primary surgery and recently, mesopancreatic excision (MPE) was correlated to complete resection. To attain an even higher rate of R0(CRM-) resections in the future, neoadjuvant therapy in patients with a progressive disease seems a promising tool. We analyzed radiographic and histopathological treatment response and mesopancreatic tumor infiltration in patients who received neoadjuvant therapy prior to MPE. The aim of our study was to evaluate the need for MPE following neoadjuvant therapy and if multi-detector computed tomographically (MDCT) evaluated treatment response correlates with mesopancreatic (MP) infiltration.

Method: Radiographic, clinicopathological and survival parameters of 27 consecutive patients who underwent neoadjuvant therapy prior to MPE were evaluated. The mesopancreatic fat tissue was histopathologically analyzed and the 1 mm-rule (CRM) was applied.

Results: In the study collective, both the rate of R0 resection R0(CRM-) and the rate of mesopancreatic fat infiltration was 62.9%. Patients with MP infiltration showed a lower tumor response. Surgical resection status was dependent on MP infiltration and tumor response status. Patients with MDCT-predicted tumor response were less prone to MP infiltration. When compared to patients after upfront surgery, MP infiltration and local recurrence rate was significantly lower after neoadjuvant treatment.

Conclusion: MPE remains warranted after neoadjuvant therapy. Mesopancreatic fat invasion was still evident in the majority of our patients following neoadjuvant treatment. MDCT-predicted tumor response did not exclude mesopancreatic fat infiltration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers14010068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750596PMC
December 2021

Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia.

Cancers (Basel) 2021 Dec 8;13(24). Epub 2021 Dec 8.

Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, 40225 Düsseldorf, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13246188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699458PMC
December 2021

Pathologic Examination of Pancreatic Specimens Resected for Treated Pancreatic Ductal Adenocarcinoma: Recommendations From the Pancreatobiliary Pathology Society.

Am J Surg Pathol 2021 Dec 10. Epub 2021 Dec 10.

Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX Deciphex Pty, Ltd. Dublin, Ireland Department of Pathology, University of California San Diego, La Jolla Department of Pathology, University of California San Francisco, San Francisco, CA Department of Pathology, Cleveland Clinic, Cleveland, OH Institute of Pathology, University Hospital of Duesseldorf, Duesseldorf, Germany Oncology Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA Department of Pathology & Clinical Labs, Rogel Cancer Center, University of Michigan, Ann Arbor, MI Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Department of Pathology, University and Hospital Trust of Verona, Verona, Italy Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN Department of Pathology, Emory University Hospital, Atlanta, GA Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD Department of Pathology, Koc University Hospital and KUTTAM Research Center, Istanbul, Turkey.

Currently, there are no internationally accepted consensus guidelines for pathologic evaluation of posttherapy pancreatectomy specimens. The Neoadjuvant Therapy Working Group of Pancreatobiliary Pathology Society was formed in 2018 to review grossing protocols, literature, and major issues and to develop recommendations for pathologic evaluation of posttherapy pancreatectomy specimens. The working group generated the following recommendations: (1) Systematic and standardized grossing and sampling protocols should be adopted for pancreatectomy specimens for treated pancreatic ductal adenocarcinoma (PDAC). (2) Consecutive mapping sections along the largest gross tumor dimension are recommended to validate tumor size by histology as required by the College of American Pathologists (CAP) cancer protocol. (3) Tumor size of treated PDACs should be measured microscopically as the largest dimension of tumor outer limits that is bound by viable tumor cells, including intervening stroma. (4) The MD Anderson grading system for tumor response has a better correlation with prognosis and better interobserver concordance among pathologists than does the CAP system. (5) A case should not be classified as a complete response unless the entire pancreas, peripancreatic tissues, ampulla of Vater, common bile duct, and duodenum adjacent to the pancreas are submitted for microscopic examination. (6) Future studies on tumor response of lymph node metastases, molecular and/or immunohistochemical markers, as well as application of artificial intelligence in grading tumor response of treated PDAC are needed. In summary, systematic, standardized pathologic evaluation, accurate tumor size measurement, and reproducible tumor response grading to neoadjuvant therapy are needed for optimal patient care. The criteria and discussions provided here may provide guidance towards these goals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001853DOI Listing
December 2021

Multiparametric Circulating Tumor Cell Analysis to Select Targeted Therapies for Breast Cancer Patients.

Cancers (Basel) 2021 Nov 29;13(23). Epub 2021 Nov 29.

Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany.

Background: The analysis of liquid biopsies, e.g., circulating tumor cells (CTCs) is an appealing diagnostic concept for targeted therapy selection. In this proof-of-concept study, we aimed to perform multiparametric analyses of CTCs to select targeted therapies for metastatic breast cancer patients.

Methods: First, CTCs of five metastatic breast cancer patients were analyzed by whole exome sequencing (WES). Based on the results, one patient was selected and monitored by longitudinal and multiparametric liquid biopsy analyses over more than three years, including WES, RNA profiling, and in vitro drug testing of CTCs.

Results: Mutations addressable by targeted therapies were detected in all patients, including mutations that were not detected in biopsies of the primary tumor. For the index patient, the clonal evolution of the tumor cells was retraced and resistance mechanisms were identified. The AKT1 E17K mutation was uncovered as the driver of the metastatic process. Drug testing on the patient's CTCs confirmed the efficacy of drugs targeting the AKT1 pathway. During a targeted therapy chosen based on the CTC characterization and including the mTOR inhibitor everolimus, CTC numbers dropped by 97.3% and the disease remained stable as determined by computer tomography/magnetic resonance imaging.

Conclusion: These results illustrate the strength of a multiparametric CTC analysis to choose and validate targeted therapies to optimize cancer treatment in the future. Furthermore, from a scientific point of view, such studies promote the understanding of the biology of CTCs during different treatment regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13236004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657376PMC
November 2021

Targeting abundant survivin expression in liposarcoma: subtype dependent therapy responses to YM155 treatment.

J Cancer Res Clin Oncol 2021 Dec 3. Epub 2021 Dec 3.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, Bldg. 12.46, 40225, Duesseldorf, Germany.

Purpose: Liposarcoma (LPS) represent the largest group of malignant soft tissue tumours comprising a heterogeneous group of subtypes in which the degrees of chemoresistance and radiosensitivity strongly vary. Consequently, it is of utmost interest to establish novel therapeutic regimens based on molecular targets.

Methods: Immunohistochemical staining of survivin was performed in tissue microarrays comprising 49 primary LPS specimens. LPS cell lines were treated with survivin antagonist YM155 and doxorubicin or etoposide alone as well as in combination. Changes in cell viability were investigated and the synergistic effect of a combined therapy analysed.

Results: Immunohistochemistry revealed an abundant expression of survivin in LPS that significantly concurred with less-differentiated tumour subtypes and grading. In vitro, we demonstrated the impact of the survivin inhibitor YM155 on dedifferentiated LPS (DDLPS) and, even more imposing, pleomorphic LPS (PLS) tumour cell viability with a strong induction of apoptosis. A combined treatment of doxorubicin or etoposide with YM155 augmented the cytotoxic effects on DDLPS and PLS cells.

Conclusion: These findings support the significant role of survivin in the oncogenesis and progression of LPS subtypes providing a rationale to target survivin in eligible in-vivo models and to pioneer clinical applications of survivin-specific substances unfolding their therapeutic potential in LPS patients prospectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-021-03871-5DOI Listing
December 2021

Native glycan fragments detected by MALDI mass spectrometry imaging are independent prognostic factors in pancreatic ductal adenocarcinoma.

EJNMMI Res 2021 Dec 1;11(1):120. Epub 2021 Dec 1.

Research Unit Analytical Pathology, Helmholtz Zentrum Munich, 85764, Neuherberg, Germany.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date. The impressively developed stroma that surrounds and modulates the behavior of cancer cells is one of the main factors regulating the PDAC growth, metastasis and therapy resistance. Here, we postulate that stromal and cancer cell compartments differentiate in protein/lipid glycosylation patterns and analyze differences in glycan fragments in those compartments with clinicopathologic correlates.

Results: We analyzed native glycan fragments in 109 human FFPE PDAC samples using high mass resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometric imaging (MALDI-FT-ICR-MSI). Our method allows detection of native glycan fragments without previous digestion with PNGase or any other biochemical reaction. With this method, 8 and 18 native glycans were identified as uniquely expressed in only stromal or only cancer cell compartment, respectively. Kaplan-Meier survival model identified glycan fragments that are expressed in cancer cell or stromal compartment and significantly associated with patient outcome. Among cancer cell region-specific glycans, 10 predicted better and 6 worse patient survival. In the stroma, 1 glycan predicted good and 4 poor patient survival. Using factor analysis as a dimension reduction method, we were able to group the identified glycans in 2 factors. Multivariate analysis revealed that these factors can be used as independent survival prognostic elements with regard to the established Union for International Cancer Control (UICC) classification both in tumor and stroma regions.

Conclusion: Our method allows in situ detection of naturally occurring glycans in FFPE samples of human PDAC tissue and highlights the differences among glycans found in stromal and cancer cell compartment offering a basis for further exploration on the role of specific glycans in cancer-stroma communication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13550-021-00862-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636555PMC
December 2021

Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19.

Eur J Med Res 2021 Sep 16;26(1):107. Epub 2021 Sep 16.

Medical Faculty, University of Dusseldorf, Dusseldorf, Germany.

Background: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5).

Patient And Methods: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation.

Results: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing.

Conclusion: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40001-021-00560-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444184PMC
September 2021

Pre-Operative MDCT Staging Predicts Mesopancreatic Fat Infiltration-A Novel Marker for Neoadjuvant Treatment?

Cancers (Basel) 2021 Aug 28;13(17). Epub 2021 Aug 28.

Department of General, Visceral, Thoracic and Pediatric Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany.

The rates of microscopic incomplete resections (R1/R0CRM+) in patients receiving standard pancreaticoduodenectomy for PDAC remain very high. One reason may be the reported high rates of mesopancreatic fat infiltration. In this large cohort study, we used available histopathological specimens of the retropancreatic fat and correlated high resolution CT-scans with the microscopic tumor infiltration of this area. We found that preoperative MDCT scans are suitable to detect cancerous infiltration of this mesopancreatic tissue and this, in turn, was a significant indicator for both incomplete surgical resection (R1/R0CRM+) and worse overall survival. These findings indicate that a neoadjuvant treatment in PDAC patients with CT-morphologically positive infiltration of the mesopancreas may result in better local control and thus improved resection rates. Mesopancreatic fat stranding should thus be considered in the decision for neoadjuvant therapy. Due to the persistently high rates of R1 resections, neoadjuvant treatment and mesopancreatic excision (MPE) for ductal adenocarcinoma of the pancreatic head (hPDAC) have recently become a topic of interest. While radiographic cut-off for borderline resectability has been described, the necessary extent of surgery has not been established. It has not yet been elucidated whether pre-operative multi-detector computed tomography (MDCT) staging reliably predicts local mesopancreatic (MP) fat infiltration and tumor extension. Two hundred and forty two hPDAC patients that underwent MPE were analyzed. Radiographic re-evaluation was performed on (1) mesopancreatic fat stranding (MPS) and stranding to peripancreatic vessels, as well as (2) tumor diameter and anatomy, including contact to peripancreatic vessels (SMA, GDA, CHA, PV, SMV). Routinely resected mesopancreatic and perivascular (SMA and PV/SMV) tissue was histopathologically re-analyzed and histopathology correlated with radiographic findings. A logistic regression of survival was performed. MDCT-predicted tumor diameter correlated with pathological T-stage, whereas presumed tumor contact and fat stranding to SMA and PV/SMV predicted and correlated with histological cancerous infiltration. Importantly, mesopancreatic fat stranding predicted MP cancerous infiltration. Positive MP infiltration was evident in over 78%. MPS and higher CT-predicted tumor diameter correlated with higher R1 resection rates. Patients with positive MP stranding had a significantly worse overall survival ( = 0.023). A detailed preoperative radiographic assessment can predict mesopancreatic infiltration and tumor morphology and should influence the decision for primary surgery, as well as the extent of surgery. To increase the rate of R0CRM- resections, MPS should be considered in the decision for neoadjuvant therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13174361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430607PMC
August 2021

[Pancreatic pathology between 2005 and 2021: we're making progress!]

Pathologe 2021 09 26;42(5):451-452. Epub 2021 Aug 26.

Institut für Pathologie, Heinrich-Heine-Universität und Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00292-021-00962-5DOI Listing
September 2021

[Pancreatic pathology].

Pathologe 2021 09 26;42(5):449-450. Epub 2021 Aug 26.

Institut für Pathologie, Universitätsmedizin der JGU Mainz, Langenbeckstraße 1, 55131, Mainz, Deutschland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00292-021-00963-4DOI Listing
September 2021

[Intraductal neoplasms of the pancreas].

Pathologe 2021 Sep 17;42(5):472-483. Epub 2021 Aug 17.

Institut für Pathologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Deutschland.

The latest WHO classification of tumors of the digestive system (2019) has introduced new concepts for the stratification of intraductal neoplasms of the pancreas, mostly based on molecular genetics and malignant potential. Among them, pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMN) are both precursors of pancreatic ductal adenocarcinoma, whereas intraductal oncocytic papillary neoplasms (IOPN) and intraductal tubulopapillary neoplasms (ITPN) are usually associated with less aggressive subtypes of pancreatic cancer and therefore have a much better prognosis. Hence, it is of utmost importance to correctly classify these lesions and to distinguish them from each other as well as from other nonductal types of neoplasms, which can rarely display an intraductal growth, such as neuroendocrine tumors and acinar cell carcinomas. PanIN are microscopic lesions with limited clinical significance. In contrast, all other intraductal neoplasms can be identified as cystic processes and/or solid tumors by means of imaging, thereby setting an indication for a potential surgical resection. This review presents diagnostically relevant aspects of intraductal neoplasms of the pancreas, which are instrumental for the discussion within interdisciplinary tumor boards (resection vs. watch-and-wait strategies) as well as to determine the extent of resection intraoperatively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00292-021-00966-1DOI Listing
September 2021

Para-aortic lymph nodes and ductal adenocarcinoma of the pancreas: Distant neighbors?

Surgery 2021 12 13;170(6):1807-1814. Epub 2021 Aug 13.

Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany.

Background: Para-aortic lymph nodes in the ductal adenocarcinoma of the pancreatic head are regarded as distant metastases. Chemotherapy is considered the only treatment option if para-aortic lymph nodes metastases are detected preoperatively or intraoperatively. The role of standardized para-aortic lymph node lymphadenectomy during pancreaticoduodenectomy remains controversial. The aim of this study was to evaluate complication profiles and survival.

Methods: All cases of ductal adenocarcinoma of the pancreatic head were evaluated from a prospectively maintained database (n = 289). Para-aortic lymph node lymphadenectomy was routinely performed in all patients with suspected ductal adenocarcinoma of the pancreatic head. Subgroup analysis was performed between patients with histologically positive (+) and negative (-) para-aortic lymph nodes. Patients receiving pancreaticoduodenectomy without para-aortic lymph node lymphadenectomy for other causes served as a control group.

Results: A total of 192 patients received para-aortic lymph node lymphadenectomy, of which 41 were positive for para-aortic lymph node metastases. In 97 patients with ductal adenocarcinoma of the pancreatic head, no para-aortic lymph node lymphadenectomy was performed owing to postoperative pancreatic ductal adenocarcinoma diagnosis. Clinicopathologic data were homogenously distributed. Hospital stay and postoperative morbidity demonstrated no significant difference between the 3 subgroups. The median overall survival of 19.63 months (95% confidence interval: 14.57-24.79 months) in para-aortic lymph node- patients was not statistically different when compared with the median overall survival of 18.22 months (95% confidence interval: 12.68-23.75 months) in para-aortic lymph node + patients (log-rank test P = .223). Preoperative computed tomography was a poor predictor for para-aortic lymph node status (sensitivity = 10.3%, specificity = 97.8%).

Conclusion: This study represents the largest cohort receiving routine para-aortic lymph node lymphadenectomy. Extended lymphadenectomy can be performed safely and, although disease-free survival of para-aortic lymph node+ patients was significantly shorter, overall survival and postrelapse survival were on par with that of para-aortic lymph node- patients. Preoperative computed tomography indicating para-aortic lymph node metastasis should not preclude curative resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surg.2021.06.045DOI Listing
December 2021

Dataset for the reporting of carcinoma of the exocrine pancreas: recommendations from the International Collaboration on Cancer Reporting (ICCR).

Histopathology 2021 Dec 22;79(6):902-912. Epub 2021 Sep 22.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Centre, Nashville, TN, USA.

Aims: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations.

Methods And Results: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website.

Conclusions: This first international dataset for cancer of the exocrine pancreas is intended to promote high-quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.14540DOI Listing
December 2021

[Standardized diagnosis of pancreatic head carcinoma].

Pathologe 2021 Sep 6;42(5):453-463. Epub 2021 Aug 6.

Institut für Pathologie, Heinrich-Heine-Universität und Universitätsklinikum Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Deutschland.

Most pancreatic ductal adenocarcinomas are localized in the pancreatic head. Due to the complex anatomic relationships with the surrounding organs and vascular structures in the retroperitoneal space and to the presence of numerous transection margins and dissection planes, pancreatic head resections belong to the most complex specimens concerning grossing and sampling for histopathologic analysis.Here we discuss current guidelines for standardized grossing and reporting of pancreatic cancer, with special reference to the assessment of the resection margin status. The importance of standardized reporting for the sake of completeness, comprehensibility, comparability, and quality control as well as for the integration of pathology reports in interdisciplinary digital workflows and artificial intelligence applications will be emphasized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00292-021-00971-4DOI Listing
September 2021

[Preoperative diagnostics of pancreatic neoplasms].

Pathologe 2021 Sep 22;42(5):491-500. Epub 2021 Jul 22.

Institut für Pathologie, Heinrich-Heine-Universität und Universitätsklinikum Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Deutschland.

While patients with clinico-radiologically diagnosed resectable pancreatic cancer usually undergo surgery without preoperative cytological or histopathological diagnostics, patients with inoperable tumors or ambiguous findings in imaging often undergo EUS-FNA or EUS-FNB (endoscopic ultrasound-guided fine-needle aspiration or endoscopic ultrasound-guided fine-needle biopsy). In many cases, this concerns pancreatic cystic lesions, which can range from benign inflammatory pseudocysts to invasive pancreatic cancer emerging from intraductal papillary mucinous neoplasms (IPMNs) or mucinous cystic neoplasms (MCNs). However, the evaluation of EUS-FNA material can be especially hampered by contamination with gastric or enteric cells or mucin, degenerative changes, or low or even no cellularity of the sample. Next-generation-sequencing-based molecular analyses, especially of cystic lesions, can significantly increase the accuracy of EUS-FNA diagnostics of the pancreas. Interpretation of morphological and molecular data considering each case's clinico-radiological context is crucial. While reliable molecular markers for the detection of mucinous and specific nonmucinous pancreatic neoplasms already exist, establishing valid markers for the detection of high-grade lesions is an urgent future goal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00292-021-00972-3DOI Listing
September 2021

Whole Exome Sequencing of Biliary Tubulopapillary Neoplasms Reveals Common Mutations in Chromatin Remodeling Genes.

Cancers (Basel) 2021 Jun 1;13(11). Epub 2021 Jun 1.

Institute of Pathology, School of Medicine, Technische Universität München, 81675 Munich, Germany.

The molecular carcinogenesis of intraductal tubulopapillary neoplasms (ITPN), recently described as rare neoplasms in the pancreato-biliary tract with a favorable prognosis despite a high incidence of associated pancreato-biliary adenocarcinoma, is still poorly understood. To identify driver genes, chromosomal gains and losses, mutational signatures, key signaling pathways, and potential therapeutic targets, the molecular profile of 11 biliary and 6 pancreatic ITPNs, associated with invasive adenocarcinoma in 14/17 cases, are studied by whole exome sequencing (WES). The WES of 17 ITPNs reveals common copy number variants (CNVs) broadly distributed across the genome, with recurrent chromosomal deletions primarily in 1p36 and 9p21 affecting the tumor suppressors and , respectively, and gains in 1q affecting the prominent oncogene . The identified somatic nucleotide variants (SNVs) involve few core signaling pathways despite high genetic heterogeneity with diverse mutational spectra: Chromatin remodeling, the cell cycle, and DNA damage/repair. An OncoKB search identifies putative actionable genomic targets in 35% of the cases (6/17), including recurrent missense mutations of the gene in biliary ITPNs (2/11, 18%). Our results show that somatic SNV in classical cancer genes, typically associated with pancreato-biliary carcinogenesis, were absent (, , , and others) to rare ( and , 6%, respectively) in ITPNs. Mutational signature pattern analysis reveals a predominance of an age-related pattern. Our findings highlight that biliary ITPN and classical cholangiocarcinoma display commonalities, in particular mutations in genes of the chromatin remodeling pathway, and appear, therefore, more closely related than pancreatic ITPN and classical pancreatic ductal adenocarcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13112742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198366PMC
June 2021

Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.

Clin Case Rep 2021 May 24;9(5):e04068. Epub 2021 May 24.

Clinic for Gastroenterology, Hepatology and Infectious Diseases Heinrich-Heine-University Düsseldorf Düsseldorf Germany.

This case of secondary sclerosing cholangitis (SSC-CIP) emphasizes the need to provide follow-up care for patients that have recovered from COVID-19 in order to understand the complexity of SARS-CoV-2 associated sequela.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.4068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142800PMC
May 2021

CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation.

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, D06120 Halle/Saale, Germany.

The transcription factor CUX1 has been implicated in either tumor suppression or progression, depending on the cancer entity and the prevalent CUX1 isoform. Previously, we could show that CUX1 acts as an important mediator of tumor cell proliferation and resistance to apoptosis in pancreatic cancer cell lines. However, in vivo evidence for its impact on pancreatic carcinogenesis, isoform-specific effects and downstream signaling cascades are missing. We crossbred two different CUX1 isoform mouse models (p200 CUX1 and p110 CUX1) with KC (KrasLSL-G12D/+; Ptf1aCre/+) mice, a genetic model for pancreatic precursor lesions (PanIN). In the context of oncogenic KRASs, both mice KCCux1p200 and KCCux1p110 led to increased PanIN formation and development of invasive pancreatic ductal adenocarcinomata (PDAC). In KCCux1p110 mice, tumor development was dramatically more accelerated, leading to formation of invasive PDAC within 4 weeks. In vitro and in vivo, we could show that CUX1 enhanced proliferation by activating MEK-ERK signaling via an upstream increase of ADAM17 protein, which in turn led to an activation of EGFR. Additionally, CUX1 further enhanced MEK-ERK activation through upregulation of the serine/threonine kinase MOS, phosphorylating MEK in a KRAS-independent manner. We identified p110 CUX1 as major driver of pancreatic cancer formation in the context of mutant KRAS. These results provide the first in vivo evidence for the importance of CUX1 in the development of pancreatic cancer, and highlight the importance of CUX1-dependent signaling pathways as potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13102462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158495PMC
May 2021

Pancreatic ductal adenocarcinoma concomitant with pancreatic metastases of clear-cell renal cell carcinoma: a case report.

J Med Case Rep 2021 May 31;15(1):314. Epub 2021 May 31.

Institute of Pathology, Heinrich Heine University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.

Background: Metastatic spread to the pancreas is a rare event. Renal cell carcinoma represents one possible site of origin of pancreatic metastases. Renal cell carcinoma often metastasizes late and exclusively to the pancreas, suggesting a special role of renal cell carcinoma among primaries metastasizing to the pancreas. Even rarer, renal cell carcinoma may occur simultaneously with pancreatic ductal adenocarcinoma.

Case Presentation: We present the case of a 78-year-old male Caucasian patient with a history of clear-cell renal cell carcinoma treated with oncological left nephrectomy 20 years before. The patient was diagnosed with pancreatic ductal adenocarcinoma by fine-needle aspiration cytology. At our institution, he received neoadjuvant therapy with folic acid, fluorouracil, irinotecan, oxaliplatin for borderline-resectable pancreatic ductal adenocarcinoma, and subsequently underwent total pancreatectomy. Upon resection, pancreatic ductal adenocarcinoma as well as two metachronous metastases of clear-cell renal cell carcinoma occurring simultaneously and cospatially with pancreatic ductal adenocarcinoma were diagnosed in the pancreatic body.

Conclusions: Renal cell carcinoma metastases of the pancreas are rare and often occur decades after the initial diagnosis of renal cell carcinoma. The combination of renal cell carcinoma metastases and pancreatic ductal adenocarcinoma is even rarer. However, the possibility should be considered by clinicians, radiologists, and pathologists. The special role of renal cell carcinoma as a site of origin of pancreatic metastasis should be further elucidated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13256-021-02768-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168005PMC
May 2021

Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis.

J Hepatol 2021 09 17;75(3):634-646. Epub 2021 Apr 17.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis.

Methods: TGR5-expression and -localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4, Abcb4/Tgr5 and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4 mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models.

Results: TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4 livers, in Abcb4 extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4 mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfβ2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4 BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4 livers.

Conclusions: Reduced TGR5 levels in BECs from patients with PSC and Abcb4 mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA.

Lay Summary: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease-associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. Bile acid (BA) toxicity may contribute to the development and disease progression of PSC. TGR5 is a membrane-bound receptor for BAs, which is found on bile ducts and protects bile ducts from BA toxicity. In this study, we show that TGR5 levels were reduced in bile ducts from PSC livers and in bile ducts from a genetic mouse model of PSC. Our investigations indicate that lower levels of TGR5 in bile ducts may contribute to PSC development and progression. Furthermore, treatment with norUDCA, a drug currently being tested in a phase III trial for PSC, restored TGR5 levels in biliary epithelial cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.03.029DOI Listing
September 2021

Decapneization as supportive therapy for the treatment of status asthmaticus: a case report.

J Med Case Rep 2021 Apr 8;15(1):200. Epub 2021 Apr 8.

Unit of Intensive Care, Department of Emergency, "A. Cardarelli" Hospital, Naples, Italy.

Background: Acute severe asthma is a life-threatening medical emergency. Characteristics of asthma include increased airway resistance and dynamic pulmonary hyperinflation that can manifest in dangerous levels of hypercapnia and acidosis, with significant mortality and morbidity. Severe respiratory distress can lead to endotracheal intubation followed by mechanical ventilation, which can cause increased air trapping with dynamic hyperinflation, predisposing the lungs to barotraumas.

Case Presentation: The present case report describes the use of the minimally invasive ECCOR ProLUNG (Estor) with protective low-tidal-volume ventilation, in a Caucasian patient with near-fatal asthma and with no response to conventional therapy.

Conclusions: Since hypercarbia rather than hypoxemia is the primary abnormality in status asthmaticus, a rescue therapeutic strategy combining the ECCOR membrane ProLUNG (Estor) with ultra-protective low-tidal-volume ventilation can be successfully applied to limit the risk of severe barotrauma during invasive mechanical ventilation. ECCOR ProLUNG is a partial respiratory support technique that, based on the use of an extracorporeal circuit with a gas-exchange membrane, achieves relevant CO clearance directly from the blood using double-lumen venous-venous vascular access, at blood flow in the range of 0.4-1.0 L/minute.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13256-021-02689-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045444PMC
April 2021

Stroma composition and proliferative activity are related to therapy response in neoadjuvant treated pancreatic ductal adenocarcinoma.

Histol Histopathol 2021 Jul 26;36(7):733-742. Epub 2021 Mar 26.

Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany.

Background: Tumor regression grading (TRG) based on histopathology is the main tool to assess therapy effects after neoadjuvant therapy (NAT) of pancreatic ductal adenocarcinoma (PDAC). However, reliable markers to distinguish therapy effects from pre-existing tumor features are lacking. The aim of this study was the characterization of PDAC after NAT, focusing on the stroma.

Material And Methods: Tissue samples from patients resected for PDAC after NAT (n=27) were analyzed. TRG was assessed using the Royal North Shore (RNS) system. Stromal composition was evaluated by Movat's stain. Immunohistochemistry (IH) for Ki-67 and five previously established stroma markers (alpha-Crystallin B, alpha-Smooth muscle actin (alpha-SMA), Neurotrophin-3 (NT-3), SPARC and Tenascin C) was also performed. Results were compared with therapy-naïve PDACs (n=10).

Results: Most cases showed a moderate response (RNS 2; 74%), while 15% displayed a poor response (RNS 3), and 11% a good response (RNS 1). No complete response was observed. Poor regression was associated with mucin-rich stroma, while good regression was associated with collagen-rich stroma. Cases with poorer therapy response had significantly higher proliferation. Higher peritumoral staining intensity for alpha-SMA and Tenascin C also showed a trend towards an association with poor regression.

Conclusions: Similar to the stroma in therapy-naïve PDAC, the stroma of PDAC after NAT is heterogeneous. Distinguishing between desmoplastic stroma and therapy-induced fibrosis by single markers is not possible. Movat's pentachrome stain, IH for Ki-67, and to some extent for Tenascin C and alpha-SMA, can help detect poor histopathological response to NAT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14670/HH-18-332DOI Listing
July 2021

Detection of gene fusions using targeted next-generation sequencing: a comparative evaluation.

BMC Med Genomics 2021 02 27;14(1):62. Epub 2021 Feb 27.

Institute of Pathology, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

Background: Gene fusions represent promising targets for cancer therapy in lung cancer. Reliable detection of multiple gene fusions is therefore essential.

Methods: Five commercially available parallel sequencing assays were evaluated for their ability to detect gene fusions in eight cell lines and 18 FFPE tissue samples carrying a variety of known gene fusions. Four RNA-based assays and one DNA-based assay were compared; two were hybrid capture-based, TruSight Tumor 170 Assay (Illumina) and SureSelect XT HS Custom Panel (Agilent), and three were amplicon-based, Archer FusionPlex Lung Panel (ArcherDX), QIAseq RNAscan Custom Panel (Qiagen) and Oncomine Focus Assay (Thermo Fisher Scientific).

Results: The Illumina assay detected all tested fusions and showed the smallest number of false positive results. Both, the ArcherDX and Qiagen panels missed only one fusion event. Among the RNA-based assays, the Qiagen panel had the highest number of false positive events. The Oncomine Focus Assay (Thermo Fisher Scientific) was the least adequate assay for our purposes, seven fusions were not covered by the assay and two fusions were classified as uncertain. The DNA-based SureSelect XT HS Custom Panel (Agilent) missed three fusions and nine fusions were only called by one software version. Additionally, many false positive fusions were observed.

Conclusions: In summary, especially RNA-based parallel sequencing approaches are potent tools for reliable detection of targetable gene fusions in clinical diagnostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-021-00909-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912891PMC
February 2021

Diagnosis and management of secondary causes of steatohepatitis.

J Hepatol 2021 06 10;74(6):1455-1471. Epub 2021 Feb 10.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address:

The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.01.045DOI Listing
June 2021

Molecular analysis of cyst fluids improves the diagnostic accuracy of pre-operative assessment of pancreatic cystic lesions.

Sci Rep 2021 02 3;11(1):2901. Epub 2021 Feb 3.

Institute of Pathology, Heinrich-Heine University and University Hospital of Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.

Pancreatic cystic lesions (PCL) are increasingly diagnosed. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) cytology is often used for diagnostic confirmation but can be inconclusive. In this study, the role of molecular analyses in the pre-operative diagnostics of PCL is evaluated. Targeted Next Generation Sequencing (NGS) applied on cytology smears was retrospectively evaluated in a cohort of 37 resected PCL. Usefulness of NGS on fresh cyst fluids was tested in a prospective cohort of patients with newly diagnosed PCL (n = 71). In the retrospective cohort, cytology plus NGS displayed higher sensitivity (94.1% vs. 87.1%) and specificity (100% vs. 50%) than cytology alone for the detection of mucinous neoplasms. In the prospective cohort, sensitivity and specificity of conventional cytology alone were 54.2% and 100% for the detection of mucinous neoplasia and 50.0% and 100% for the detection of high-grade dysplasia, respectively. Adding NGS, all lesions which underwent histopathologic verification (12/71, 17%) could be classified without false positive or false negative results regarding the detection of mucinous neoplasm so far. NGS analysis of cfDNA in PCL fluids is feasible and can increase diagnostic accuracy in the detection of mucinous neoplasms compared to cytology alone. However, algorithms for the detection of high-risk lesions need further improvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-81065-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858638PMC
February 2021

Nonmucinous Cystic Lesions of the Pancreas.

Arch Pathol Lab Med 2021 Jan 27. Epub 2021 Jan 27.

From the Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany.

Context.—: Pancreatic cystic lesions are increasingly diagnosed. Among other criteria, they are often distinguished in mucinous versus nonmucinous cysts. Mucinous pancreatic cystic lesions have received increasing attention, especially those known as precursors of pancreatic ductal adenocarcinoma. However, the group of nonmucinous cystic lesions of the pancreas includes numerous entities that may pose a diagnostic challenge. Their accurate diagnosis and classification are crucial for adequate patient management.

Objective.—: To review the spectrum of nonmucinous cystic lesions of the pancreas, taking into consideration their epidemiology and typical clinical context, their characteristic gross morphology and histomorphology, as well as their immunohistochemical and molecular profile.

Data Sources.—: Literature was searched and reviewed with MEDLINE via PubMed. Macroscopic and microscopic images were obtained from the archives of the Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Germany.

Conclusions.—: Nonmucinous cysts of the pancreas comprise numerous, mostly rare entities displaying different biological behaviors. The most frequent are serous cystic neoplasms, solid-pseudopapillary neoplasms, cystic neuroendocrine tumors, and pancreatitis-associated pseudocysts. Accurate diagnosis can be achieved if characteristic clinical context, histomorphology, and immunoprofile are taken into account.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2020-0446-RADOI Listing
January 2021

Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis.

Gut 2022 Feb 19;71(2):391-401. Epub 2021 Jan 19.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

Objective: A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options.

Design: We analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling.

Results: Patients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but mutations occurred exclusively in invasive CCA and mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin.

Conclusion: Integrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2020-322983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762040PMC
February 2022

Spectral diffusion analysis of kidney intravoxel incoherent motion MRI in healthy volunteers and patients with renal pathologies.

Magn Reson Med 2021 06 18;85(6):3085-3095. Epub 2021 Jan 18.

Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich Heine University Dusseldorf, Düsseldorf, Germany.

Purpose: To assess the feasibility of measuring tubular and vascular signal fractions in the human kidney using nonnegative least-square (NNLS) analysis of intravoxel incoherent motion data collected in healthy volunteers and patients with renal pathologies.

Methods: MR imaging was performed at 3 Tesla in 12 healthy subjects and 3 patients with various kidney pathologies (fibrotic kidney disease, failed renal graft, and renal masses). Relative signal fractions f and mean diffusivities of the diffusion components in the cortex, medulla, and renal lesions were obtained using the regularized NNLS fitting of the intravoxel incoherent motion data. Test-retest repeatability of the NNLS approach was tested in 5 volunteers scanned twice.

Results: In the healthy kidneys, the NNLS method yielded diffusion spectra with 3 distinguishable components that may be linked to the slow tissue water diffusion, intermediate tubular and vascular flow, and fast blood flow in larger vessels with the relative signal fractions, f , f and f , respectively. In the pathological kidneys, the diffusion spectra varied substantially from those acquired in the healthy kidneys. Overall, the renal cyst showed substantially higher f and lower f , whereas the fibrotic kidney, failed renal graft, and renal cell carcinoma demonstrated the opposite trend.

Conclusion: NNLS-based intravoxel incoherent motion could potentially become a valuable tool in assessing changes in tubular and vascular volume fractions under pathophysiological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrm.28631DOI Listing
June 2021

Bile-Based Cell-Free DNA Analysis Is a Reliable Diagnostic Tool in Pancreatobiliary Cancer.

Cancers (Basel) 2020 Dec 25;13(1). Epub 2020 Dec 25.

Institute of Pathology, Heinrich-Heine-University and University Hospital of Duesseldorf, 40225 Duesseldorf, Germany.

Currently available serum biomarkers for pancreatobiliary cancers lack sensitivity and specificity and ultimate diagnosis still requires invasive procedures for histological confirmation. The detection of tumor-specific genetic aberrations with utilization of cell free DNA (cfDNA) is a less invasive approach than traditional tissue biopsies; however, it has not been implemented into clinical routine. In this study, we investigated bile as a liquid biopsy source in pancreatobiliary cancers and compared its potential as cell-free DNA source to plasma. Blood (n = 37) and bile (n = 21) samples were collected from patients affected by pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (CCA) or with non-malignant biliary obstructions (blood n = 16; bile n = 21). Panel-based next generation sequencing (NGS) and digital droplet PCR (ddPCR) were applied for tumor mutation profiling. NGS results from matched tumor tissues (n = 29) served as comparison. Sequencing of cfDNA from bile resulted in detection of 96.2% of the pathogenic tumor mutations found in matched tissue samples. On the other hand, only 31.6% of pathogenic tumor mutations found in tissue could be detected in plasma. In a direct comparison, only half of the mutations detected in bile cfDNA were concordantly detected in plasma from the same patients. Panel NGS and ddPCR displayed comparable sensitivity. In conclusion, bile is a suitable source of cfDNA for the diagnosis of pancreatobiliary cancer and performs more reliably than plasma. Although primary diagnosis still requires histologic confirmation, bile-derived cfDNA could offer an alternative if tissue sampling is not feasible and might allow less invasive disease monitoring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13010039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818177PMC
December 2020
-->