Publications by authors named "Hans Kreipe"

322 Publications

TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer.

Cancer Med 2021 Dec 14;10(23):8581-8594. Epub 2021 Nov 14.

Hannover Medical School, Institute of Pathology, Hannover, Germany.

Background: Whereas the genomic landscape of endocrine-resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non-responsiveness to endocrine treatment in luminal early breast cancer.

Methods: In this study, 622 estrogen receptor-expressing breast cancer cases treated with short-term preoperative endocrine therapy (pET) from the WSG-ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3-week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post-pET Ki67 <10%) versus slightly, moderately, and severely impaired (post-pET Ki67 10%-19%, 20%-34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next-generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization.

Results: ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53-mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen- and aromatase inhibitor-based pET (p = 0.0005 each).

Conclusion: We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53-mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.4376DOI Listing
December 2021

[Axel Georgii : 02 August 1927-07 February 2021].

Authors:
Hans H Kreipe

Pathologe 2021 Oct 20. Epub 2021 Oct 20.

Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00292-021-01017-5DOI Listing
October 2021

Immune Markers and Tumor-Related Processes Predict Neoadjuvant Therapy Response in the WSG-ADAPT HER2-Positive/Hormone Receptor-Positive Trial in Early Breast Cancer.

Cancers (Basel) 2021 Sep 29;13(19). Epub 2021 Sep 29.

The West German Study Group, 41061 Mönchengladbach, Germany.

Prognostic or predictive biomarkers in HER2-positive early breast cancer (EBC) may inform treatment optimization. The ADAPT HER2-positive/hormone receptor-positive phase II trial (NCT01779206) demonstrated pathological complete response (pCR) rates of ~40% following de-escalated treatment with 12 weeks neoadjuvant ado-trastuzumab emtansine (T-DM1) ± endocrine therapy. In this exploratory analysis, we evaluated potential early predictors of response to neoadjuvant therapy. The effects of mutations and immune (CD8 and PD-L1) and apoptotic markers (BCL2 and MCL1) on pCR rates were assessed, along with intrinsic BC subtypes. Immune response and pCR were lower in -mutated tumors compared with wildtype. Increased BCL2 at baseline in all patients and at Cycle 2 in the T-DM1 arms was associated with lower pCR. In the T-DM1 arms only, the HER2-enriched subtype was associated with increased pCR rate (54% vs. 28%). These findings support further prospective pCR-driven de-escalation studies in patients with HER2-positive EBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13194884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508505PMC
September 2021

Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors.

Cancers (Basel) 2021 Jul 22;13(15). Epub 2021 Jul 22.

Department of Diagnostic and Theranostic Medicine, Department of Pathology, Institute Curie, PSL-Research University, 26 rue d'Ulm, 75005 Paris, France.

Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in -deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13153695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345067PMC
July 2021

Status quo of ALK testing in lung cancer: results of an EQA scheme based on in-situ hybridization, immunohistochemistry, and RNA/DNA sequencing.

Virchows Arch 2021 Aug 25;479(2):247-255. Epub 2021 Jun 25.

Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany.

With this external quality assessment (EQA) scheme, we aim to investigate the diagnostic performance of the currently available methods for the detection of ALK alterations in non-small cell lung cancer on a national scale, namely, in situ hybridization (ISH), immunohistochemistry (IHC), and RNA/DNA sequencing (NGS). The EQA scheme cohort consisted of ten specimens, including four ALK positive and six ALK negative samples, which were thoroughly pretested using IHC, ISH, and RNA/DNA NGS. Unstained tumor sections were provided to the 57 participants, and the results were retrieved via an online questionnaire. ISH was used by 29, IHC by 38, and RNA/DNA sequencing by 19 participants. Twenty-eight institutions (97%) passed the ring trial using ISH, 33 (87%) by using IHC, and 18 (95%) by using NGS. The highest sensitivity and interrater agreement (Fleiss ' kappa) was observed for RNA/DNA sequencing (99%, 0.975), followed by ISH (94%, 0.898) and IHC (92%, 0.888). However, the proportion of samples that were not evaluable due to bad tissue quality was also higher for RNA/DNA sequencing (4%) compared with ISH (0.7%) and IHC (0.5%). While all three methods produced reliable results between the different institutions, the highest sensitivity and concordance were observed for RNA/DNA sequencing. These findings encourage the broad implementation of this method in routine diagnostic, although the application might be limited by technical capacity, economical restrictions, and tissue quality of formalin-fixed samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-021-03106-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364534PMC
August 2021

The use of breast ultrasound for prediction of pathologic complete response in different subtypes of early breast cancer within the WSG-ADAPT subtrials.

Breast 2021 Oct 14;59:58-66. Epub 2021 Jun 14.

West German Study Group, Ludwig-Weber-Strasse 15, 41061, Moenchengladbach, Germany; Breast Center Niederrhein, Ev. Hospital Bethesda, Ludwig-Weber-Strasse 15, 41061, Moenchengladbach, Germany.

Objective: We assessed the value of breast ultrasound (US) performed at week 3 and 6 and at the end (EOT) of neoadjuvant therapy (NAT) for prediction of pathologic complete response (pCR, ypT0/is ypN0) in patients with HR+/HER2+, HR-/HER2-or HR-/HER2+ early breast cancer enrolled in the WSG-ADAPT subtrials.

Methods: US was performed at week 3 and 6 of NAT and at EOT in 401, 517, and 553 patients, respectively. Tumors with complete or partial response by US (RECIST 1.1) were classified as responders and those with stable or progressive disease as non-responders.

Results: pCR rate was higher in US responders than in non-responders. US tended to yield the highest positive predictive value in HR-/HER2+ (69%) and HR-/HER2-tumors (65%) at week 3, and the highest negative predictive value in HR+/HER2+ tumors at week 6 and at EOT (88.9% and 86.9%, respectively) and in HR-/HER2-tumors at EOT (87.9%). Multivariable analysis of patients with US at week 3 and 6 identified tumor subtype (HR-/HER2+ vs HR+/HER2+; odds ratio (OR) 2.77, 95%CI 1.45-5.29, and OR 4.17, 95%CI 2.26-7.68, respectively) and each 10% change in lesion dimension on US from baseline (OR 1.15, 95%CI 1.08-1.24, and OR 1.25, 95%CI 1.16-1.35, respectively) as parameters associated with pCR.

Conclusions: Our data support the use of week 3 and EOT US for prediction of pCR in response-guided NAT and in planning of breast-conserving surgery. Change in tumor diameter on US as a continuous variable could be a valuable alternative to categorical RECIST 1.1 criteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239457PMC
October 2021

Immune cell composition and functional marker dynamics from multiplexed immunohistochemistry to predict response to neoadjuvant chemotherapy in the WSG-ADAPT-TN trial.

J Immunother Cancer 2021 05;9(5)

West German Study Group, Moenchengladbach, Germany.

Background: The association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored.

Methods: Multiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression.

Results: Compared with no change in immune cell composition and functional markers, transition from 'cold' to 'hot' (below-median and above-median marker level at baseline, respectively) suggested higher pCR rates for PD1-positive CD4 (tumor: OR=1.55, 95% CI 0.45 to 5.42; stroma: OR=2.65, 95% CI 0.65 to 10.71) and PD1-positive CD8 infiltrates (tumor: OR=1.77, 95% CI 0.60 to 5.20; stroma: OR=1.25, 95% CI 0.41 to 3.84; tumor+stroma: OR=1.62, 95% CI 0.51 to 5.12). No pCR was observed after 'hot-to-cold' transition in PD1-positive CD8 cells. pCR rates appeared lower after hot-to-cold transitions in T cells (tumor: OR=0.26, 95% CI 0.03 to 2.34; stroma: OR=0.35, 95% CI 0.04 to 3.25; tumor+stroma: OR=0.00, 95% CI 0.00 to 1.04) and PD1-positive CD4 cells (tumor: OR=0.60, 95% CI 0.11 to 3.35; stroma: OR=0.22, 95% CI 0.03 to 1.92; tumor+stroma: OR=0.32, 95% CI 0.04 to 2.94). Higher pCR rates collated with 'altered' distribution (levels below-median and above-median in tumor and stroma, respectively) of T cell (OR=3.50, 95% CI 0.84 to 14.56) and PD1-positive CD4 cells (OR=4.50, 95% CI 1.01 to 20.14).

Conclusion: Our exploratory findings indicate that comprehensive analysis of early immune infiltrate dynamics complements currently investigated predictive markers for pCR and may have a potential to improve guidance for individualized de-escalation/escalation strategies in TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-002198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108653PMC
May 2021

[Relevant mutations in predictive breast cancer pathology].

Pathologe 2021 Jul 6;42(4):399-404. Epub 2021 Apr 6.

Institut für Pathologie, Universitätsklinikum Heidelberg, Heidelberg, Deutschland.

Whereas predictive immunohistochemistry has represented a core element of breast cancer classification for decades, predictive molecular pathology, with the exception of in situ hybridization for assessment of HER2 amplification, has only recently gained importance because novel drugs have been approved for treatment of metastatic disease. For the use of PARP inhibitors, proof of BRCA1 or BRCA2 mutation is mandatory. When mutation of the catalytic subunit α of the phosphatidylinositol‑4.5‑bisphosphate 3‑kinase gene (PIK3CA) is present, which can be encountered in up to 40% of luminal breast cancers, the option for treatment with the specific inhibitor alpelisib arises. The HER2 -encoded growth factor receptor contributes to neoplastic transformation not only by amplification and overexpression but also by activating the mutation of the kinase domain, which is responsive to tyrosine kinase inhibitors of the tucatinib/neratinib type. Up to 30% of metastatic and endocrine treated luminal breast cancers acquire an activating mutation of the estrogen receptor gene ESR1, resulting in an autocrine and ligand-independent growth stimulation resistant to aromatase inhibitors. Larotrectinib-sensitive mutation of tropomyosinreceptor kinase is present in up to 50% of secretory breast cancers, whereas the other histologic subtypes display an incidence of below 1%. In conclusion, predictive molecular pathology has gained importance in metastatic breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00292-021-00929-6DOI Listing
July 2021

Transcription factor AP-2beta in development, differentiation and tumorigenesis.

Int J Cancer 2021 09 26;149(6):1221-1227. Epub 2021 Mar 26.

Institute of Pathology, Hannover Medical School, Hannover, Germany.

To date, the AP-2 family of transcription factors comprises five members. Transcription factor AP-2beta (TFAP2B)/AP-2β was first described in 1995. Several studies indicate a critical role of AP-2β in the development of tissues and organs of ectodermal, neuroectodermal and also mesodermal origin. Germline mutation of TFAP2B is known to cause the Char syndrome, an autosomal dominant disorder characterized by facial dysmorphism, patent ductus arteriosus and anatomical abnormalities of the fifth digit. Furthermore, single-nucleotide polymorphisms in TFAP2B were linked to obesity and specific personality traits. In neoplasias, AP-2β was first described in alveolar rhabdomyosarcoma. Immunohistochemical staining of AP-2β is a recommended ancillary test for the histopathological diagnosis of this uncommon childhood malignancy. In neuroblastoma, AP-2β supports noradrenergic differentiation. Recently, the function of AP-2β in breast cancer (BC) has gained interest. AP-2β is associated with the lobular BC subtype. Moreover, AP-2β controls BC cell proliferation and has a prognostic impact in patients with BC. This review provides a comprehensive overview of the current knowledge about AP-2β and its function in organ development, differentiation and tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33558DOI Listing
September 2021

Genome-wide DNA methylation profiling is able to identify prefibrotic PMF cases at risk for progression to myelofibrosis.

Clin Epigenetics 2021 02 4;13(1):28. Epub 2021 Feb 4.

Institute of Pathology, Medical School Hannover, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background: Patients suffering from the BCR-ABL1-negative myeloproliferative disease prefibrotic primary myelofibrosis (pre-PMF) have a certain risk for progression to myelofibrosis. Accurate risk estimation for this fibrotic progression is of prognostic importance and clinically relevant. Commonly applied risk scores are based on clinical, cytogenetic, and genetic data but do not include epigenetic modifications. Therefore, we evaluated the assessment of genome-wide DNA methylation patterns for their ability to predict fibrotic progression in PMF patients.

Results: For this purpose, the DNA methylation profile was analyzed genome-wide in a training set of 22 bone marrow trephines from patients with either fibrotic progression (n = 12) or stable disease over several years (n = 10) using the 850 k EPIC array from Illumina. The DNA methylation classifier constructed from this data set was validated in an independently measured test set of additional 11 bone marrow trephines (7 with stable disease, 4 with fibrotic progress). Hierarchical clustering of methylation β-values and linear discriminant classification yielded very good discrimination between both patient groups. By gene ontology analysis, the most differentially methylated CpG sites are primarily associated with genes involved in cell-cell and cell-matrix interactions.

Conclusions: In conclusion, we could show that genome-wide DNA methylation profiling of bone marrow trephines is feasible under routine diagnostic conditions and, more importantly, is able to predict fibrotic progression in pre-fibrotic primary myelofibrosis with high accuracy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-021-01010-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860011PMC
February 2021

Combination of myeloproliferative neoplasm driver gene activation with mutations of splice factor or epigenetic modifier genes increases risk of rapid blastic progression.

Eur J Haematol 2021 Apr 1;106(4):520-528. Epub 2021 Feb 1.

Institut für Pathologie, Medizinische Hochschule Hannover, Hannover, Germany.

Objectives: Myeloproliferative neoplasms (MPN) comprising polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) follow a bi-phasic course of disease with fibrotic and/or blastic progression. At presentation in the chronic phase, currently there are only insufficient tools to predict the risk of progression in individual cases.

Methods: In this study, chronic phase MPN (16 PMF, 11 PV, and 11 MPN unclassified) with blastic transformation during course of disease (n = 38, median follow-up 5.3 years) were analyzed by high-throughput sequencing. MPN cases with a comparable follow-up period and without evidence of blast increase served as control (n = 63, median follow-up 5.8 years).

Results: Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, DNMT3A) found at presentation were not significantly associated with blastic transformation. By contrast, mutations of SRSF2, U2AF1, and IDH1/2 at first presentation were frequently observed in the progression cohort (13/38, 34.2%) and were completely missing in the control group without blast transformation during follow-up (P = .0007 for SRSF2; P = .0063 for U2AF1 and IDH1/2).

Conclusion: Unlike frequent ARCH/CHIP alterations (TET2, ASXL1, DNMT3A), mutations in SRSF2, IDH1/2, and U2AF1 when manifest already at first presentation provide an independent risk factor for rapid blast transformation of MPN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13579DOI Listing
April 2021

Chromosome 2q gain and epigenetic silencing of GATA3 in microglandular adenosis of the breast.

J Pathol Clin Res 2021 May 31;7(3):220-232. Epub 2020 Dec 31.

Institute of Pathology, Hannover Medical School, Hannover, Germany.

Microglandular adenosis (MGA) represents a rare neoplasm of the mammary gland, which in a subset of cases may be associated with triple-negative breast cancer (BC). The biology of MGA is poorly understood. In this study, eight MGA cases (n = 4 with and n = 4 without associated BC) were subjected to a comprehensive characterization using immunohistochemistry, genome-wide DNA copy number (CN) profiling, fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and DNA methylation profiling using 850 K arrays and bisulfite pyrosequencing. Median patient age was 61 years (range 57-76 years). MGA lesions were estrogen receptor (ER)-negative, progesterone receptor-negative, HER2-negative, and S100-positive. DNA CN alterations (CNAs) were complex or limited to few gains and losses. CN gain on chromosome 2q was the most common CNA and was validated by FISH in five of eight cases. NGS demonstrated an average of two mutations per case (range 0-5) affecting 10 different genes (ARID1A, ATM, CTNNB1, FBXW7, FGFR2, MET, PIK3CA, PMS2, PTEN, and TP53). CNAs and mutations were similar in MGA and adjacent BC, indicating clonal relatedness. DNA methylation profiling identified aberrant hypermethylation of CpG sites within GATA3, a key transcription factor required for luminal differentiation. Immunohistochemistry showed regular GATA3 protein expression in the normal mammary epithelium and in ER-positive BC. Conversely, GATA3 was reduced or lost in all MGA cases tested (8/8). In conclusion, MGA is characterized by common CN gain on chromosome 2q and loss of GATA3. Epigenetic inactivation of GATA3 may provide a new clue to the peculiar biology of this rare neoplasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cjp2.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073017PMC
May 2021

Clinically latent and autopsy-verified inflammatory disorders and malignant tumours in transplant patients.

J Clin Pathol 2020 Dec 28. Epub 2020 Dec 28.

Institute of Pathology, Hannover Medical School, Hannover, Germany

Aims: The number of clinical autopsies decreases while the rate of missed relevant diagnoses is known to be 2%-20%. In this study, we focused on postmortem examinations of patients after transplantation of solid organs.

Methods: A total of 122 cases were assessed for this study. Transplant organs included liver (LiTx; n=42/122, 34%), heart (n=8/122, 7%), lungs (n=32/122, 26%), kidney (KTx; n=38/122, 31%) and KTx+LiTx (n=2/122, 2%).

Results: The most frequent autopsy-verified causes of death were cardiac or respiratory failure (together n=85/122, 70%). The frequency of malignant tumours that were identified at autopsy was 5% (n=6/122). In 3% (n=4/122) of cases, Goldman class I discrepancies between clinical diagnosis and autopsy findings were identified.

Conclusions: The rate of missed relevant diagnoses might be relatively low, but these cases nevertheless refute the contention that modern diagnostic techniques negate the need for autopsies in patients who died after transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2020-207080DOI Listing
December 2020

Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group.

J Natl Cancer Inst 2021 Jul;113(7):808-819

University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.

Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor-positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djaa201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487652PMC
July 2021

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.

Cell Stem Cell 2021 04 9;28(4):637-652.e8. Epub 2020 Dec 9.

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands; Department of Cell Biology, Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; Oncode Institute, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands. Electronic address:

Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stem.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024900PMC
April 2021

The run-in phase of the prospective WSG-ADAPT HR+/HER2- trial demonstrates the feasibility of a study design combining static and dynamic biomarker assessments for individualized therapy in early breast cancer.

Ther Adv Med Oncol 2020 23;12:1758835920973130. Epub 2020 Nov 23.

Breast Center, Department OB&GYN and CCCLMU, LMU University Hospital, Marchioninistrasse 15, Munich DE-81377, Germany.

Background: Endocrine sensitivity, as determined by response of the proliferation marker Ki-67 to short-term preoperative endocrine therapy (ET), is currently not included in adjuvant treatment decisions in hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer (BC).

Methods: The prospective WSG-ADAPT HR+/HER2- trial included patients with N0/N1 early BC who were candidates for adjuvant chemotherapy based on clinical-pathological criteria alone. The trial utilized a genomic assessment [the Recurrence Score (RS)] plus endocrine sensitivity testing to guide treatment. All patients received 3 (±1) weeks of preoperative induction ET. According to protocol, patients with RS 0-11 or RS 12-25 plus endocrine proliferation response (EPR, post-induction Ki-67 ⩽ 10%) were to be spared adjuvant chemotherapy.

Results: The ADAPT HR+/HER2- trial run-in phase included 407 patients with baseline RS, of whom 386 (median age: 54 years) had complete data for Ki-67 at both baseline and post-induction. RS distribution: 23.1% RS 0-11, 58.3% RS 12-25, and 18.7% RS 26-100. EPR occurred in 84.3%, 76.0%, and 36.1% of these RS groups, respectively. Differences in EPR proportions (RS 26-100 others, RS 0-11 others) were significant (both  < 0.001); Ki-67 quotients were higher for RS 26-100 ( = 0.02, Mann-Whitney). In premenopausal women ( = 146, mostly tamoxifen-treated), median quotient of Ki-67 level (post/pre) was significantly higher than in postmenopausal women ( = 222, mostly aromatase-inhibitor treated; 0.67 0.25,  < 0.001). EPR was significantly associated with baseline estrogen-receptor status as determined by immunohistochemistry ( = 0.002) or real-time polymerase chain reaction ( < 0.001). Also, a strong correlation was observed between RS measured pre- and post-ET (R = 0.7,  = 181).

Conclusions: This phase of the WSG-ADAPT HR+/HER2- trial confirms trial design estimates of RS and EPR. It indicates that the ADAPT concept of combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible using the EPR criterion post-induction Ki-67 ⩽ 10%.

Clinicaltrialsgov Identifier: NCT01779206.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1758835920973130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692353PMC
November 2020

Bicentric Retrospective Analysis of en Bloc Resection and Muscularis Mucosae Detection Rate in Non-Muscle Invasive Bladder Tumors: A Real-World Scenario.

Adv Ther 2021 01 22;38(1):258-267. Epub 2020 Oct 22.

Institute of Pathology, University Medical Center Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538, Luebeck, Germany.

Introduction: For risk stratification of non-muscle invasive bladder cancer (NMIBC), the depth of stromal invasion can be further classified, where the lamina muscularis mucosae (MM) serves as a reference structure. While the overall identifiability of MM in standard transurethral specimens is low, en bloc resection may help in identification and overall orientation. The aims of this study were to report the detection rate of MM in en bloc resected bladder tumors (ERBT) and to provide real-world information on tissue stability and preservation of en bloc architecture during recovery and processing for histopathologic evaluation.

Methods: Thirty-four ERBT specimens were histologically re-evaluated with regard to MM detectability and structure as well as the presence of en bloc architecture and further histologic features. Associations with tumor size and energy source and within histologic parameters were assessed by standard Pearson's chi-squared analyses and Cramér's V effect size testing (V).

Results: The first parameter assessed was MM detection rate. In 19 out of 34 samples (56%) MM was detectable: scattered in 9 cases (26%), interrupted in 8 cases (24%) and continuous in 2 cases (6%). The second parameter assessed was preservation of en bloc architecture. In 11 out of 34 samples (32%), en bloc architecture could not be confirmed, and these samples served as a reference group for the detection of MM. Preservation of en bloc architecture was associated with an increased MM detection rate (MM in en bloc preserved 16/23, 70% vs. non-preserved 3/11, 27%; p = 0.020; V = 0.398) and with tumor size (p = 0.005; V = 0.595). Medium-sized tumors (1.1-2 cm) were best preserved. The choice of energy source did not show relevant association with en bloc architecture (p = n.s.).

Conclusions: In line with recent publications, ERBT increases the MM detection rate considerably. However, a third of the ERBT specimens lost en bloc architecture during sample recovery and processing. Tumor size is a relevant factor, with optimal architecture preservation between 1 and 2 cm. Optimizing resection techniques, recovery, transport, and diagnostic processing of ERBT samples is warranted to verify the diagnostic value of MM-based substaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12325-020-01529-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854421PMC
January 2021

A multicenter prospective, randomized, placebo-controlled phase II/III trial for preemptive acute graft-versus-host disease therapy.

Leukemia 2021 06 20;35(6):1763-1772. Epub 2020 Oct 20.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD_MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD_MS17 classification factor above 0.1 to receive either prednisolone (2-2.5 mg/kg, N = 44) or placebo (N = 47; N = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66-4.32, P = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group (P = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-01059-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179847PMC
June 2021

Differential impact of prognostic parameters in hormone receptor-positive lobular breast cancer.

Cancer 2020 11 11;126(22):4847-4858. Epub 2020 Aug 11.

Institute of Pathology, Hannover Medical School, Hannover, Germany.

Background: Invasive lobular breast cancer (BC) is the second most common BC subtype. Prognostic parameters (tumor classification, lymph node status, histologic grade, Oncotype DX recurrence score [RS], progesterone receptor status, and Ki67 index) were retrospectively studied in a large, prospective clinical trial encompassing 2585 patients who had hormone receptor-positive early BC (the West German Study Group PlanB trial).

Methods: BCs were centrally reviewed and classified as lobular (n = 353; 14%) or nonlobular (n = 2232; 86%). The median follow-up was 60 months. Five-year disease-free survival (DFS) estimates were obtained using the Kaplan-Meier method. Prognostic parameters were evaluated using Cox proportional hazard models.

Results: Lobular BC was associated with higher tumor classification, higher lymph node status, lower histologic grade, lower Ki67 index, and low or intermediate RS. The prevalence of high RS (RS range, 26-100) was 3-fold lower in patients who had lobular BC compared with those who had nonlobular BC (8% vs 24%; P < .001). However, 5-year DFS estimates for lobular and nonlobular BC were similar (92.1% and 92.3%, respectively; P = .673). In multivariate analyses, prognostic parameters for DFS in lobular BC included grade 3 (hazard ratio, 5.06; 95% CI, 1.91-13.39) and a pathologic lymph node status (pN) of pN3 (hazard ratio, 12.16; 95% CI, 3.87-38.24), but not RS. By contrast, prognostic parameters in nonlobular BC included grade 3 (hazard ratio, 1.65; 95% CI, 1.11-2.44), pN3 (hazard ratio, 3.68; 95% CI, 1.60-8.46), and high RS (hazard ratio, 2.49; 95% CI, 1.69-3.68).

Conclusions: Lobular BC is associated with low and intermediate RS, although 5-year DFS is similar to that of nonlobular BC. The effect of the RS in lobular BC appears to be distinct from that in nonlobular BC. For risk assessment, the RS needs to be complemented by clinicopathologic parameters for therapy decision making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33104DOI Listing
November 2020

Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN.

Blood 2020 10;136(18):2051-2064

Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) that leads to progressive bone marrow (BM) fibrosis. Although the cellular mutations involved in the pathogenesis of PMF have been extensively investigated, the sequential events that drive stromal activation and fibrosis by hematopoietic-stromal cross-talk remain elusive. Using an unbiased approach and validation in patients with MPN, we determined that the differential spatial expression of the chemokine CXCL4/platelet factor-4 marks the progression of fibrosis. We show that the absence of hematopoietic CXCL4 ameliorates the MPN phenotype, reduces stromal cell activation and BM fibrosis, and decreases the activation of profibrotic pathways in megakaryocytes, inflammation in fibrosis-driving cells, and JAK/STAT activation in both megakaryocytes and stromal cells in 3 murine PMF models. Our data indicate that higher CXCL4 expression in MPN has profibrotic effects and is a mediator of the characteristic inflammation. Therefore, targeting CXCL4 might be a promising strategy to reduce inflammation in PMF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019004095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678060PMC
October 2020

mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer.

Cancers (Basel) 2020 Jul 14;12(7). Epub 2020 Jul 14.

Department of Medical Oncology, Hospital Clínic de Barcelona, 08036 Barcelona, Spain.

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene mRNA. We analyzed expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20-8.41% of tumors across 15 cancer types as -high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12071902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409149PMC
July 2020

E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements.

Mod Pathol 2020 12 22;33(12):2483-2498. Epub 2020 Jun 22.

Institute of Pathology, Hannover Medical School, Hannover, Germany.

Loss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer (ILBC). Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell adhesion. E-cadherin to P-cadherin expression switching can rescue AJs and cell adhesion. However, P-cadherin has not been implicated in ILBC, so far. We aimed to characterize 13 ILBCs with exceptional histomorphology, which we termed ILBCs with tubular elements. The CDH1 mutational status was determined by next generation sequencing and whole-genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were ER-positive (13/13) and HER2-negative (13/13) and harbored deleterious CDH1 mutations (11/13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (9/11). E-cadherin expression was lost or reduced in noncohesive tumor cells and in admixed tubular elements (13/13). Beta-catenin expression was lost in noncohesive tumor cells, but was retained in tubular elements (11/13), indicating focal rescue of AJ formation. N-cadherin and R-cadherin were always negative (0/13). Strikingly, P-cadherin was commonly positive (12/13) and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ (LCIS) was always P-cadherin-negative (0/7). In a reference cohort of LCIS specimens, P-cadherin was constantly not expressed (0/25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36/268, 13%) were associated with triple-negative nonlobular breast cancer (P < 0.001). Compared with ILBCs from the reference cohort, P-cadherin expression was more common in ILBCs with tubular elements (12/13 versus 7/84, P < 0.001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-0591-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685979PMC
December 2020

Evidence-based guidelines for managing patients with primary ER+ HER2- breast cancer deferred from surgery due to the COVID-19 pandemic.

NPJ Breast Cancer 2020 8;6:21. Epub 2020 Jun 8.

West German Study Group, Mönchengladbach, Germany.

Many patients with ER+ HER2- primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER <6 or ER 6 and PgR <6) (ii) a biopsy for Ki67 analysis (on-treatment Ki67) could be considered after 2-4 weeks of NeoET (a: ER 7 or 8 and PgR <6 or b: ER 6 or 7 and PgR ≥6) or (iii) NeoET is an acceptable course of action (ER 8 and PgR ≥6). Cut-offs for percentage of cells positive are also given. For group (ii), a high early on-treatment level of Ki67 (>10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2- breast cancer during and in the aftermath of the COVID-19 crisis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-020-0168-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280290PMC
June 2020

Association of TILs with clinical parameters, Recurrence Score® results, and prognosis in patients with early HER2-negative breast cancer (BC)-a translational analysis of the prospective WSG PlanB trial.

Breast Cancer Res 2020 05 14;22(1):47. Epub 2020 May 14.

West German Study Group, Mönchengladbach, Germany.

Background: The presence of tumor-infiltrating lymphocytes has been associated with prognosis and chemotherapy response, particularly in high-risk breast cancer subtypes. There is limited data so far as to (i) how tumor-infiltrating lymphocyte (TIL) measurements correlate with genomic measurements such as the Oncotype DX Recurrence Score® and (ii) whether the survival impact of TIL measurements varies according to different adjuvant systemic therapies.

Methods: The WSG PlanB trial compared an anthracycline-free chemotherapy regimen (6x docetaxel/cyclophosphamide, TC) to an anthracycline-taxane sequence (4xEC followed by 4x docetaxel) in patients with intermediate-risk, HER2-negative early breast cancer (EBC). Patients with HR-positive HER2-negative EBC were further stratified to receive endocrine therapy alone vs. chemotherapy followed by endocrine therapy based on Recurrence Score results and nodal status. In this analysis, three independent observers quantified and categorized the presence of TILs among tumor samples from patients in PlanB. TIL measurements were correlated with clinical/pathological parameters and treatment outcome overall and according to the treatment arm.

Results: Disease-free survival (DFS) rates were significantly better (p = .04) in HR-negative patients with high vs. intermediate TIL levels and were higher in low vs. intermediate TIL patients, however with borderline significance only (p = .06). There were no significant differences among TIL categories in HR+ patients. High RS categories, HR-negative status, and high KI67 were independently and significantly associated with high TIL categories. There was no significant impact of TIL category on DFS in patients treated by endocrine therapy only; however, in patients receiving chemotherapy, DFS in the intermediate TIL category was lower than that in the other categories.

Conclusion: Although the presence of high TILs is associated with negative prognostic parameters such as high KI67 and HR-negative status among patients with HR-positive HER2-negative EBC, patients with high TILs show a favorable 5-year DFS in both HR-positive/HER2-negative and triple-negative breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13058-020-01283-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227091PMC
May 2020

NTRK testing: First results of the QuiP-EQA scheme and a comprehensive map of NTRK fusion variants and their diagnostic coverage by targeted RNA-based NGS assays.

Genes Chromosomes Cancer 2020 08 9;59(8):445-453. Epub 2020 May 9.

Institute of Pathology, Technical University Munich (TUM), Munich, Germany.

Gene fusions involving the three neurotrophic tyrosine receptor kinase genes NTRK1, NTRK2, or NTRK3 were identified as oncogenic drivers in many cancer types. Two small molecule inhibitors have been tested in clinical trials recently and require the detection of a NTRK fusion gene prior to therapeutic application. Fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (tNGS) assays are commonly used for diagnostic profiling of gene fusions. In the presented study we applied an external quality assessment (EQA) scheme in order to investigate the suitability of FISH and RNA-/DNA-based tNGS for detection of NTRK fusions in a multinational and multicentric ring trial. In total 27 participants registered for this study. Nine institutions took part in the FISH-based and 18 in the NGS-based round robin test, the latter additionally subdivided into low-input and high-input NGS methods (regarding nucleic acid input). Regardless of the testing method applied, all participants received tumor sections of 10 formalin-fixed and paraffin-embedded (FFPE) tissue blocks for in situ hybridization or RNA/DNA extraction, and the results were submitted via an online questionnaire. For FISH testing, eight of nine (88.8%) participants, and for NGS-based testing 15 of 18 (83.3%) participants accomplished the round robin test successfully. The overall high success rate demonstrates that FISH- and tNGS-based NTRK testing can be well established in a routine diagnostic setting. Complementing this dataset, we provide an updated in silico analysis on the coverage of more than 150 NTRK fusion variants by several commercially available RNA-based tNGS panels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22853DOI Listing
August 2020

A 19-year-old patient with atypical chronic myeloid leukemia.

Ann Hematol 2020 May 19;99(5):1145-1148. Epub 2020 Mar 19.

Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Am Klinikum 1, 07740, Jena, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-03992-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196939PMC
May 2020

Feasibility of Combined Detection of Gene Mutations and Fusion Transcripts in Bone Marrow Trephines from Leukemic Neoplasms.

J Mol Diagn 2020 04 7;22(4):591-598. Epub 2020 Feb 7.

Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany.

Chromosomal translocations resulting in fusion genes represent important oncogenic drivers and potential therapeutic targets in rare leukemia subtypes. Formalin-fixed, paraffin-embedded trephines are frequently used in hematologic diagnostic tests and provide relevant access to leukemic cells for further studies, for example, phenotyping in bone marrow fibrosis. However, high-throughput molecular analysis of nucleic acids obtained from this material is challenging, especially the reliable detection of RNA transcripts. Sixty-three formalin-fixed, paraffin-embedded bone marrow trephines of patients with chronic eosinophilic leukemia, chronic myeloid leukemia, acute myeloid leukemia, and myeloproliferative neoplasms were analyzed for gene mutations and the presence of fusion transcripts with a commercial amplicon-based next-generation sequencing approach. Fusion transcripts relevant for diagnosis and therapy could be detected and validated (by RT-PCR) in 25 patients (39.7%). Retrospectively selected material, up to 10 years old, was used for this purpose, and only one sample failed in the RNA analysis (1.6%). This study concludes that amplicon-based fusion transcript detection in bone marrow trephines is feasible and that bone marrow trephines taken for histologic assessment can also be applied for high-throughput molecular analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2020.01.004DOI Listing
April 2020

Chronic progressive pulmonary paracoccidioidomycosis in a female immigrant from Venezuela.

Ther Adv Respir Dis 2019 Jan-Dec;13:1753466619894913

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.

Paracoccidioidomycosis (PCM) is a fungal infection caused by and . It is endemic to South and Central America. While PCM frequently remains latent, the disease can reactivate years after the initial infection. As the disease is rare outside the endemic area, and symptoms can mimic other pulmonary diseases, correct diagnosis can be challenging for clinicians in developed countries. In this report, we present the case of a 57-year-old female Venezuelan immigrant with PCM. She was initially misdiagnosed with sarcoidosis and treated with corticosteroids, leading to an exacerbation of the infection requiring intensive care. Because cultivation of sp. is slow and unsensitive, we opted for microscopic observation of fungal elements and molecular testing on a tissue biopsy and (BAL) together with antibody detection. This allowed the diagnosis of PCM, enabling specific management. PCM and other imported mycoses should be considered as a differential diagnosis in patients originating from South and Central America displaying symptoms suggestive of sarcoidosis. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1753466619894913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918496PMC
June 2020

Mutations associated with age-related clonal hematopoiesis in PMF patients with rapid progression to myelofibrosis.

Leukemia 2020 05 27;34(5):1364-1372. Epub 2019 Nov 27.

Institute of Pathology, Hannover Medical School, Carl-Neuberg Str. 1, 30623, Hannover, Germany.

Besides histopathological findings there are no indicators of increased risk for fibrotic progression in myeloproliferative neoplasms (MPN). Age-related clonal hematopoiesis (ARCH/CHIP) is a frequent finding in the elderly and combinations with MPN driver mutations (JAK2, MPL, and CALR) have been described. To determine the impact of ARCH/CHIP-related mutations for development of fibrosis in primary myelofibrosis (PMF), the mutational status of cases with fibrotic progression from grade 0 to grade 2/3 (n = 77) as evidenced by follow-up bone marrow biopsies (median 6.2 years) was compared with prefibrotic PMF samples without development of fibrosis (n = 27; median follow-up 7.3 years). Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, and DNMT3A) demonstrable at presentation were not connected with fibrotic progression. However, mutations which are rarely found in ARCH/CHIP (SRSF2, U2AF1, SF3B1, IDH1/2, and EZH2) were present in 24.7% of cases with later development of fibrosis and not detectable in cases staying free from fibrosis (P = 0.0028). Determination of the tumor mutational burden (TMB) in a subgroup of cases (n = 32) did not show significant differences (7.68 mutations/MB vs. 6.85 mutations/MB). We conclude that mutations rarely found in ARCH/CHIP provide an independent risk factor for rapid fibrotic progression (median 2.0 years) when manifest already at first presentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-019-0668-5DOI Listing
May 2020
-->