Publications by authors named "Arndt Hartmann"

657 Publications

SWI/SNF-deficient undifferentiated/rhabdoid carcinoma of the gallbladder carrying a POLE mutation in a 30-year-old woman: a case report.

Diagn Pathol 2021 Jun 12;16(1):52. Epub 2021 Jun 12.

Institute of Pathology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.

Background: Undifferentiated carcinoma of the biliary tract are highly aggressive malignancies. In other organs, a subgroup of undifferentiated carcinoma related to SWI/SNF complex-deficiency have been described.

Case Presentation: A 30-year-old woman presented with rising inflammatory markers (C-reactive protein (CRP)). Ultrasound examination revealed a large tumor of the liver. A computed tomography scan was performed and was primarily interpreted as a tumor-forming liver abscess, possibly caused by gallbladder perforation. Subsequent liver segment resection was performed. Microscopic examination showed an undifferentiated carcinoma with rhabdoid morphology and prominent inflammatory infiltrate in the gallbladder base. With SWI/SNF immunohistochemistry, intact expression of SMARCB1, SMARCA4, ARID1A, but loss of SMARCA2 and PBRM1 was detected. Next-generation-sequencing detected KRAS, PBRM1 and ARID1B mutations, a deleterious splice-site mutation in the POLE-gene and a mutation in the TP53-gene.

Conclusions: We were able to demonstrate loss of SMARCA2 expression and mutations characteristic of an SWI/SNF-deficient carcinoma in a tumor derived from the gallbladder. This is the first reported case of an undifferentiated carcinoma with rhabdoid features in the gallbladder carrying a POLE mutation and SWI/SNF-deficiency of PBRM1 and SMARCA2.
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http://dx.doi.org/10.1186/s13000-021-01112-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196506PMC
June 2021

Deep learning-based classification of blue light cystoscopy imaging during transurethral resection of bladder tumors.

Sci Rep 2021 Jun 2;11(1):11629. Epub 2021 Jun 2.

Institute of Physical Chemistry and Abbe Center of Photonics (IPC), Friedrich-Schiller-University, Jena, Germany.

Bladder cancer is one of the top 10 frequently occurring cancers and leads to most cancer deaths worldwide. Recently, blue light (BL) cystoscopy-based photodynamic diagnosis was introduced as a unique technology to enhance the detection of bladder cancer, particularly for the detection of flat and small lesions. Here, we aim to demonstrate a BL image-based artificial intelligence (AI) diagnostic platform using 216 BL images, that were acquired in four different urological departments and pathologically identified with respect to cancer malignancy, invasiveness, and grading. Thereafter, four pre-trained convolution neural networks were utilized to predict image malignancy, invasiveness, and grading. The results indicated that the classification sensitivity and specificity of malignant lesions are 95.77% and 87.84%, while the mean sensitivity and mean specificity of tumor invasiveness are 88% and 96.56%, respectively. This small multicenter clinical study clearly shows the potential of AI based classification of BL images allowing for better treatment decisions and potentially higher detection rates.
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http://dx.doi.org/10.1038/s41598-021-91081-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172542PMC
June 2021

KRT20, KRT5, ESR1 and ERBB2 Expression Can Predict Pathologic Outcome in Patients Undergoing Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-Invasive Bladder Cancer.

J Pers Med 2021 May 26;11(6). Epub 2021 May 26.

Department of Urology, Marien Hospital, Ruhr-University Bochum, 44625 Herne, Germany.

Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival, especially those with pathological complete response (pCR). The response to NAC according to molecular subtypes has been discussed. Molecular targets such as estrogen receptor (ESR1) and human epidermal growth factor receptor 2 (ERBB2) play an important role in breast cancer management and have also been associated with urothelial bladder cancer. Hence, the association of Keratin 20 (KRT20) Keratin 5 (KRT5), ESR1, and ERBB2 mRNA expression in MIBC at transurethral resection (TUR-BT) with pCR after NAC was analyzed retrospectively. Formalin-fixed paraffin-embedded tumour tissue samples from TUR-BT of 54 patients (42 males, 12 females, median age of 64) with MIBC were analyzed for KRT20, KRT5, ESR1, and ERBB2 mRNA expression. After NAC, RC was performed, and the specimens were evaluated for pCR. Statistical analyses comprised nonparametric and chi testing, partition models, and Spearman correlation analyses. After NAC, 22 out of 54 patients (40.7%) had pCR. Tumours with an elevated expression of markers associated with luminal differentiation (KRT20, ERBB2, ESR1) were associated with a higher chance of pCR (55% vs. 15.8%, = 0.009). Elevated ERBB2 expression was positively correlated with luminal expression features such as KRT20, and negatively with basal characteristics such as KRT5. Patients with MIBC showing a high expression of ERBB2, ESR1, or KRT20 have a significantly higher chance of pCR following NAC. These findings might improve patient selection for NAC in MIBC.
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http://dx.doi.org/10.3390/jpm11060473DOI Listing
May 2021

Serum miRNAs Support the Indication for MRI-Ultrasound Fusion-Guided Biopsy of the Prostate in Patients with Low-PI-RADS Lesions.

Cells 2021 May 25;10(6). Epub 2021 May 25.

Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany.

Multiparametric MRI (mpMRI) and targeted biopsy of the prostate enhance the tumor detection rate. However, the prediction of clinically significant prostate cancer (PCa) is still limited. Our study tested the additional value of serum levels of selected miRNAs in combination with clinical and mpMRI information for PCa prediction and classification. A total of 289 patients underwent targeted mpMRI-ultrasound fusion-guided prostate biopsy complemented by systematic biopsy. Serum miRNA levels of miRNAs (miR-141, miR-375, miR-21-5p, miR-320b, miR-210-3p, let-7c, and miR-486) were determined by quantitative PCR. Detection of any PCa and of significant PCa were the outcome variables. The patient age, pre-biopsy PSA level, previous biopsy procedure, PI-RADS score, and serum miRNA levels were covariates for regularized binary logistic regression models. The addition of miRNA expression of miR-486 and let-7c to the baseline model, containing only clinical parameters, increased the predictive accuracy. Particularly in patients with PI-RADS ≤3, we determined a sensitivity for detecting significant PCa (Gleason score ≥ 7a corresponding to Grade group ≥2) of 95.2%, and an NPV for absence of significant PCa of 97.1%. This accuracy could be useful to support patient counseling in selected cases.
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http://dx.doi.org/10.3390/cells10061315DOI Listing
May 2021

Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients.

Cancers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany.

Background: Immune therapy has gained significant importance in managing urothelial cancer. The value of PD-L1 remains a matter of controversy, thus requiring an in-depth analysis of its biological and clinical relevance.

Methods: A total of 193 tumors of muscle-invasive bladder cancer patients (MIBC) were assessed with four PD-L1 assays. PD-L1 scoring results were correlated with data from a comprehensive digital-spatial immune-profiling panel using descriptive statistics, hierarchical clustering and uni-/multivariable survival analyses.

Results: PD-L1 scoring algorithms are heterogeneous (agreements from 63.1% to 87.7%), and stems from different constellations of immune and tumor cells (IC/TC). While Ventana IC5% algorithm identifies tumors with high inflammation and favorable baseline prognosis, CPS10 and the TCarea25%/ICarea25% algorithm identify tumors with TC and IC expression. Spatially organized immune phenotypes, which correlate either with high PD-L1 IC expression and favorable prognosis or constitutive PD-L1 TC expression and poor baseline prognosis, cannot be resolved properly by PD-L1 algorithms. PD-L1 negative tumors with relevant immune infiltration can be detected by sTILs scoring on HE slides and digital CD8 scoring.

Conclusions: Contemporary PD-L1 scoring algorithms are not sufficient to resolve spatially distributed MIBC immune phenotypes and their clinical implications. A more comprehensive view of immune phenotypes along with the integration of spatial PD-L1 expression on IC and TC is necessary in order to stratify patients for ICI.
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http://dx.doi.org/10.3390/cancers13102327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150350PMC
May 2021

Detection of Microcalcifications in Spiral Breast Computed Tomography with Photon-Counting Detector Is Feasible: A Specimen Study.

Diagnostics (Basel) 2021 May 9;11(5). Epub 2021 May 9.

Department of Radiology, University Hospital Erlangen, Maximiliansplatz 3, 91054 Erlangen, Germany.

The primary objective of the study was to compare a spiral breast computed tomography system (SBCT) to digital breast tomosynthesis (DBT) for the detection of microcalcifications (MCs) in breast specimens. The secondary objective was to compare various reconstruction modes in SBCT. In total, 54 breast biopsy specimens were examined with mammography as a standard reference, with DBT, and with a dedicated SBCT containing a photon-counting detector. Three different reconstruction modes were applied for SBCT datasets (Recon1 = voxel size (0.15 mm), smooth kernel; Recon2 = voxel size (0.05 mm), smooth kernel; Recon3 = voxel size (0.05 mm), sharp kernel). Sensitivity and specificity of DBT and SBCT for the detection of suspicious MCs were analyzed, and the McNemar test was used for comparisons. Diagnostic confidence of the two readers (Likert Scale 1 = not confident; 5 = completely confident) was analyzed with ANOVA. Regarding detection of MCs, reader 1 had a higher sensitivity for DBT (94.3%) and Recon2 (94.9%) compared to Recon1 (88.5%; < 0.05), while sensitivity for Recon3 was 92.4%. Respectively, reader 2 had a higher sensitivity for DBT (93.0%), Recon2 (92.4%), and Recon3 (93.0%) compared to Recon1 (86.0%; < 0.05). Specificities ranged from 84.7-94.9% for both readers ( > 0.05). The diagnostic confidence of reader 1 was better with SBCT than with DBT (DBT 4.48 ± 0.88, Recon1 4.77 ± 0.66, Recon2 4.89 ± 0.44, and Recon3 4.75 ± 0.72; DBT vs. Recon1/2/3: < 0.05), while reader 2 found no differences. Sensitivity and specificity for the detection of MCs in breast specimens is equal for DBT and SBCT when a small voxel size of (0.05 mm) is used with an equal or better diagnostic confidence for SBCT compared to DBT.
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http://dx.doi.org/10.3390/diagnostics11050848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151348PMC
May 2021

DEK-AFF2 Carcinoma of the Sinonasal Region and Skull Base: Detailed Clinicopathologic Characterization of a Distinctive Entity.

Am J Surg Pathol 2021 May 27. Epub 2021 May 27.

Departments of Pathology Oncology Ophthalmology Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital, Erlangen, Germany Department of Laboratory Medicine and Pathobiology, University of Toronto Department of Pathology & Laboratory Medicine, Mount Sinai Hospital Department of Pathology, Sunnybrook Health Sciences Centre Department of Pathology, University Health Network, Toronto, ON Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX Department of Pathology, Kaiser Permanente Walnut Creek Medical Center, Walnut Creek, CA Department of Head and Neck Pathology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

A novel DEK-AFF2 fusion was recently reported in 4 nonkeratinizing squamous cell carcinomas of the sinonasal region and skull base, including 1 with exceptional response to immunotherapy, but it is not yet clear if this rearrangement defines a unique clinicopathologic category or represents a rare event. This study aims to characterize a larger cohort of carcinomas with DEK-AFF2 fusions to assess whether they truly constitute a distinctive entity. Among 27 sinonasal and skull base nonkeratinizing squamous cell carcinoma that were negative for human papillomavirus and Epstein-Barr virus, RNA sequencing identified DEK-AFF2 fusions in 13 cases (48%). Nine were centered in the nasal cavity, 2 in the middle ear/temporal bone, 1 in the nasopharynx, and 1 in the orbit. These tumors displayed recurrent histologic features including (1) complex endophytic and exophytic, frequently papilloma-like growth, (2) transitional epithelium with eosinophilic to amphophilic cytoplasm, (3) absent or minimal keratinization with occasional compact keratin pearls, (4) monotonous nuclei, and (5) prominent tumor-infiltrating neutrophils or stromal lymphocytes. This appearance not only overlaps with high-grade basaloid sinonasal carcinomas but also with benign papillomas and tumors reported as low-grade papillary Schneiderian carcinoma. However, DEK-AFF2 carcinomas showed frequent local recurrence, cervical lymph node metastases, and distant metastasis with 2 deaths from disease, confirming they are aggressive malignancies despite relatively bland histology. Overall, the distinctive molecular, histologic, and clinical features of DEK-AFF2 carcinomas suggest they represent a unique entity in the sinonasal region. This tumor merits increased pathologic recognition to better understand its prognostic and therapeutic implications.
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http://dx.doi.org/10.1097/PAS.0000000000001741DOI Listing
May 2021

[MSI testing : What is new? What should be considered? German version].

Pathologe 2021 May 27. Epub 2021 May 27.

Institut für Pathologie, Universitätsklinikum Köln, Kerpener Str. 62, 50937, Köln, Deutschland.

Based on new trial data regarding immune checkpoint inhibitors (ICIs), the detection of high-grade microsatellite instability (MSI-H) or underlying deficient mismatch repair protein (dMMR) is now becoming increasingly important for predicting treatment response. For the first time, a PD‑1 ICI (pembrolizumab) has been approved by the European Medicines Agency (EMA) for first-line treatment of advanced (stage IV) dMMR/MSI‑H colorectal cancer (CRC). Further indications, such as dMMR/MSI‑H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI‑H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.
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http://dx.doi.org/10.1007/s00292-021-00944-7DOI Listing
May 2021

Endometrial delay is found to be part of a normal individual dynamic transformation process.

Arch Gynecol Obstet 2021 May 19. Epub 2021 May 19.

Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.

Purpose: Limited information is clinically available concerning endometrial receptivity; assessing endometrial transformation status is therefore an urgent topic in assisted reproductive technology. This study aimed to investigate individual endometrial transformation rates during the secretory phase in subfertile patients using personal endometrial transformation analysis.

Methods: Monitoring was carried out during the secretory phase to obtain endometrial receptivity profiles. For the investigation, two endometrial biopsies were taken within one menstrual cycle. The extended endometrial dating was based on the Noyes criteria, combined with immunohistochemical analyses of hormone receptors and proliferation marker Ki-67. Biopsies were taken mainly at days ovulation (OV, n = 76)/hormone replacement therapy (HRT, n = 58) + 5 and + 10.

Results: The results of the two biopsies were correlated with the clinically expected day of the cycle and showed temporal delays or hypercompensations, diverging from the expected cycle days by 0.5-5 days. In comparison with the first biopsies, the transformation rate in the second biopsies showed compensation, augmented delay, or constant transformation in 48.69, 22.37, and 28.94% of cases for ovulation in natural cycles and 56.89, 25.85, and 17.26% for HRT cycles, respectively.

Conclusion: The study revealed an individually dynamic transformation process of the endometrium, with the ability to compensate or enlarge an initial "delay", which is now identified as a normal individual transformation process during the secretory phase. This information is of great importance for the scientific investigation of dynamic changes in endometrial tissue, as well as for the timing of embryo transfers.
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http://dx.doi.org/10.1007/s00404-021-06086-8DOI Listing
May 2021

BiasCorrector: Fast and accurate correction of all types of experimental biases in quantitative DNA methylation data derived by different technologies.

Int J Cancer 2021 May 17. Epub 2021 May 17.

Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Quantification of DNA methylation in neoplastic cells is crucial both from mechanistic and diagnostic perspectives. However, such measurements are prone to different experimental biases. Polymerase chain reaction (PCR) bias results in an unequal recovery of methylated and unmethylated alleles at the sample preparation step. Post-PCR biases get introduced additionally by the readout processes. Correcting the biases is more practicable than optimising experimental conditions, as demonstrated previously. However, utilisation of our earlier developed algorithm strongly necessitates automation. Here, we present two R packages: rBiasCorrection, the core algorithms to correct biases; and BiasCorrector, its web-based graphical user interface frontend. The software detects and analyses experimental biases in calibration DNA samples at a single base resolution by using cubic polynomial and hyperbolic regression. The correction coefficients from the best regression type are employed to compensate for the bias. Three common technologies-bisulphite pyrosequencing, next-generation sequencing and oligonucleotide microarrays-were used to comprehensively test BiasCorrector. We demonstrate the accuracy of BiasCorrector's performance and reveal technology-specific PCR- and post-PCR biases. BiasCorrector effectively eliminates biases regardless of their nature, locus, the number of interrogated methylation sites and the detection method, thus representing a user-friendly tool for producing accurate epigenetic results.
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http://dx.doi.org/10.1002/ijc.33681DOI Listing
May 2021

Endogenous Retroviral-K Envelope Is a Novel Tumor Antigen and Prognostic Indicator of Renal Cell Carcinoma.

Front Oncol 2021 22;11:657187. Epub 2021 Apr 22.

Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany.

Renal cell carcinoma (RCC) is one of the ten most common cancers for men and women with an approximate 75% overall 5-year survival. Sixteen histological tumor subtypes exist and the most common are papillary, chromophobe and clear cell renal cell carcinoma (ccRCC) representing 85% of all RCC. Although epigenetically silenced, endogenous retroviral (ERV) genes become activated in tumors and function to ignite immune responses. Research has intensified to understand ERV protein function and their role as tumor antigens and targets for cancer (immune) therapy. ERV-K env is overexpressed and implicated as a therapeutic target for breast cancer, however studies in RCC are limited. In this investigation a human RCC tissue microarray (TMA) (n=374) predominantly consisting of the most common histological tumor subtypes was hybridized with an ERV-K env antibody and correlated with patient clinical data. TMA results showed the highest amount of ERV-K env protein expression and the strongest significant membrane expression in ccRCC versus other RCC subtypes. High ERV-K env total protein expression of all tumor subtypes significantly correlated with low tumor grading and a longer disease specific survival using multivariable analyses. Cell proliferation and invasion were assayed using the kidney cell lines HEK293 with wild-type p53 and a ccRCC cell line MZ1257RC mutated for p53. Transfecting these cell lines with a codon optimized overexpressing CMV vector was performed with or without 5'-Aza-2'-deoxycytidine (Aza) treatment to sustain promoter de-methylation. MZ1257RC showed induction of expression and significantly increased both proliferation and invasion in the presence or absence of Aza. HEK293 cells demonstrated a restriction of expression and invasion with no changes in proliferation in the absence of Aza. However, in the presence of Aza despite increased expression, an inhibition of HEK293 proliferation and a further restriction of invasion was found. This study supports ERV-K env as a single prognostic indicator for better survival of RCC, which we propose represents a new tumor antigen. In addition, ERV-K env significantly regulates proliferation and invasion depending on p53 status and Aza treatment.
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http://dx.doi.org/10.3389/fonc.2021.657187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100683PMC
April 2021

Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer.

Cancers (Basel) 2021 Apr 19;13(8). Epub 2021 Apr 19.

Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054 Bayern, Germany.

To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m d1-3 and docetaxel 75 mg/m d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC ( = 0.018). In the total population ( = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors.
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http://dx.doi.org/10.3390/cancers13081959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073509PMC
April 2021

Select hyperactivating NLRP3 ligands enhance the T1- and T17-inducing potential of human type 2 conventional dendritic cells.

Sci Signal 2021 Apr 27;14(680). Epub 2021 Apr 27.

Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, 91052 Erlangen, Germany.

The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1β is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and response without pyroptosis. When cDC2 were stimulated with ligands that relatively weakly activated the inflammasome, the cells did not enter pyroptosis but instead secreted IL-12 family cytokines and IL-1β. These cytokines induced prominent T helper type 1 (T1) and T17 responses that were superior to those seen in response to Toll-like receptor (TLR) stimulation alone or to stronger, classical inflammasome ligands. These findings not only define the human cDC2 subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases but may also inform new approaches for adjuvant and vaccine development.
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http://dx.doi.org/10.1126/scisignal.abe1757DOI Listing
April 2021

NSD3-NUTM1-rearranged carcinoma of the median neck/thyroid bed developing after recent thyroidectomy for sclerosing mucoepidermoid carcinoma with eosinophilia: report of an extraordinary case.

Virchows Arch 2021 Apr 23. Epub 2021 Apr 23.

Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is an exceedingly rare low-grade thyroid malignancy of unknown histogenesis. NUT carcinoma is another rare, highly aggressive neoplasm with predilection for the midline, defined by recurrent NUTM1 fusions. The bromodomain family genes (BRD4 or BRD3) and rarely NSD3, ZNF532, or others are known fusion partners. We describe an extraordinary case of a 42-year-old female with a thyroid SMECE treated by thyroidectomy and neck dissection. She presented 6 months later with extensive midline recurrence encasing/compressing the trachea. Biopsy revealed poorly differentiated carcinoma with abrupt squamous differentiation, suggestive of NUT carcinoma. Immunohistochemistry confirmed expression of monoclonal NUT antibody. Targeted RNA sequencing revealed the NSD3-NUTM1 fusion in the NUT carcinoma, but not in the SMECE. This unique case highlights unusual sequential origin of two exceptionally rare entities at same anatomic site and underlines the necessity of sampling unexpectedly aggressive recurrences of otherwise indolent malignancies.
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http://dx.doi.org/10.1007/s00428-021-03103-8DOI Listing
April 2021

Lipomatous Solitary Fibrous Tumors Harbor Rare NAB2-STAT6 Fusion Variants and Show Up-Regulation of the Gene PPARG, Encoding for a Regulator of Adipocyte Differentiation.

Am J Pathol 2021 Apr 20. Epub 2021 Apr 20.

Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Solitary fibrous tumors (SFTs) harbor activating NAB2-STAT6 gene fusions. Different variants of the NAB2-STAT6 gene fusion have been associated with distinct clinicopathologic features. Lipomatous SFTs are a morphologic variant of SFTs, characterized by a fat-forming tumor component. Our aim was to evaluate NAB2-STAT6 fusion variants and to further study the molecular genetic features in a cohort of lipomatous SFTs. A hybrid-capture-based next-generation sequencing panel was employed to detect NAB2-STAT6 gene fusions at the RNA level. In addition, the RNA expression levels of 507 genes were evaluated using this panel, and were compared with a control cohort of nonlipomatous SFTs. Notably, 5 of 11 (45%) of lipomatous SFTs in the current series harbored the uncommon NAB2 exon 4-STAT6 exon 4 gene fusion variant, which is observed in only 0.9% to 1.4% of nonlipomatous SFTs. Furthermore, lipomatous SFTs displayed significant differences in gene expression compared with their nonlipomatous counterparts, including up-regulation of the gene peroxisome proliferator activated receptor-γ (PPARG). Peroxisome proliferator activated receptor-γ is a nuclear receptor regulating adipocyte differentiation, providing a possible explanation for the fat-forming component in lipomatous SFTs. In summary, the current study provides a possible molecular genetic basis for the distinct morphologic features of lipomatous SFTs.
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http://dx.doi.org/10.1016/j.ajpath.2021.03.012DOI Listing
April 2021

ALK Rearrangements Characterize 2 Distinct Types of Salivary Gland Carcinomas: Clinicopathologic and Molecular Analysis of 4 Cases and Literature Review.

Am J Surg Pathol 2021 Mar 22. Epub 2021 Mar 22.

*Institute of Pathology ¶Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen §DERMPATH Muenchen ∥Institute of Pathology, Ludwig Maximilians University, Munich, Germany †Department of Pathology, Charles University, Faculty of Medicine in Plzen ‡Bioptic Laboratory Ltd, Plzen, Czech Republic #Department of Translational Research, University of Pisa, School of Medicine, Pisa, Italy.

The majority of salivary gland carcinomas are characterized by recurrent gene fusions that proved highly valuable diagnostically, but only rarely of therapeutic impact. Most of these fusion-positive carcinomas belong to the low-grade or intermediate-grade biological category. To date, only 5 cases of salivary gland carcinomas carrying an oncogenic ALK fusion have been reported in 4 recent studies, but their phenotypic spectrum and their nosological classification remain uncharacterized. We herein describe in detail the clinicopathologic and molecular features of 4 ALK-fusion-positive salivary carcinomas and review previously reported cases to assess if they could be classified into a defined World Health Organization (WHO) category. Patients were 3 men and 1 woman aged from 67 to 79 years (median: 70 y). All tumors originated in the parotid gland. Their size ranged from 1.1 to 3 cm (mean, 2 cm). Three tumors were de novo high-grade salivary duct carcinomas (SDCs) and 1 was a low-grade intercalated-type intraductal carcinoma. Histologically, high-grade tumors were predominantly solid, composed of intimately admixed basal (CK5, androgen) and luminal (CK5, androgen) components. The remarkable basal component showed squamoid basophilic pattern imparting an adenosquamous-like appearance in all cases. Conventional apocrine intraductal high-grade carcinoma was noted in 1 case. Prominent intraductal growth of the solid basal component (highlighted by p63 staining) was seen in all cases. The tumor cells expressed CK7 (3/3), mammaglobin (3/3, 1 focal), GATA3 (3/3, 1 focal), variably CK5 (3/3), and focally the androgen receptor (1/3), but lacked expression of HER2/neu, SOX10, MUC4, TTF1, S100, and Napsin A. The low-grade tumor showed classic histologic and immunophenotypic features of intercalated-type noninvasive intraductal carcinoma. Molecular profiling showed rearrangements involving exon 20 of ALK in all cases, confirmed by ALK immunohistochemistry (IHC and FISH). The fusion partner was EML4 (n=2) and STRN (n=1) in high-grade tumors and EML4 in the intraductal carcinoma. Two patients with high-grade tumors developed progressive disease (1 died at 9 mo; 1 alive under palliative therapy at 5 mo). This series and a review of 5 published cases indicate that ALK rearrangements characterize 2 distinct subsets of salivary gland carcinomas in the spectrum of high-grade androgen-poor, basal-like SDC (total reported: 5 cases) and low-grade intercalated-type intraductal carcinomas (4 cases). Given the therapeutic relevance of ALK fusions, inclusion of ALK IHC in any atypical-looking or androgen-poor SDC and in high-grade adenocarcinoma-not otherwise specified is recommended. Absence of aberrant ALK expression in genetically characterized secretory (n=15) and intraductal (n=9) carcinomas lacking ALK fusions underlines the value of ALK IHC as a diagnostic screening method for identifying potential cases.
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http://dx.doi.org/10.1097/PAS.0000000000001698DOI Listing
March 2021

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer.

Nat Commun 2021 04 16;12(1):2301. Epub 2021 Apr 16.

Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
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http://dx.doi.org/10.1038/s41467-021-22465-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052448PMC
April 2021

miRNA Expression Characterizes Histological Subtypes and Metastasis in Penile Squamous Cell Carcinoma.

Cancers (Basel) 2021 Mar 23;13(6). Epub 2021 Mar 23.

Department of Urology and Paediatric Urology, Saarland University, 66421 Homburg, Germany.

Although microRNAs are described as promising biomarkers in many tumor types, little is known about their role in PSCC. Thus, we attempted to identify miRNAs involved in tumor development and metastasis in distinct histological subtypes considering the impact of HPV infection. In a first step, microarray analyses were performed on RNA from formalin-fixed, paraffin-embedded tumor (22), and normal (8) tissue samples. Microarray data were validated for selected miRNAs by qRT-PCR on an enlarged cohort, including 27 tumor and 18 normal tissues. We found 876 significantly differentially expressed miRNAs ( ≤ 0.01) between HPV-positive and HPV-negative tumor samples by microarray analysis. Although no significant differences were detected between normal and tumor tissue in the whole cohort, specific expression patterns occurred in distinct histological subtypes, such as HPV-negative usual PSCC (95 differentially expressed miRNAs, ≤ 0.05) and HPV-positive basaloid/warty subtypes (247 differentially expressed miRNAs, ≤ 0.05). Selected miRNAs were confirmed by qRT-PCR. Furthermore, microarray data revealed 118 miRNAs ( ≤ 0.01) that were significantly differentially expressed in metastatic versus non-metastatic usual PSCC. The lower expression levels for miR-137 and miR-328-3p in metastatic usual PSCC were validated by qRT-PCR. The results of this study confirmed that specific miRNAs could serve as potential diagnostic and prognostic markers in single PSCC subtypes and are associated with HPV-dependent pathways.
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http://dx.doi.org/10.3390/cancers13061480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004785PMC
March 2021

Neoadjuvant Chemoradiation Combined with Regional Hyperthermia in Locally Advanced or Recurrent Rectal Cancer.

Cancers (Basel) 2021 Mar 13;13(6). Epub 2021 Mar 13.

Department of Radiation Oncology, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer.

Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any locally recurrent rectal cancer were included (HyRec-Trial, ClinicalTrials.gov Identifier: NCT01716949). Patients received radiotherapy with concurrent 5-Fluororuracil (5-FU)/Capecitabine and Oxaliplatin, and RHT. Stage 1 feasibility analysis evaluated dose-limiting toxicities (DLT) after 19 patients, stage 2 after 59 evaluable patients. Analysis of the pCR rate was based on histopathological reports.

Results: the feasibility rates for stages 1 and 2 were 90% (17/19) and 73% (43/59), respectively. In the intention-to-treat population the pCR rate was 19% (20/105; 90% confidence interval (CI) 13.0-26.5). In the per-protocol-analysis, complete tumor regression was seen in 28% (18/64) and 38% (3/8) of the patients with LARC and LRRC, respectively. Complete resection rates (R0) among patients with LARC and LRRC who received surgery were 99% (78/84) and 67% (8/12).

Conclusions: the intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC.
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http://dx.doi.org/10.3390/cancers13061279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001688PMC
March 2021

Mutations in and Other Panel Genes in Patients With Metastatic Breast Cancer -Association With Patient and Disease Characteristics and Effect on Prognosis.

J Clin Oncol 2021 May 29;39(15):1619-1630. Epub 2021 Mar 29.

Department of Gynecology and Obstetrics, Carl Gustav Carus Faculty of Medicine and University Hospital, Technical University of Dresden, Dresden, Germany.

Purpose: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome.

Patients And Methods: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed.

Results: Germline mutations in 12 established BC predisposition genes (including and ) were detected in 271 (10.4%) patients. A mutation in or was seen in 129 patients (5.0%). mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% 6.6%, < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC.

Conclusion: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.
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http://dx.doi.org/10.1200/JCO.20.01200DOI Listing
May 2021

Validation of the "Inflammatory Bowel Disease - Distribution, Chronicity, Activity (IBD-DCA) Score" for Ulcerative Colitis and Crohn´s disease.

J Crohns Colitis 2021 Mar 27. Epub 2021 Mar 27.

Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany.

Background And Aims: Histological scoring plays a key role in the assessment of disease activity in ulcerative colitis (UC) and is also important in Crohn´s disease (CD). Currently, there is no common scoring available for UC and CD. We aimed to validate the Inflammatory Bowel Disease (IBD) - Distribution (D), Chronicity (C), Activity (A) score (IBD-DCA score) for histological disease activity assessment in IBD.

Methods: Inter- and intra-rater reliability were assessed by 16 observers on biopsy specimen from 59 patients with UC and 25 patients with CD. Construct validity and responsiveness to treatment were retrospectively evaluated on a second cohort of 30 patients.

Results: Inter-rater reliability was moderate to good for the UC cohort (intraclass correlation coefficients (ICCs) = 0.645, 0.623, 0.767 for D, C and A, respectively) and at best moderate for the CD cohort (ICC = 0.690, 0.303, 0.733 for D, C and A, respectively). Intra-rater agreement ranged from good to excellent in both cohorts. Correlation with the Nancy Histological Index (NHI) was moderate and strong with the Simplified Geboes Score (SGS) and a Visual Analog Scale (VAS). Large effect sizes (ES) were obtained for all three parameters. External responsiveness analysis revealed correlated changes between IBD-DCA score and NHI, SGS and VAS.

Conclusions: The IBD-DCA score is a simple histological activity score for UC and CD, agreed and validated by a large group of IBD specialists. It provides reliable information on treatment response. Therefore, it has potential value for use in routine diagnostics as well as clinical studies.
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http://dx.doi.org/10.1093/ecco-jcc/jjab055DOI Listing
March 2021

International Society of Urological Pathology Expert Opinion on Grading of Urothelial Carcinoma.

Eur Urol Focus 2021 Mar 23. Epub 2021 Mar 23.

Indiana University School of Medicine, Indianapolis, IN, USA.

Context: Grading is the mainstay for treatment decisions for patients with non-muscle-invasive bladder cancer (NMIBC).

Objective: To determine the requirements for an optimal grading system for NMIBC via expert opinion.

Evidence Acquisition: A multidisciplinary working group established by the International Society of Urological Pathology reviewed available clinical, histopathological, and molecular evidence for an optimal grading system for bladder cancer.

Evidence Synthesis: Bladder cancer grading is a continuum and five different grading systems based on historical grounds could be envisaged. Splitting of the World Health Organization (WHO) 2004 low-grade class for NMIBC lacks diagnostic reproducibility and molecular-genetic support, while showing little difference in progression rate. Subdividing the clinically heterogeneous WHO 2004 high-grade class for NMIBC into intermediate and high risk categories using the WHO 1973 grading is supported by both clinical and molecular-genetic findings. Grading criteria for the WHO 1973 scheme were detailed on the basis of literature findings and expert opinion.

Conclusions: Splitting of the WHO 2004 high-grade category into WHO 1973 grade 2 and 3 subsets is recommended. Provision of more detailed histological criteria for the WHO 1973 grading might facilitate the general acceptance of a hybrid four-tiered grading system or-as a preferred option-a more reproducible three-tiered system distinguishing low-, intermediate (high)-, and high-grade NMIBC.

Patient Summary: Improvement of the current systems for grading bladder cancer may result in better informed treatment decisions for patients with bladder cancer.
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http://dx.doi.org/10.1016/j.euf.2021.03.017DOI Listing
March 2021

Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors - An analysis of 2765 patients from neoadjuvant clinical trials.

Eur J Cancer 2021 May 18;148:159-170. Epub 2021 Mar 18.

German Breast Group (GBG Forschungs GmbH), Neu-Isenburg, Germany. Electronic address:

Aim: To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC.

Methods: We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1-9%) and strong-positive (ER or PR 10-100%) HR-expression in neoadjuvant clinical trial cohorts (n = 2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n = 38).

Results: Ninety-four (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7%) and women with TNBC (35.5%). DFS and DDFS were also not different [for DFS, hazard ratio 1.26, 95%-CI (confidence interval) : 0.87-1.83, log-rank test p = 0.951; for DDFS, hazard ratio 1.17, 95%-CI: 0.78-1.76, log-rank test p = 0.774]. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38, 95%-CI: 0.23-0.63), but better DFS (hazard ratio 0.48, 95%-CI: 0.33-0.70) and DDFS (hazard ratio 0.49, 95%-CI: 0.33-0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%).

Conclusion: Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC.
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http://dx.doi.org/10.1016/j.ejca.2021.02.020DOI Listing
May 2021

Tumour-Infiltrating Lymphocytes (TILs) and PD-L1 Expression Correlate with Lymph Node Metastasis, High-Grade Transformation and Shorter Metastasis-Free Survival in Patients with Acinic Cell Carcinoma (AciCC) of the Salivary Glands.

Cancers (Basel) 2021 Feb 25;13(5). Epub 2021 Feb 25.

Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Waldstrasse 1, 91054 Erlangen, Germany.

Objectives: The aim of this study was to assess the number of tumour-infiltrating lymphocytes (TILs) and the expression of (PD-L1) in Acinic Cell Carcinoma (AciCC) of the salivary glands, to enable a correlation with clinico-pathological features and to analyse their prognostic impact.

Methods: This single centre retrospective study represents a cohort of 36 primary AciCCs with long-term clinical follow-up. Immunohistochemically defined immune cell subtypes, i.e., those expressing T-cell markers (CD3, CD4 and CD8) or a B-cell marker (CD20) were characterized on tumour tissue sections. The number of TILs was quantitatively evaluated using software for digital bioimage analysis (QuPath). PD-L1 expression on the tumour cells and on immune cells was assessed immunohistochemically employing established scoring criteria: tumour proportion score (TPS), Ventana immune cell score (IC-Score) and combined positive score (CPS).

Results: Higher numbers of tumour-infiltrating T- and B-lymphocytes were significantly associated with high-grade transformation. Furthermore, higher counts of T-lymphocytes correlated with node-positive disease. There was a significant correlation between higher levels of PD-L1 expression and lymph node metastases as well as the occurrence of high-grade transformation. Moreover, PD-L1 CPS was associated with poor prognosis regarding metastasis-free survival ( = 0.049).

Conclusions: The current study is the first to demonstrate an association between PD-L1 expression and lymph node metastases as well as grading in AciCCs. In conclusion, increased immune cell infiltration of T and B cells as well as higher levels of PD-L1 expression in AciCC in association with high-grade transformation, lymph node metastasis and unfavourable prognosis suggests a relevant interaction between tumour cells and immune cell infiltrates in a subset of AciCCs, and might represent a rationale for immune checkpoint inhibition.
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http://dx.doi.org/10.3390/cancers13050965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956490PMC
February 2021

[Practical aspects of COVID-19 autopsies].

Pathologe 2021 Mar 24;42(2):197-207. Epub 2021 Feb 24.

Institut für Pathologie und pathologische Anatomie, Technische Universität München, München, Deutschland.

Background: The COVID-19 pandemic represents a so far unknown challenge for the medical community. Autopsies are important for studying this disease, but their safety was challenged at the beginning of the pandemic.

Objectives: To determine whether COVID-19 autopsies can be performed under existing legal conditions and which safety standards are required.

Materials And Methods: The autopsy procedure undertaken in five institutions in Germany, Austria, and Switzerland is detailed with respect to legal and safety standards.

Results: In all institutions the autopsies were performed in technically feasible rooms. The personal equipment consisted of functional clothing including a disposable gown and apron, a surgical cap, eye protection, FFP‑3 masks, and two pairs of gloves. In four institutions, complete autopsies were performed; in one institution the ultrasound-guided biopsy within the postmortal imaging and biopsy program. The latter does not allow the appreciation of gross organ pathology; however, it is able to retrieve standardized biopsies for diagnostic and research purposes. Several scientific articles in highly ranked journals resulted from these autopsies and allowed deep insights into organ damage and conclusions to better understand the pathomechanisms. Viral RNA was frequently detectable in the COVID-19 deceased, but the issue of infectivity remains unresolved and it is questionable if Ct values are greater than 30.

Conclusions: With appropriate safeguards, autopsies of people who have died from COVID-19 can be performed safely and are highly relevant to medical research.
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http://dx.doi.org/10.1007/s00292-021-00925-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903213PMC
March 2021

Eosinophilic cystitis mimicking bladder cancer-considerations on the management based upon a case report and a review of the literature.

Virchows Arch 2021 Feb 12. Epub 2021 Feb 12.

Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.

The hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and infiltration of various organs with eosinophils. Eosinophilic cystitis (EC), mimicking bladder cancer clinically but also in ultrasound and in radiographic imaging, is one potential manifestation of the HES occurring in adults as well as in children. This case report describes the course of disease in a 57-year-old male presenting with severe gait disorders and symptoms of a low compliance bladder caused by a large retropubic tumor. After extensive urine and serologic examination and histologic confirmation of EC the patient was subjected to medical treatment with cetirizine and prednisolone for 5 weeks. While gait disorders rapidly resolved, micturition normalized only 10 months after initiation of therapy. Based upon this course the authors recommend patience and reluctance concerning radical surgical intervention in EC. Key Points • Eosinophilic cystitis is a rare condition with app. 200 cases reported, so far. • Etiology of eosinophilic cystitis is obscure, but allergies and parasitic infections may trigger the disease. • Genetic alterations (e.g., BRAF mutations) may predispose for the disease • Corticosteroids and antihistamines are the backbone of therapy and may be complemented by antibiotics and non-steroidal anti-inflammatory drugs in case of concomitant (underlying) infections. • As recovery can occur even after a long time, radical surgery should be restricted to highly selected cases.
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http://dx.doi.org/10.1007/s00428-021-03049-xDOI Listing
February 2021

Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers.

Genes (Basel) 2021 Feb 5;12(2). Epub 2021 Feb 5.

Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.

Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal mutational status, as well as to discern how tumors develop.

Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the promoter was analyzed by SNaPshot analysis including three hot spot regions (-57, -124 or -146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit.

Results: promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for mutations. No significant differences of telomere length were observed.

Conclusions: Examining multiple whole-organ mapping bladders we conclude that promoter mutations may be an early step in bladder cancer carcinogenesis as supported by mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.
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http://dx.doi.org/10.3390/genes12020230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915609PMC
February 2021

Human papilloma virus genotype distribution in women with premalignant or malignant lesions of the uterine cervix.

Arch Gynecol Obstet 2021 Feb 4. Epub 2021 Feb 4.

Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen University Hospital, Universitätsstrasse 21-23, 91054, Erlangen, Germany.

Objective: Cervical cancer is caused by persistent infection with high-risk human papillomavirus (hrHPV). Cytology-based national screening programs have reduced the incidence and mortality of cervical cancer. Different hrHPV subtypes have different carcinogenic potentials. This study evaluated the distribution of different types of hrHPV relative to age in cervical cancer and its precursor lesions.

Methods: HPV testing was performed between November 2018 and February 2020 using the Abbott RealTime high-risk HPV assay on an Abbott m2000sp instrument. This assay separately detects HPV-16, HPV-18, and a pool of 12 additional hrHPV types (HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, and -68).

Results: The study included 652 women with HPV samples and biopsies of the cervix or histology samples obtained during surgery. In all, 30.8% (95% CI, 27.3-34.6%) were HPV-negative. Among HPV-positive women, HPV-16, HPV-18, and "HPV other" types were found in 33.5, 4.4, and 49.4%, respectively. Cervical intraepithelial neoplasia (CIN) 3/high-grade squamous intraepithelial lesions (HSILs) in women ≤ 34 years were positive for HPV-16 in 54.5% of cases and in those ≥ 35 years in 45.4% of cases. Among women with cervical cancer, 75.8% were infected with HPV-16 or had coinfection with HPV-16 and "HPV other".

Conclusions: HPV-16 is the most common type of hrHPV in HSIL + lesions. It is more common in women diagnosed with CIN 3/HSIL who are aged ≤ 35 and is decreasing with age. Therefore, women age ≥ 35 with persistent infection with this type of hrHPV need careful surveillance, as they are at high risk of progression to cervical cancer.
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http://dx.doi.org/10.1007/s00404-021-05986-zDOI Listing
February 2021

Undifferentiated large cell/rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non-small cell lung cancer (NSCLC): clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases.

Virchows Arch 2021 Jan 27. Epub 2021 Jan 27.

Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute and Departments of Pathology and Cell Biology and Oncologic Sciences, University of South Florida, Tampa, FL, USA.

Undifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications.
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http://dx.doi.org/10.1007/s00428-021-03032-6DOI Listing
January 2021