TY - JOUR AB - Recent progress in computational pathology has been driven by deep learning. While code and data availability are essential to reproduce findings from preceding publications, ensuring a deep learning model's reusability is more challenging. For that, the codebase should be well-documented and easy to integrate into existing workflows and models should be robust toward noise and generalizable toward data from different sources. Strikingly, only a few computational pathology algorithms have been reused by other researchers so far, let alone employed in a clinical setting. To assess the current state of reproducibility and reusability of computational pathology algorithms, we evaluated peer-reviewed articles available in PubMed, published between January 2019 and March 2021, in 5 use cases: stain normalization; tissue type segmentation; evaluation of cell-level features; genetic alteration prediction; and inference of grading, staging, and prognostic information. We compiled criteria for data and code availability and statistical result analysis and assessed them in 160 publications. We found that only one-quarter (41 of 160 publications) made code publicly available. Among these 41 studies, three-quarters (30 of 41) analyzed their results statistically, half of them (20 of 41) released their trained model weights, and approximately a third (16 of 41) used an independent cohort for evaluation. Our review is intended for both pathologists interested in deep learning and researchers applying algorithms to computational pathology challenges. We provide a detailed overview of publications with published code in the field, list reusable data handling tools, and provide criteria for reproducibility and reusability. AU - Wagner, S. AU - Matek, C. AU - Shetab Boushehri, S. AU - Boxberg, M.* AU - Lamm, L. AU - Sadafi, A. AU - Winter, D. AU - Marr, C. AU - Peng, T. C1 - 68663 C2 - 54868 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - Built to last? Reproducibility and reusability of deep learning algorithms in computational pathology. JO - Mod. Pathol. VL - 37 IS - 1 PB - Elsevier Science Inc PY - 2024 SN - 0893-3952 ER - TY - JOUR AU - Dislich, B.* AU - Stein, A. AU - Seiler, C.A.* AU - Walch, A.K. AU - Berezowska, S.* AU - Zlobec, I.* AU - Galvan, J.A.* AU - Langer, R.* C1 - 48063 C2 - 39891 CY - New York SP - 170A TI - Low frequency of epithelial PD-L1 staining in esophageal and other gastrointestinal adenocarcinomas. JO - Mod. Pathol. VL - 29 PB - Nature Publishing Group PY - 2016 SN - 0893-3952 ER - TY - JOUR AU - Li, J.* AU - Dawidek, T.* AU - Liegsalz, V.* AU - Tzalis, V.* AU - Feuchtinger, A. AU - Avril, S.* C1 - 48065 C2 - 39890 CY - New York SP - 53A TI - Intratumoral heterogeneity of common protein biomarkers assessed by immunohistochemistry in breast cancer tissues. JO - Mod. Pathol. VL - 29 PB - Nature Publishing Group PY - 2016 SN - 0893-3952 ER - TY - JOUR AB - We aimed to determine the rate of hepatitis E virus (HEV) infection, a recently increasingly recognized disease in the Western world, in liver transplant patients by direct molecular testing of liver tissue. A RT-PCR assay was designed for detecting the HEV open reading frame (ORF) 2/3 gene region in formalin-fixed, paraffin-embedded tissues, and applied to all liver biopsies (n=683) taken 4 weeks or later from all patients (n=282) after liver transplantation of two large academic centers. HEV-RNA was detected in ten biopsies from four different patients (rate: 1%). Histology in early HEV infection was variable including cases with only few hepatocellular apoptoses, no or only minute inflammation. Hepatitis lasted for at least 6 months in 3/4 patients. Serologic testing for HEV-RNA in a subcohort (159 patients) was positive in five patients (rate: 3%), resulting in an overall HEV detection rate of 3% (8/282). In case both liver tissue and sera of a patient were available from the same time period, all cases tested positive in one material were also tested positive in the other material, respectively. All patients had de novo autochthonous infection with HEV genotype 3. Our data confirm that HEV infection is a relevant cause of liver injury after liver transplantation. Molecular testing for HEV in routinely processed transplant liver biopsies is powerful for evaluating patients with elevated transaminases of unknown origin. Histology of HEV infection under immunosuppression in the early phase is distinct from HEV infection in immunocompetent individuals. AU - Protzer, U. AU - Böhm, F.* AU - Longerich, T.* AU - Seebach, J. AU - Heidary Navid, M.* AU - Friemel, J.* AU - Marques-Maggio, E.* AU - Bawohl, M.* AU - Heikenwälder, M. AU - Schirmacher, P.* AU - Dutkowski, P.* AU - Clavien, P.A.* AU - Schemmer, P.* AU - Schnitzler, P.* AU - Gotthardt, D.* AU - Müllhaupt, B.* AU - Weber, A.* C1 - 42807 C2 - 35354 CY - New York SP - 523-532 TI - Molecular detection of Hepatitis E Virus (HEV) in liver biopsies after liver transplantation. JO - Mod. Pathol. VL - 28 IS - 4 PB - Nature Publishing Group PY - 2015 SN - 0893-3952 ER - TY - JOUR AB - Hematogenous spread determines the outcome of osteosarcoma (OS) patients, but the pathogenesis of developing metastatic disease is still unclear. Chemokines are critical regulators of cell trafficking and adhesion, and have been reported to be aberrantly expressed and to correlate with an unfavorable prognosis and metastatic spread in several malignant tumors. The chemokine receptors CXCR4 and CXCR7 together with their common ligand CXCL12 form one of the most important chemokine axes in this context. To investigate a potential role of these chemokines in OSs, we analyzed their expression in a series of 223 well-characterized and pretherapeutic OS samples. Interestingly, we found the expression of CXCL12 and CXCR4 to correlate with a better long-term outcome and with a lower prevalence of metastases. These findings suggest a distinct role of CXCR4/CXCR7/CXCL12 signaling in the tumors of bone, as has also been previously described in acute leukemia. As many malignant tumors metastasize to bone, and tumor cells are thought to be directed to bone in response to CXCL12, OS cells expressing both CXCL12 and the corresponding receptors might be detained at their site of origin. The disruption of CXCR4/CXCR7/CXCL12 signaling could therefore be crucial in OSs for the migration of tumor cells from bone into circulation and for developing systemic disease. AU - Baumhoer, D. AU - Smida, J. AU - Zillmer, S. AU - Rosemann, M. AU - Atkinson, M.J. AU - Nelson, P.J.* AU - Jundt, G.* AU - von Luettichau, I.* AU - Nathrath, M. C1 - 7918 C2 - 29918 SP - 522-528 TI - Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma. JO - Mod. Pathol. VL - 25 IS - 4 PB - Nature Publishing Group PY - 2012 SN - 0893-3952 ER - TY - JOUR AB - We present a series of 10 primary esophageal melanomas of Caucasian patients characterized clinicopathologically and on the molecular level. Mutation analysis for c-Kit (exons 9, 11, 13 and 17), PDGFR (exons 12, 14 and 18), NRAS and KRAS were determined using PCR and direct sequencing. Analysis of the V600E mutation of BRAF was performed using mutation-specific PCR. Expression of c-Kit and PDGFR-A was additionally determined using immunohistochemistry. One tumor harbored a missense mutation in the c-Kit (p.F504L) and in the KRAS gene (p.G12S). A different c-Kit mutation (c.1507_1508 ins TTGCCT) was detected in another case. A third case had a V600E BRAF mutation. Using immunohistochemistry, c-Kit expression could be detected in all cases. The two cases with c-Kit mutations showed high c-Kit expression. None of the tumors showed a PDGFR mutation or expression or a NRAS mutation. We conclude that molecular analysis can identify targets for a specific therapy such as tyrosin kinase inhibitors as additional treatment option in these highly malignant tumors. AU - Langer, R.* AU - Becker, K.* AU - Feith, M.* AU - Friess, H.* AU - Höfler, H. AU - Keller, G.* C1 - 6465 C2 - 28743 SP - 495-501 TI - Genetic aberrations in primary esophageal melanomas: Molecular analysis of c-KIT, PDGFR, KRAS, NRAS and BRAF in a series of 10 cases. JO - Mod. Pathol. VL - 24 IS - 4 PB - Nature Publ. Group PY - 2011 SN - 0893-3952 ER - TY - JOUR AB - Amplification and overexpression of ErbB2 (Her2) is a frequent event in oesophageal adenocarcinomas. Assessment of ErbB2 status is crucial for identifying patients who are likely to benefit from treatment with trastuzumab. In this study, we performed a comprehensive analysis of ErbB2 amplification and expression in 142 oesophageal adenocarcinomas by comparing the most commonly used methods for ErbB2 assessment: ErbB2 expression was determined by immunohistochemistry and was scored (0, 1+, 2+ and 3+) according to a recently described modified scoring system for gastric cancer. ErbB2 amplification was evaluated by bright field double in situ hybridisation. The results were compared with pathologic features, patients' survival and previously published data from fluorescence in situ hybridisation analysis. On the basis of immunohistochemistry, which was applicable in 110 cores of the cases, 83 tumours (75%) had a score of 0 or 1+ (immunohistochemistry negative), 13 tumours (12%) were scored as 2+ and 14 tumours (13%) were scored as 3+. In situ hybridisation data were obtained from 142 cases. There was a highly significant correlation of immunohistochemistry, bright field in situ hybridisation and fluorescent in situ hybridisation (P<0.001 each). In total, 41 tumours (29%) were categorised as ErbB2 positive, which was defined as immunohistochemistry 3+ and/or an ErbB2/Chr17 quotient of ≥2 as assessed by either bright field double in situ hybridisation or fluorescence in situ hybridisation. ErbB2 positivity was observed more frequently in tumours with lower differentiation grades (P=0.029). Patients with ErbB2-positive tumours had a significantly worse prognosis, both in univariate analysis (P=0.004) and in multivariate analysis (P=0.03). In conclusion, we demonstrate that a significant number of oesophageal adenocarcinomas are positive for ErbB2. Assessment of ErbB2 amplification can be equivalently performed by conventional fluorescence in situ hybridisation or other light-microscopy-based methods, such as the novel bright field double in situ hybridisation technique. AU - Langer, R.* AU - Rauser, S. AU - Feith, M.* AU - Nährig, J.M.* AU - Feuchtinger, A. AU - Friess, H.* AU - Höfler, H. AU - Walch, A.K. C1 - 6569 C2 - 28880 CY - New York, NY SP - 908-916 TI - Assessment of ErbB2 (Her2) in oesophageal adenocarcinomas: Summary of a revised immunohistochemical evaluation system, bright field double in situ hybridisation and fluorescence in situ hybridisation. JO - Mod. Pathol. VL - 24 IS - 7 PB - Nature Publ. Group PY - 2011 SN - 0893-3952 ER - TY - JOUR AB - Rho GTPases are a family of major regulators of E-cadherin-mediated cell adhesion that are implicated in the carcinogenic process by deregulated expression of the family members itself or of upstream modulators or downstream effectors. Combined investigation of the Rho GTPase Rac1, the effector protein IQGAP1 and the activator Tiam1 in relation to expression or mutation of E-cadherin in gastric adenocarcinomas has not been reported. The aim of the study was to determine the expression and prognostic significance of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric adenocarcinomas. Gastric carcinomas of 76 patients were investigated immunohistochemically in a tissue microarray study for expression of Rac1, IQGAP1, Tiam1 and E-cadherin. Correlations with clinical and follow-up data were examined. Moderate or strong reactivity for Rac1 was observed in 46% and for Tiam1 in 56% of tumors. Expression of IQGAP1 was present in 59% and of E-cadherin in 87% of tumors. While Rac1 and E-cadherin expression were not related to prognosis, a trend was observed between a lack of IQGAP1 expression (log-rank 0.088) as well as presence of Tiam1 (log-rank 0.097) and favorable prognosis in Kaplan-Meier survival analysis. Expression of Rac1 was positively linked to IQGAP1 expression (P=0.007, r=0.343) and tended to be inversely associated with expression of E-cadherin (P=0.055, r=-0.245). In conclusion, we observed deregulated expression of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric cancer. We present evidence that either upregulation (for Rac1 and IQGAP1) or downregulation (for Tiam1 and E-cadherin) occurs. Rac1 and E-cadherin expression were not related to prognosis, while trends pointing to favorable prognosis of patients with Tiam1 expression and a lack of IQGAP1 expression were observed. These results indicate that the investigated regulators of E-cadherin-mediated cell adhesion play a role in gastric carcinogenesis. AU - Walch, A.K. AU - Seidl, S.* AU - Hermannstädter, C.* AU - Rauser, S. AU - Deplazes, J.* AU - Langer, R.* AU - von, Weyhern, C.H.* AU - Sarbia, M.* AU - Busch, R.* AU - Feith, M.* AU - Gillen, S.* AU - Höfler, H. AU - Luber, B.* C1 - 1874 C2 - 25230 SP - 544-552 TI - Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer. JO - Mod. Pathol. VL - 21 IS - 5 PB - Nature Publ. Group PY - 2008 SN - 0893-3952 ER - TY - JOUR AU - Gamboa-Dominguez, A.* AU - Dominguez-Fonseca, C.* AU - Quintanilla-Martinez, L. AU - Reyes-Gutierrez, E.* AU - Green, D.* AU - Angeles-Angeles, A.* AU - Busch, R.* AU - Hermannstädter, Ch.* AU - Nährig, J.* AU - Becker, K.-F. AU - Becker, I.* C1 - 2196 C2 - 21857 SP - 579-587 TI - Epidermal growth factor receptor expression correlates with poor survival in gastric adenocarcinoma from Mexican patients: A multivariate analysis using a standardized immunohistochemical detection system. JO - Mod. Pathol. VL - 17 PY - 2004 SN - 0893-3952 ER - TY - JOUR AB - Lymph node metastasis is one of the strongest negative prognostic factors for patients with Barrett's adenocarcinoma (BCA). However, despite the importance of the metastatic process in BCA, the molecular basis of it remains poorly understood. To search for cytogenetic events associated with metastasis in regional or distant lymph nodes in BCA, we investigated 8 primary BCA and their lymph node metastases and compared them with 18 nonmetastatic BCA. In metastatic primary BCA, we observed significantly more DNA gains on 3q (P = .013), 17q (P = .019), and 22q (P = .021) compared with nonmetastatic primary BCA. No statistically significant correlation could be observed between DNA copy number changes and the histopathologic stage, grade, or survival (P > .05). The most frequent alteration observed only in lymph node metastases but not in the related primary tumor was loss of 2q (5 of 8). Coamplification of 7p and chromosome 17 was found in 6 of 8 lymph node metastases. A comparison of DNA copy number changes between primary tumors and their corresponding metastases indicated a high degree of genetic heterogeneity. Fluorescence in situ hybridization analysis demonstrated the involvement of the Her-2/neu gene in primary BCA and its related lymph node metastases. Each of the investigated primary tumors and related lymph node metastases also showed striking heterogeneity with respect to Her-2/neu, with several areas displaying different levels of amplification. In summary, our data indicate that DNA copy number changes on 2q, 3q, 7p, 17q, and 22q may be involved in the metastatic process in BCA. Furthermore, the striking genetic heterogeneity that we found between primary BCA and its lymph node metastases may underlie BCA's poor responsiveness to therapy and could help explain why prognostic biomarkers measured exclusively in primary tumors give an incomplete view of the biologic potential of BCA. AU - Walch, A.K. AU - Zitzelsberger, H. AU - Bink, K.* AU - Hutzler, P. AU - Bruch, J. AU - Braselmann, H. AU - Aubele, M. AU - Müller, J.* AU - Stein, H.* AU - Siewert, J.R.* AU - Höfler, H. AU - Werner, M.* C1 - 23354 C2 - 31124 SP - 814-824 TI - Molecular genetic changes in metastatic primary Barrett's adenocarcinoma and related lymph node metastases: Comparison with nonmetastatic Barrett's adenocarcinoma. JO - Mod. Pathol. VL - 13 IS - 7 PB - Nature Publishing Group PY - 2000 SN - 0893-3952 ER -