BACKGROUND: Innovative information technologies open new possibilities for diagnostics and promise to improve patient care. However, the integration of data- and computing-intensive procedures into diagnostic workflows a...BACKGROUND: Innovative information technologies open new possibilities for diagnostics and promise to improve patient care. However, the integration of data- and computing-intensive procedures into diagnostic workflows also poses risks and considerable challenges for pathologists. OBJECTIVES: Considering technical, operational, and regulatory aspects, we present a holistic and systematic approach for the adoption of digital and computational pathology. MATERIAL AND METHODS: We discuss challenges for the implementation of computational diagnostic procedures and analyze regulatory frameworks for risk-based assessment and monitoring of software as an in vitro diagnostic device. Applying regulatory science, we develop an approach to streamline adoption of digital workflows in pathology. RESULTS: Data- and computing-intensive workflows in digital pathology are complex and underscore the need for computational and regulatory science as a central part of pathological diagnostics. To promote the adoption of computational diagnostics, we have founded an interdisciplinary initiative (the Alliance) that focuses on regulatory research in the field of digital pathology and works closely with a number of expert and interest groups on the precompetitive development of standards for computational workflows. DISCUSSION: The inclusion of different stakeholder groups and the coordination of technical, operational, and regulatory aspects is necessary to maintain the balance between progress and safety in diagnostics and to make innovations quickly and safely available for patient care.
The field of molecular pathology has revolutionized our understanding of relevant oncogenic alterations in cancer and yielded new diagnostic tools and therapeutic approaches for personalized oncology, especially for mali...The field of molecular pathology has revolutionized our understanding of relevant oncogenic alterations in cancer and yielded new diagnostic tools and therapeutic approaches for personalized oncology, especially for malignancies of adulthood. However, many pediatric tumors, such as Ewing sarcoma, are characterized by a remarkable paucity of recurrent driver mutations, which are usually not suitable as drug targets. Despite the relative homogeneity of the somatic mutational profiles, these tumors nevertheless exhibit a relatively strong clinical heterogeneity, indicating additional modulating factors. In this regard, a recent study could demonstrate that the mode of action of the EWSR1-FLI1 (Ewing sarcoma breakpoint region 1-Friend leukema integration 1) fusion oncoprotein, which is pathognomonic for Ewing sarcoma, is influenced by inherited genetic variants in regulatory DNA elements, which may ultimately affect the course of the disease and also enable new therapeutic options. Thus, these investigations demonstrate in the Ewing sarcoma model that the function of a driver mutation needs to be interpreted in its germline context, which should be taken into account in an integrative approach by the molecular pathology of the future.
NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infanti...NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.
Walter Büngeler is one of the best known German pathologists of the 20th century. He became internationally known for his basic research on leukaemia and the pathology of tumours. In 1936 he left Europe for Brazil but re...Walter Büngeler is one of the best known German pathologists of the 20th century. He became internationally known for his basic research on leukaemia and the pathology of tumours. In 1936 he left Europe for Brazil but returned in 1942. After 1945, he staged himself as a political victim who had been expelled first by the National Socialists and later from Brazil. In fact, with this portrayal he succeeded in passing the denazification procedure without any damage and in continuing and considerably expanding his university career. Until the recent past, Büngeler was described in the relevant literature as a Nazi critic or victim. But does the presentation handed down by Büngeler stand up to a critical examination of the facts?On the basis of contemporary sources, the article reveals serious differences between Büngeler's statements and historical facts. It can be shown that Büngeler's allegations in denazification were incorrect in all relevant aspects.
In order to regulate their phosphate uptake, patients with end-stage renal disease rely on phosphate binders such as lanthanum carbonate (LC). The earliest histopathological reports of this rare entity in the gastrointes...In order to regulate their phosphate uptake, patients with end-stage renal disease rely on phosphate binders such as lanthanum carbonate (LC). The earliest histopathological reports of this rare entity in the gastrointestinal mucosa were described and published in 2015.We present a case of an 80-year-old patient with LC gastro-enteropathy. Histopathologically it can mimic other drug-induced depositions and even infectious or neoplastic entities. Evaluation of the patient's medical and especially drug history is essential to obtain the appropriate diagnosis. We present an overview of the clinical presentation and histological differential diagnosis of LC.
During the Second World War, the German Wehrmacht and the SS tested various chemical warfare agents on prisoners of concentration camps. The SS needed a pathologist to do this. Therefore, Reichsarzt SS Ernst-Robert Grawi...During the Second World War, the German Wehrmacht and the SS tested various chemical warfare agents on prisoners of concentration camps. The SS needed a pathologist to do this. Therefore, Reichsarzt SS Ernst-Robert Grawitz recruited the 32-year-old Hans Wolfgang Sachs. Despite his position as senior pathologist at the office of the Reichsarzt SS, Sachs was spared interrogation and prosecution after 1945, although the prosecution presented a document about chemical warfare and human experiments during the Nuremberg medical trial. In this, Sachs was named as a participant in so-called "N-Stoff" (chlorine trifluoride) experiments. Little is known about Sachs to this day. This article is intended to close this gap. Of particular interest are the motives and reasons why Sachs joined the party and the SS, as well as his career after 1945.
Invariant natural killer T cells (iNKT cells) are a small subset of T lymphocytes that are equipped with various immunoregulatory cytokines and cytotoxic effector molecules. Immune responses can be modulated efficiently...Invariant natural killer T cells (iNKT cells) are a small subset of T lymphocytes that are equipped with various immunoregulatory cytokines and cytotoxic effector molecules. Immune responses can be modulated efficiently by their interaction with other cells of the innate and adaptive immune system. Also, iNKT cells can promote apoptosis of malignant cells. Therefore, iNKT cells play a particular role in infectious diseases, malignant diseases, autoimmunity and alloimmunity. After allogeneic hematopoietic cell transplantation, iNKT cells induce immune tolerance and promote graft-versus-tumor effects. Recent advances in automated cell processing under good manufacturing practice (GMP) conditions and genetic modifications of effector cells pave the way for clinical translation of iNKT cell therapy.
BACKGROUND: Due to further developments in the diagnosis of glandular cervical changes with the definition of several new entities, the exact classification of these can only be achieved with the help of cytomorphology a...BACKGROUND: Due to further developments in the diagnosis of glandular cervical changes with the definition of several new entities, the exact classification of these can only be achieved with the help of cytomorphology and additive methods. OBJECTIVES AND METHODS: The aim of this work is to give an overview of the status and future perspectives of cytomorphological diagnostics and biomarkers in this setting. Our own expertise and literature data were considered and evaluated. We especially covered the benign group including microglandular hyperplasia, tubal metaplasia, and reactive withdrawal induced changes, as well as adenocarcinoma in situ of usual type and invasive adenocarcinoma of usual type. RESULTS AND CONCLUSIONS: Immunocytochemical markers may occasionally take a role in the evaluation of benign endocervical glandular proliferations, the mainstay of their interpretation occurs morphologically in the conventional routinely stained smears. Adenocarcinoma in situ of usual type has very characteristic cytological criteria, which are reproducible in daily work, and p16 positivity is a very useful marker for this HPV-related lesion. The present classification of invasive adenocarcinomas of the endocervix requires knowledge of new immunohistochemical and molecular technologies. Due to HPV vaccination we can expect a decrease of HPV associated adenocarcinomas and a relative increase of HPV negative, clinically more aggressive adenocarcinomas. The cytological features of some groups of non-HPV-associated adenocarcinomas are not specific. In these instances, the different biomarkers are more helpful.
Besides histopathological findings, there are no indicators of increased risk for fibrotic progression in myeloproliferative neoplasms (MPNs). Age-related clonal hematopoiesis (ARCH) or clonal hematopoiesis of indetermin...Besides histopathological findings, there are no indicators of increased risk for fibrotic progression in myeloproliferative neoplasms (MPNs). Age-related clonal hematopoiesis (ARCH) or clonal hematopoiesis of indetermined potential (CHIP) are frequent findings 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 the 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 to prefibrotic PMF samples without the development of fibrosis (n = 27; median follow-up 7.3 years). Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, DNMT3A) demonstrable at presentation were not connected with fibrotic progression. However, mutations that 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 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 already manifest at first presentation.
CARTs (T-cells with a chimeric antigen receptor) are one of the most innovative and exciting developments in cancer medicine. In August 2018, two novel drugs were approved in the European Union, both for the treatment of...CARTs (T-cells with a chimeric antigen receptor) are one of the most innovative and exciting developments in cancer medicine. In August 2018, two novel drugs were approved in the European Union, both for the treatment of relapsed and refractory aggressive lymphoma, one of them also for the treatment of acute lymphoblastic leukemia in children and young adults up to 25 years. In the foreseeable future, further approvals are expected, e.g., in mantle cell lymphoma and multiple myeloma. Clinical trials with new constructs are ongoing in almost all cancer entities. The introduction of this completely new principle implicates unusual challenges: (1) The use of genetically modified "living drugs" is challenging from a regulatory point of view and might require a lifelong surveillance of the patient, (2) companies and authorities make high demands on the quality management at the sites, (3) the price of about 280,000 € for the approved treatments rises new socioeconomic and ethical questions. However, CARTs will change the therapeutic landscape in many cancers in upcoming years.