Usefulness of BATF3 immunohistochemistry in diagnosing classical Hodgkin lymphoma

It is well recognized that the AP-1 transcription factor BATF3 is constitutively expressed in Hodgkin/Reed-Sternberg (HRS) cells, but its potential as a diagnostic marker for classical Hodgkin lymphoma (cHL) has not yet been addressed. In this study, we performed immunohistochemistry and analyzed the BATF3 expression in lymphoma cells on 218 lymphoma samples belonging to 14 different lymphoma entities. We observed varying degrees of BATF3 expression in nearly half of the cases (n = 100) with BATF3 expression being a constitutive feature of cHL (n = 53) and anaplastic large cell lymphoma (ALCL). By scoring BATF3 expression (BATF3-score) we observed constitutively high BATF3-scores in cHL and ALCL and low to moderate BATF3-scores in all other entities examined. Western blot analysis confirmed BATF3 protein expression in cell lysates from cHL cell lines (n = 7). Thus, BATF3 can be considered a useful IHC marker for the diagnosis of cHL as it is highly sensitive and sufficiently specific when analyzed by BATF3-scoring

Kleinzelliges neuroendokrines Karzinom des Kopf-Hals-Bereichs: eine Übersichtsarbeit und Fallserie

Einleitung Kleinzellige neuroendokrine Karzinome (KNK) des Larynx sind eine seltene Tumorentität mit schlechter Prognose bei einer 5-Jahres-Überlebensrate nach Standardtherapie mit primärer Radiochemotherapie (pRCT) von 5 %. Methoden Es erfolgte eine systematische Literaturrecherche auf PubMed mit den Suchbegriffen „small cell neuroendocrine carcinoma“ und „head and neck“ sowie die Aufarbeitung von Patientenfällen aus unserer Klinik. Ergebnisse Die Recherche ergab keine großen randomisierten kontrollierten Studien zur Standardtherapie. Bisherige Therapiestrategien basieren auf den Erfahrungen bei kleinzelligen Karzinomen der Lunge. 0,5 % aller KNK treten im Kopf-Hals-Bereich auf. In unserer Klinik wurden in 12 Jahren 9 KNK diagnostiziert, 2 davon mit laryngealer Manifestation. Wir berichten über einen 29-jährigen Patienten mit Erstdiagnose (ED) eines Larynx-KNK im Frühjahr 2018. Im Staging zeigten sich zervikale Lymphknotenmetastasen, eine Fernmetastasierung wurde ausgeschlossen. Es erfolgte eine pRCT mit Cisplatin/Etoposid mit darauffolgender Komplettremission. Im Re-Staging 6 Monate nach ED zeigten sich Metastasen-suspekte Lungenherde. Unter 6 Zyklen palliativer Systemtherapie mit Cyclophosphamid, Adriamycin und Vincristin kam es zu einer partiellen Remission. Nach 12 Monaten erfolgte bei Progress die Therapieumstellung auf den PD-1-Antikörper Nivolumab. Der Patient verstarb 22 Monate nach ED an einer tumorbedingten Massenblutung mit Verlegung der Atemwege. Schlussfolgerung Bisher existieren keine Studienergebnisse über den Einsatz von Nivolumab als Third-Line-Therapie bei KNK. Die Analyse einer NTRK-Fusion (neurotrophe Tyrosin-Rezeptor-Kinase) oder einer Folatrezeptor-Expression sollte erwogen werden zur Evaluation einer Tropomyosin-Rezeptor-Kinase-Inhibitor- oder einer Radionuklidtherapie

Usefulness of BATF3 Immunohistochemistry in Diagnosing Classical Hodgkin Lymphoma

It is well recognized that the AP-1 transcription factor BATF3 is constitutively expressed in Hodgkin/Reed-Sternberg (HRS) cells, but its potential as a diagnostic marker for classical Hodgkin lymphoma (cHL) has not yet been addressed. In this study, we performed immunohistochemistry and analyzed the BATF3 expression in lymphoma cells on 218 lymphoma samples belonging to 14 different lymphoma entities. We observed varying degrees of BATF3 expression in nearly half of the cases (n = 100) with BATF3 expression being a constitutive feature of cHL (n = 53) and anaplastic large cell lymphoma (ALCL). By scoring BATF3 expression (BATF3-score) we observed constitutively high BATF3-scores in cHL and ALCL and low to moderate BATF3-scores in all other entities examined. Western blot analysis confirmed BATF3 protein expression in cell lysates from cHL cell lines (n = 7). Thus, BATF3 can be considered a useful IHC marker for the diagnosis of cHL as it is highly sensitive and sufficiently specific when analyzed by BATF3-scoring

Heterogeneous expression of predictive biomarkers PD-L1 and TIGIT in non-mucinous lung adenocarcinoma and corresponding lymph node metastasis: A challenge for clinical biomarker testing

The use of immune checkpoint inhibitors (ICI) targeting the PD-L1:PD1 interaction revolutionized tumor treatment by re-activating the anti-tumoral capacity of the immune system. Assessment of tumor mutational burden, microsatellite instability, or expression of the surface marker PD-L1 have been used to predict individual response to ICI therapy. However, the predicted response does not always correspond to the actual therapy outcome. We hypothesize that tumor heterogeneity might be a major cause of this inconsistency. In this respect we recently demonstrated that PD-L1 shows heterogenous expression in the different growth patterns of non-small cell lung cancer (NSCLC) - lepidic, acinar, papillary, micropapillary and solid. Furthermore, additional inhibitory receptors, like T cell immunoglobulin and ITIM domain (TIGIT), appear to be heterogeneously expressed and affect the outcome of anti-PD-L1 treatment. Given this heterogeneity in the primary tumor, we set out to analyze the situation in corresponding lymph node metastases, since these are often used to obtain biopsy material for tumor diagnosis, staging and molecular analysis. Again, we observed heterogeneous expression of PD-1, PD-L1, TIGIT, Nectin-2 and PVR in relation to different regions and growth pattern distribution that varied between the primary tumor and their metastases. Together, our study underscores the complex situation regarding the heterogeneity of NSCLC samples and suggest that the analysis of a small biopsy from lymph node metastases may not be sufficient to ensure a reliable prediction of ICI therapy success

Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis

Cardiomyopathies with intracellular inclusions are a distinct subset of cardiomyopathies whereas basophilic degeneration (BD) of the heart describes inclusions in cardiomyocytes of the aging heart, which have not yet been related to a specific disease condition or to a distinct type of protein inclusion. To address the question whether BD represents a specific pathological feature and whether it is linked to a distinct disease condition we studied 62 autopsy cases. BD inclusions exhibited an immunohistochemical staining pattern related to glycosylated, δ- or η-secretase-derived N-terminal cleavage products of the amyloid precursor protein (sAPPδ/η) or shorter fragments of sAPPη. BD aggregates were found in the myocardium of both ventricles and atria with highest amounts in the atria and lowest in the interventricular septum. The frequency of BD-lesions correlated with age, degree of myocardial fibrosis in individuals with arterial hypertension, and the severity of cerebral amyloid angiopathy (CAA). The intracytoplasmic deposition of N-terminal sAPPδ/η fragments in BD indicates a specific inclusion body pathology related to APP metabolism. The correlation with the severity of CAA, which is related to the APP-derived amyloid β-protein, supports this point of view and suggests a possible link between myocardial and cerebrovascular APP-related lesions.status: publishe

Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis

Abstract Cardiomyopathies with intracellular inclusions are a distinct subset of cardiomyopathies whereas basophilic degeneration (BD) of the heart describes inclusions in cardiomyocytes of the aging heart, which have not yet been related to a specific disease condition or to a distinct type of protein inclusion. To address the question whether BD represents a specific pathological feature and whether it is linked to a distinct disease condition we studied 62 autopsy cases. BD inclusions exhibited an immunohistochemical staining pattern related to glycosylated, δ- or η-secretase-derived N-terminal cleavage products of the amyloid precursor protein (sAPPδ/η) or shorter fragments of sAPPη. BD aggregates were found in the myocardium of both ventricles and atria with highest amounts in the atria and lowest in the interventricular septum. The frequency of BD-lesions correlated with age, degree of myocardial fibrosis in individuals with arterial hypertension, and the severity of cerebral amyloid angiopathy (CAA). The intracytoplasmic deposition of N-terminal sAPPδ/η fragments in BD indicates a specific inclusion body pathology related to APP metabolism. The correlation with the severity of CAA, which is related to the APP-derived amyloid β-protein, supports this point of view and suggests a possible link between myocardial and cerebrovascular APP-related lesions

U-DCS: characterization of the first permanent human dendritic sarcoma cell line

A dendritic cell sarcoma cell line, U-DCS, was established from a dendritic cell sarcoma in a 53-year-old Caucasian male patient. Since its establishment, U-DCS has maintained stable phenotypic characteristics in vitro and has a doubling time of approximately 2 days under standard culture conditions. U-DCS is growing with typical dendritic cell morphology in tissue and expresses the dendritic cell sarcoma immunophenotypic markers S100 protein, MHCI, MHCII, and vimentin. Expression analysis revealed transcripts for the toll-like receptors TLR3, -4, -9 and DDX58 (RIG-I), but not for TLR2. U-DCS shows functional features of dendritic cells with the ability of phagocytosis and antigen-specific T cell stimulation. Karyotype-, CGH-, and mFISH analysis point to a chromosomal instability and a hypotetraploid karyotype with approximately 130 chromosomes. U-DCS is the first immortalized human dendritic cell sarcoma cell line and has some morphological and functional features of dendritic cells without dependency on growth factors

The Small GTPase RHOA Links SLP65 Activation to PTEN Function in Pre B Cells and Is Essential for the Generation and Survival of Normal and Malignant B Cells

The generation, differentiation, survival and activation of B cells are coordinated by signals emerging from the B cell antigen receptor (BCR) or its precursor, the pre-BCR. The adaptor protein SLP65 (also known as BLNK) is an important signaling factor that controls pre-B cell differentiation by down-regulation of PI3K signaling. Here, we investigated the mechanism by which SLP65 interferes with PI3K signaling. We found that SLP65 induces the activity of the small GTPase RHOA, which activates PTEN, a negative regulator of PI3K signaling, by enabling its translocation to the plasma membrane. The essential role of RHOA is confirmed by the complete block in early B cell development in conditional RhoA-deficient mice. The RhoA-deficient progenitor B cells showed defects in activation of immunoglobulin gene rearrangement and fail to survive both in vitro and in vivo. Reconstituting the RhoA-deficient cells with RhoA or Foxo1, a transcription factor repressed by PI3K signaling and activated by PTEN, completely restores the survival defect. However, the defect in differentiation can only be restored by RhoA suggesting a unique role for RHOA in B cell generation and selection. In full agreement, conditional RhoA-deficient mice develop increased amounts of autoreactive antibodies with age. RHOA function is also required at later stage, as inactivation of RhoA in peripheral B cells or in a transformed mature B cell line resulted in cell loss. Together, these data show that RHOA is the key signaling factor for B cell development and function by providing a crucial SLP65-activated link between BCR signaling and activation of PTEN. Moreover, the identified essential role of RHOA for the survival of transformed B cells offers the opportunity for targeting B cell malignancies by blocking RHOA function

INHBA is Enriched in HPV-negative Oropharyngeal Squamous Cell Carcinoma and Promotes Cancer Progression.

Patients with oropharyngeal squamous cell carcinoma (OPSCC) caused by human papilloma virus (HPV) exhibit a better prognosis than those with HPV-negative OPSCC. This study investigated the distinct molecular pathways that delineate HPV-negative from HPV-positive OPSCC to identify biologically relevant therapeutic targets. Bulk mRNA from 23 HPV-negative and 39 HPV-positive OPSCC tumors (n = 62) was sequenced to uncover the transcriptomic profiles. Differential expression followed by gene set enrichment analysis was performed to outline the top enriched biological process in the HPV-negative compared with HPV-positive entity. INHBA, the highest overexpressed gene in the HPV-negative tumor, was knocked down. Functional assays (migration, proliferation, cell death, stemness) were conducted to confirm the target's oncogenic role. Correlation analyses to reveal its impact on the tumor microenvironment were performed. We revealed that epithelial-to-mesenchymal transition (EMT) is the most enriched process in HPV-negative compared with HPV-positive OPSCC, with INHBA (inhibin beta A subunit) being the top upregulated gene. INHBA knockdown downregulated the expression of EMT transcription factors and attenuated migration, proliferation, stemness, and cell death resistance of OPSCC cells. We uncovered that INHBA associates with a pro-tumor microenvironment by negatively correlating with antitumor CD8+ T and B cells while positively correlating with pro-tumor M1 macrophages. We identified three miRNAs that are putatively involved in repressing INHBA expression. Our results indicate that the upregulation of INHBA is tumor-promoting. We propose INHBA as an attractive therapeutic target for the treatment of INHBA-enriched tumors in patients with HPV-negative OPSCC to ameliorate prognosis.SignificancePatients with HPV-negative OPSCC have a poorer prognosis due to distinct molecular pathways. This study reveals significant transcriptomic differences between HPV-negative and HPV-positive OPSCC, identifying INHBA as a key upregulated gene in HPV-negative OPSCC's oncogenic pathways. INHBA is crucial in promoting EMT, cell proliferation, and an immunosuppressive tumor environment, suggesting its potential as a therapeutic target for HPV-negative OPSCC

TABLE 1 from <i>INHBA</i> is Enriched in HPV-negative Oropharyngeal Squamous Cell Carcinoma and Promotes Cancer Progression

Clinicopathologic features of patients with OPSCC in Ulm and TCGA cohorts</p