Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal ...breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal–HER2-negative breast cancer.
Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0–10% immune cells in stromal tissue within the tumour), intermediate (11–59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts.
In the luminal–HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio HR 0·93 95% CI 0·87–0·98, p=0·011) and HER2-positive breast cancer (0·94 0·89–0·99, p=0·017), but not in luminal–HER2-negative tumours (1·02 0·96–1·09, p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 0·86–0·99, p=0·032), but had no association in HER2-positive breast cancer (0·94 0·86–1·02, p=0·11), and was associated with shorter overall survival in luminal–HER2-negative tumours (1·10 1·02–1·19, p=0·011).
Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal–HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted.
Deutsche Krebshilfe and European Commission.
In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. ...In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical).
Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. Deregulation of C/EBPα by microRNAs during granulopoiesis or acute ...myeloid leukemia development has not been studied. Here we show that oncogenic miR-182 is a strong regulator of C/EBPα. Moreover, we identify a regulatory loop between C/EBPα and miR-182. While C/EBPα blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 reduces C/EBPα protein level and impairs granulopoiesis in vitro and in vivo. In addition, miR-182 expression is highly elevated particularly in acute myeloid leukemia patients with C-terminal CEBPA mutations, thereby depicting a mechanism by which C/EBPα blocks miR-182 expression. Furthermore, we present miR-182 expression as a prognostic marker in cytogenetically high-risk acute myeloid leukemia patients. Our data demonstrate the importance of a controlled balance between C/EBPα and miR-182 for the maintenance of healthy granulopoiesis.C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.
The article continues a series of publications of Sanskrit manuscript fragments written in the Proto-Śāradā script and kept in the Serindia Collection of the Institute of Oriental Manuscripts of the ...Russian Academy of Sciences (IOM, RAS). This article contains passages of stories from the Garland of Jātakas (Jātakamālā) by Āryaśūra. The article argues that the fragment from the Serindia Collection of the IOM, RAS belongs to the same manuscript as folios from the Turfan Collection (Berlin, Germany) and the Lshun Museum (Dalian, PRC). All these scattered folios, which appear in different collections, used to be parts of one and the same manuscript of Āryaśūras Jātakamālā. The Sanskrit fragment of the Mahābodhi-jātaka from the Serindia Collection of the IOM, RAS, analyzed in this article, is a passage from a dispute between a Bodhisattva and various Indian teachers, in which the Buddhist ascetic refutes the arguments of his opponents.
In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the ...formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3'-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell-cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL.
Religion ist auf die Agenda moderner Gesellschaften zuruckgekehrt. Vor allem auerhalb Europas entfalten religiose Akteure verstarkt groe Mobilisierungskraft, erzeugen mit ihren Sinnangeboten aber ...auch neue Konflikte. Religion kann zur Integration von Gesellschaften beitragen, aber auch Polarisierungstendenzen verstarken und die der jeweils Anderen, Fremden begrunden. Die Schattenseiten religiosen Bewusstseins werden ebenso erkundet wie neue charismatische Christentumer sowie die Faszinationskraft alternativer Sinnstiftungsangebote bis hin zur Esoterik.
Hematopoiesis, the formation of blood cells from hematopoietic stem cells (HSC), is a highly regulated process. Since the discovery of microRNAs (miRNAs), several studies have shown their significant ...role in the regulation of the hematopoietic system. Impaired expression of miRNAs leads to disrupted cellular pathways and in particular causes loss of hematopoietic ability. Here, we report a previously unrecognized function of miR-143 in granulopoiesis. Hematopoietic cells undergoing granulocytic differentiation exhibited increased miR-143 expression. Overexpression or ablation of miR-143 expression resulted in accelerated granulocytic differentiation or block of differentiation, respectively. The absence of miR-143 in mice resulted in a reduced number of mature granulocytes in blood and bone marrow. Additionally, we observed an association of high miR-143 expression levels with a higher probability of survival in two different cohorts of patients with acute myeloid leukemia (AML). Overexpression of miR-143 in AML cells impaired cell growth, partially induced differentiation, and caused apoptosis. Argonaute2-RNA-Immunoprecipitation assay revealed ERK5, a member of the MAPK-family, as a target of miR-143 in myeloid cells. Further, we observed an inverse correlation of miR-143 and ERK5 in primary AML patient samples, and in CD34
HSPCs undergoing granulocytic differentiation and we confirmed functional relevance of ERK5 in myeloid cells. In conclusion, our data describe miR-143 as a relevant factor in granulocyte differentiation, whose expression may be useful as a prognostic and therapeutic factor in AML therapy.
The transcription factor CCAAT enhancer binding protein α (C/EBPα) is a master regulator in granulopoiesis and is frequently disrupted in acute myeloid leukemia (AML). We have previously shown that ...C/EBPα exerts its effects by regulating microRNAs (miRs) such as miR-223 and miR-34a. Here, we confirm miR-30c as a novel important target of C/EBPα during granulopoiesis. Thus, wild-type C/EBPα-p42 directly upregulates miR-30c expression, whereas C/EBPα-p30, found in AML, does not. miR-30c is downregulated in AML, especially in normal karyotype AML patients with CEBPA mutations. An induced C/EBPα knockout in mice leads to a significant downregulation of miR-30c expression in bone marrow cells. We identified NOTCH1 as a direct target of miR-30c. Finally, a block of miR-30c prevents C/EBPα-induced downregulation of Notch1 protein and leads to a reduced CD11b expression in myeloid differentiation. Our study presents the first evidence that C/EBPα, miR-30c, and Notch1 together play a critical role in granulocytic differentiation and AML, and particularly in AML with CEBPA mutations. These data reveal the importance of deregulated miRNA expression in leukemia and may provide novel biomarkers and therapeutic targets in AML.
•miR-30c is a direct target of C/EBPα and upregulated by C/EBPα-p42.•NOTCH1 is a direct target of miR-30c and regulated by C/EBPα and miR-30c.
Active
related (
) gene deactivates ras-related C3 botulinum toxin substrate 1 (RAC1), which plays an essential role in regulating normal hematopoiesis and in leukemia.
gene, closely related to ABR, ...acts as a tumor suppressor in chronic myeloid leukemia and has overlapping functions with
. Evidence for a putative tumor suppressor role of
has been shown in several solid tumors, in which deletion of ABR is present. Our results show downregulation of
in AML. A block of ABR prevents myeloid differentiation and leads to repression of the myeloid transcription factor C/EBPα, a major regulator of myeloid differentiation and functionally impaired in leukemia. Conversely, stable overexpression of ABR enhances myeloid differentiation. Inactivation of the known ABR target RAC1 by treatment with the RAC1 inhibitor NSC23766 resulted in an increased expression of C/EBPα in primary AML samples and in AML cell lines U937 and MV4;11. Finally, AML patients with high
expression at diagnosis showed a significant longer overall survival and patients who respond to azacitidine therapy showed a significant higher ABR expression. This is the first report showing that
expression plays a critical role in both myelopoiesis and AML. Our data indicate the tumor suppressor potential of
and underline its potential role in leukemia therapeutic strategies.
Abstract
Introduction
To date, the optimal axillary staging procedure for initially node-positive breast carcinoma patients after neoadjuvant chemotherapy (NACT) has been unclear. The aim of
the ...AXSANA study is to prospectively compare different surgical staging techniques with respect to the oncological outcome and quality of life for the patients. Little is known about current
clinical practice in Germany.
Material and Methods
In this paper we analyzed data from patients enrolled in the AXSANA study at German study sites from June 2020 to March 2022.
Results
During the period under investigation, 1135 patients were recruited at 143 study sites. More than three suspicious lymph nodes were initially found in 22% of patients. The
target lymph node (TLN) was marked in 64% of cases. This was done with clips/coils in 83% of patients, with magnetic seeds or carbon suspension in 8% each, and with a radar marker in 1% of
patients. After NACT, targeted axillary dissection (TAD) or axillary lymphadenectomy (ALND) were each planned in 48% of patients, and sentinel lymph node biopsy alone (SLNB) in 2%.
Clinically, the nodal status after NACT was found to be unremarkable in 65% of cases. Histological lymph node status was correctly assessed by palpation in 65% of patients and by sonography
in 69% of patients.
Conclusion
At the German AXSANA study sites, TAD and ALND are currently used as the most common surgical staging procedures after NACT in initially node-positive breast cancer
patients. The TLN is marked with various markers prior to NACT. Given the inadequate accuracy of clinical assessment of axillary lymph node status after NACT, it should be questioned whether
axillary dissection after NACT should be performed based on clinical assessment of nodal status alone.
Zusammenfassung
Einleitung
Das optimale axilläre Stagingverfahren für initial nodal positive MammakarzinompatientInnen nach neoadjuvanter Chemotherapie (NACT) ist bislang unklar. Die AXSANA-Studie
wird mit dem Ziel durchgeführt, die verschiedenen operativen Stagingtechniken hinsichtlich ihres onkologischen Outcomes und der Lebensqualität prospektiv miteinander zu vergleichen. Über die
aktuelle klinische Praxis in Deutschland ist wenig bekannt.
Material und Methoden
Die Daten der von Juni 2020 bis März 2022 an deutschen Studienzentren in die AXSANA-Studie aufgenommenen PatientInnen wurden analysiert.
Ergebnisse
Im Untersuchungszeitraum wurden 1135 PatientInnen an 143 Studienstandorten rekrutiert. Bei 22% der PatientInnen fanden sich initial mehr als 3 suspekte Lymphknoten. In 64%
der Fälle wurde der Target-Lymphknoten (TLN) markiert. Dabei erfolgte die Markierung bei 83% der PatientInnen mit Clips/Coils, bei je 8% mit magnetischen Seeds oder Kohlenstoffsuspension und
bei 1% mit einem Radarmarker. Bei jeweils 48% der PatientInnen wurde nach NACT eine Targeted Axillary Dissection (TAD) oder eine axilläre Lymphonodektomie (ALND) geplant, bei 2% eine
alleinige Sentinel-Lymphknoten-Biopsie (SLNB). Klinisch wurde der Nodalstatus nach NACT in 65% der Fälle als unauffällig beurteilt. Bei 65% der Frauen wurde der histologische
Lymphknotenstatus durch die Palpation und bei 69% der PatientInnen durch die Sonografie korrekt erfasst.
Schlussfolgerung
An den deutschen AXSANA-Studienzentren werden derzeit die TAD und die ALND als häufigste operative Stagingverfahren nach NACT bei primär nodal positiven
MammakarzinompatientInnen durchgeführt, wobei die Markierung des TLN vor NACT mit verschiedenen Markern erfolgt. Aufgrund der ungenügenden Genauigkeit der klinischen Beurteilung des
axillären Lymphknotenstatus nach NACT sollte kritisch hinterfragt werden, ob eine Axilladissektion nach NACT auf der Grundlage einer alleinigen klinischen Bewertung des Nodalstatus erfolgen
sollte.
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