Evaluation der Leitlinien-Adhärenz sowie klinische und histologische Charakterisierung eines Patientenkollektivs mit pankreatischen neuroendokrinen Tumoren (pNET) an einem deutschen Pankreaszentrum

Pankreatische neuroendokrine Tumoren (pNET) sind eine seltene Tumorentität. Bei solchen stellen die Anwendung medizinischer Leitlinien und die Identifizierung prognostischer Parameter wichtige Werkzeuge dar. Für 115 Erstdiagnosen von pNET am St. Josef-Hospital Bochum von 2010-19 erfolgte eine klinische und histopathologische Charakterisierung und ein Vergleich der Leitlinien-Adhärenz vor und nach Veröffentlichung der deutschen S2k-Leitlinie. Die prognostische Wertigkeit der molekularen Marker ATRX und DAXX sowie von Mismatch-Reparatur-Proteinen wurde bestimmt. Eine vollständige Leitlinien-Adhärenz war signifikant mit dem Überleben assoziiert (p=0.05). In 9% bzw. 10% der Fälle konnte ein kompletter ATRX-/DAXX-Verlust nachgewiesen werden, welcher mit einer aggressiveren Tumorbiologie assoziiert war. Nur in 4% der Fälle konnte eine hochgradige Mikrosatelliteninstabilität nachgewiesen werden. Unsere Daten unterstützen den potenziellen Wert von DAXX und ATRX als prognostische Parameter

Prognostic Performance of Inflammatory Biomarkers Based on Complete Blood Counts in COVID-19 Patients

With the end of the pandemic, COVID-19 has entered an endemic phase with expected seasonal spikes. Consequently, the implementation of easily accessible prognostic biomarkers for patients with COVID-19 remains an important area of research. In this monocentric study at a German tertiary care hospital, we determined the prognostic performance of different clinical and blood-based parameters in 412 COVID-19 patients. We evaluated the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), and absolute eosinopenia (AEP, 0/µL) of COVID-19 patients (n = 412). The Siddiqui and Mehra staging proposal, the WHO clinical progression scale, and COVID-19-associated death were used as COVID-19 outcome measures. With respect to Siddiqi and Mehra staging, patient age of older than 75 years, high C-reactive protein (CRP), absolute eosinopenia (AEP), cardiovascular comorbidities, and high ferritin were significant independent predictors for severe COVID-19. When outcome was determined according to the WHO clinical progression scale, patient age of older than 75 years, high CRP, high LDH, AEP, high neutrophil-to-lymphocyte ratio (NLR), and the presence of pulmonal comorbidities were significant independent predictors for severe COVID-19. Finally, COVID-19-associated death was predicted independently by patient age of older than 75 years, high LDH, high NLR, and AEP. Eosinopenia (< 40/µL) was observed in 74.5% of patients, and AEP in almost 45%. In conclusion, the present real-world data indicate that the NLR is superior to more complex systemic immune-inflammation biomarkers (e.g., SII and PIV) in COVID-19 prognostication. A decreased eosinophil count emerged as a potential hallmark of COVID-19 infection, whereas AEP turned out to be an accessible independent biomarker for COVID-19 severity and mortality

DAXX\it DAXX, ATRX\it ATRX, and MSI in PanNET and their metastases

$\bf Introduction:$ Studies on pancreatic neuroendocrine tumors (PanNETs) regarding loss of $\it ATRX$, $\it DAXX$, or frequency of microsatellite instability (MSI) show inconclusive results. So far, data on corresponding metastaseshave not been published. $\bf Methods:$ We performed immunohistochemistry (IHC) of $\it ATRX$, $\it DAXX$, (\it MSH2\), (\it MSH6\), (\it MLH1\), and (\it PMS2\) on 74 PanNETs and 19 metastases. $\it ATRX$- and $\it DAXX$-negative PanNETs were further sequenced for mutations. We used polymerase chain reaction for MSI on cases with IHC loss of (\it MSH2\), (\it MSH6\), (\it MLH1\), and (\it PMS2\). $\bf Results:$ Immunohistochemical loss of $\it DAXX$ and $\it ATRX$ was observed in 8/74 (11%) and 6/74 (8%) PanNETs. Loss of $\it DAXX$ immunoreactivity was statistically associated with higher tumor grade and showed a tendency toward a decreased overall survival. Sequencing of $\it DAXX$- (7/11 [64%]) and $\it ATRX$-negative (5/11 [45%]) PanNETs revealed a mutation in 6/7 (86%) and 2/5 (40%). The specificity of immunohistochemical loss of $\it DAXX$ and $\it ATRX$ for mutation was 80% and 67%, respectively. The expression status of $\it DAXX$ compared to primary tumor differs in 2/12 (17%) lymph node metastases. We further identified 3/74 (4%) tumors as MSI, associated with a poor prognosis. $\bf Discussion/Conclusion:$ Our study supports the hypothesis that a loss of $\it DAXX$ immunoreactivity can identify a more aggressive subtype of PanNET with high confidence, while $\it ATRX$ loss is a weaker indicator. Our results also strengthen the role of $\it DAXX$ immunolabeling as a prognostic marker. We could show that $\it ATRX$ might be less suitable as a surrogate for sequencing. Our results indicate that IHC of $\it DAXX$ and $\it ATRX$ may identify PanNET subtypes as targets for more aggressive therapy

Low serological prevalence of SARS-CoV-2 antibodies in cancer patients at a German University Oncology Center

$\bf Background:$ Coronavirus disease 2019 (COVID-19) cases in Germany, as in most other places in Europe or worldwide, are still highly prevalent. Vaccination rates currently remain low, putting cancer patients at a continued risk of infection with SARS-CoV-2, while prevalence of SARS-CoV-2 antibodies among cancer patients in Germany remains essentially unknown. $\bf Methods:$ Between August 2020 and February 2021, patients admitted to our hospital were prospectively enrolled in our COVID-19 biobank. Collected sera were analyzed for SARS-CoV-2-IgM/IgG using Elecsys Anti-SARS-CoV-2 assay. $\bf Results:$ One hundred and ten patients with cancer were included in this study. With 71 (65%) patients, most had active cancer treatment, mainly chemotherapy (56%). The most frequent diagnosis was gastrointestinal cancer (54%) with pancreatic cancer being the most common cancer type (24%). Hematologic malignancies were present in 21 patients (17%). Among the cancer patients first diagnosed during the pandemic, the rate of palliative treatment situations tended to be higher (76% vs. 67%, $\it p$ = 0.17). A history of SARS-CoV-2 infection was documented in 15 (14%) patients; however, SARS-CoV-2 antibodies were detected in 10 (67%) patients only. Of the patients without a history of SARS-CoV-2 infection, none displayed SARS-CoV-2 antibodies. $\bf Conclusion:$ In the present single-center experience, a low serological prevalence of SARS-CoV-2 antibodies among cancer patients even after SARS-CoV-2 infection was found. The results support continued strict preventive measures as well as efforts toward faster vaccination, due to a low immunity level in the population

Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination

OBJECTIVE: The pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood. METHODS: We here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls. RESULTS: We show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1). INTERPRETATION: In summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity

DataSheet_1_Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination.pdf

ObjectiveThe pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood.MethodsWe here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls.ResultsWe show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1).InterpretationIn summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity.</p

DataSheet_1_Impact of SARS-CoV-2 vaccination on systemic immune responses in people living with HIV.pdf

Despite the development of vaccines, which protect healthy people from severe and life-threatening Covid-19, the immunological responses of people with secondary immunodeficiencies to these vaccines remain incompletely understood. Here, we investigated the humoral and cellular immune responses elicited by mRNA-based SARS-CoV-2 vaccines in a cohort of people living with HIV (PLWH) receiving anti-retroviral therapy. While antibody responses in PLWH increased progressively after each vaccination, they were significantly reduced compared to the HIV-negative control group. This was particularly noteworthy for the Delta and Omicron variants. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase, which was comparable in both groups. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4+ T cell numbers do not necessarily interfere with cellular immune responses. Our data demonstrate that despite the lower CD4+ T cell counts SARS-CoV-2 vaccination results in potent cellular immune responses in PLWH. However, the reduced humoral response also provides strong evidence to consider PLWH as vulnerable group and suggests subsequent vaccinations being required to enhance their protection against COVID-19.</p

Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination

$\bf Objective:$ The pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells $\it via$ anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood. $\bf Methods:$ We here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls. $\bf Results:$ We show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain $CD4^{+}$ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1). $\bf Interpretation:$ In summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity

Impact of SARS-CoV-2 vaccination on systemic immune responses in people living with HIV

Despite the development of vaccines, which protect healthy people from severe and life-threatening Covid-19, the immunological responses of people with secondary immunodeficiencies to these vaccines remain incompletely understood. Here, we investigated the humoral and cellular immune responses elicited by mRNA-based SARS-CoV-2 vaccines in a cohort of people living with HIV (PLWH) receiving anti-retroviral therapy. While antibody responses in PLWH increased progressively after each vaccination, they were significantly reduced compared to the HIV-negative control group. This was particularly noteworthy for the Delta and Omicron variants. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase, which was comparable in both groups. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4+ T cell numbers do not necessarily interfere with cellular immune responses. Our data demonstrate that despite the lower CD4+ T cell counts SARS-CoV-2 vaccination results in potent cellular immune responses in PLWH. However, the reduced humoral response also provides strong evidence to consider PLWH as vulnerable group and suggests subsequent vaccinations being required to enhance their protection against COVID-19