NUT Carcinoma—An Underdiagnosed Malignancy

NUT carcinoma (NC) is a rare and highly aggressive malignancy with a dismal prognosis and a median survival of 6–9 months only. Although very few cases of NC are reported each year, the true prevalence is estimated to be much higher, with NC potentially widely underdiagnosed due to the lack of awareness. NC primarily occurs in midline structures including thorax, head, and neck; however, other sites such as pancreas and kidney are also affected, albeit at lower frequencies. NC is characterized by a single translocation involving the NUTM1 (NUT midline carcinoma family member 1) gene and different partner genes. The resulting fusion proteins initiate tumorigenesis through a mechanism involving BET (bromo-domain and extra-terminal motif) proteins such as Bromodomain-containing protein 4 (BRD4) and inordinate acetylation of chromatin, leading to the dysregulation of growth and differentiation genes. While no clinical characteristics are specific for NC, some histologic features can be indicative; therefore, patients with these tumor characteristics should be routinely tested for NUTM1. The diagnosis of NC using immunohistochemistry with a highly specific antibody is straightforward. There are currently no standard-of-care treatment options for patients with NC. However, novel therapies specifically addressing the unique tumorigenic mechanism are under investigation, including BET inhibitors. This review aims to raise awareness of this underdiagnosed cancer entity and provide all patients the opportunity to be properly diagnosed and referred to a clinical study

Successful direct acting antiviral (DAA) treatment of HCV/HIV-coinfected patients before and after liver transplantation

Objectives The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. Methods When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1);MELD range 7-21;HCC (n = 2);HCV genotype la (n = 8), 1 b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). Results Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy;subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in followup. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation;in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. Conclusion DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted

Frühe Rekonstitution zirkulierender Antikörper-sezernierender Zellen nach haploidenter Stammzelltransplantation

Die Immunrekonstitution nach einer allogenen Stammzelltransplantation hat größten Einfluss auf das Auftreten infektiologischer Komplikationen, die Auftretenswahrscheinlichkeit einer Alloreaktivität wie der GvHD und des GvM-Effekts, eines Krankheitsrezidivs und somit auch auf die Morbidität und Mortalität eines transplantierten Patienten. Daten aus früheren Studien zeigen übereinstimmend eine frühe Immunrekonstitution von Zellen des angeborenen Immunsystems, welches Granulozyten, Monozyten und NK-Zellen umfasst, während Zellen des adaptiven Immunsystems, welches insbesondere T-Lymphozyten und B-Lymphozyten beinhaltet, erst Monate nach einer allogenen Stammzelltransplantation regenerieren. Vor diesem Hintergrund, ermöglicht eine CD3+/CD19+ depletierte haploidente Stammzelltransplantation eine Beobachtung der Lymphopoese in vivo ohne den Einfluss von Immunsuppressiva. Das Ziel dieser Arbeit war es, die Rekonstitution Antikörper-produzierender Zellen bei Patienten innerhalb des ersten Jahres nach einer hämatopoetischen Stammzell¬transplantation zu untersuchen, wobei der Fokus der Untersuchung insbesondere auf den ersten Wochen nach der Transplantation lag. Die Fragestellung beruht auf der Beobachtung, dass die Entstehung reifer Plasmazellen erst etwa ein Jahr nach der Transplantation in der Literatur beschrieben ist, Antikörper zur Abwehr von Infekten jedoch bereits vorher benötigt werden und auch vorhanden sind. Insgesamt konnten bei sieben haploident transplantierten Patienten Personen-bezogenene Daten erhoben werden und Proben gewonnen werden. Das Patientenkollektiv unterscheidet sich hinsichtlich Alter bei der Erstdiagnose, Geschlecht, hämatologischer Grunderkrankung, Vortherapien und Zeitpunkt der haploidenten Transplantation erheblich. Dennoch ergibt sich bei allen sieben analysierten Patienten ein sehr einheitliches Bild bezüglich der erhobenen Ergebnisse. Alle Patienten zeigen ab Tag 14 nach der haploidenten Transplantation eine signifikante Regeneration der Leukopoese, welche hauptsächlich auf der Regeneration der neutrophilen Granulozyten beruht. Der Beginn der Lymphopoese hingegen kann frühestens nach 28 Tagen beobachtet werden, wobei eine Normalisierung der Lymphozytenwerte im Durchschnitt nach 270 Tagen nach der Transplantation erreicht wird. Trotz der verzögerten Lymphopoese kann bei allen analysierten Patienten das Auftreten Immunglobulin-exprimie¬render und –produzierender Zellen bereits nach 10 bis 30 Tagen nach der haploidenten Stammzelltransplantation beobachtet werden. Diese Zellen produzieren und exprimieren die Immunglobulinsubklassen IgA, IgG und IgM. Auch im Serum der Patienten kann in diesem Zeitraum ein Anstieg der Konzentrationen für lösliches IgA, IgG und IgM beobachtet werden. Gleichzeitig sind in diesem Zeitraum insbesondere die Expressionslevel Inflammations-assoziierter Zytokine erhöht, wohingegen Zytokine, die klassischerweise eine Rolle in der B-Zell-Differenzierung und B-Zell-Proliferation spielen, allen voran BAFF, eine untergeordnete Rolle spielen. Die identifizierte Zellpopulation, die mit dem Auftretenden der Antikörper-produzierenden Zellen signifikant korreliert und diesen vermutlich auch entspricht, zeigt den Phänotyp CD19- CD38low/+ CD27- und CD138-. Sie lässt sich somit weder klassischen Plasmazellen noch „unreiferen“ B1-B-Zellen zuordnen. Die gefundenen Zellen sind jedoch eindeutig aus dem Transplantat des Spenders hervorgegangen. Insgesamt kann somit eine frühe, bereits 2 bis 3 Wochen nach der haploidenten Stammzelltransplantation auftretende, Immunglobulin-produzierende Zellpopulation nachgewiesen werden, die einen bisher unbekannten Phänotyp aufweist und möglicherweise einen bislang nicht beschriebenen Zwischenschritt in der Entwicklung der B-Lymphozyten darstellt. Zudem kann spekuliert werden, dass es sich bei diesen frühen Immunglobilun-sezernierenden Zellen um Elemente des angeborenen und weniger des adaptiven Immunsystems handeln könnte

Inflammatory Surrogate Parameters for Predicting Ifosfamide-Induced Neurotoxicity in Sarcoma Patients

Sarcomas compromise a heterogenous group of tumors of a mesenchymal origin. Although treatment options in many solid tumors have evolved over the past decades, the treatment of advanced sarcoma is still based on conventional chemotherapeutic agents. Beside anthracyclines, alkylating agents such as ifosfamide are frequently used in sarcoma treatment. However, treatment with ifosfamide can cause severe dose- and treatment-limiting side effects, such as ifosfamide-induced neurotoxicity (IIN). Especially in sarcoma, consecutive risk assessment analyses investigating the individual factors associated with the increased incidence in IIN, remain insufficient so far. In this retrospective analysis, we investigated 172 sarcoma patients treated with ifosfamide. Out of 172 patients, 49 patients (28.5%) developed IIN. While gender, age, histologic origin, and tumor stage were not associated with the occurrence of IIN, infusion times, simultaneous radiotherapy, and concomitant use of opioids or anticonvulsants affected the risk of developing IIN. Sarcoma patients with IIN showed an alteration in several inflammatory markers, including a lower lymphocyte count, hemoglobin levels, and calcium levels, as well as elevated GGT, sodium, and CRP levels. Remarkably, the occurrence of IIN was associated with a worse prognosis regarding progression free and overall survival. In addition, high CTCAE grades were negatively associated with overall survival in sarcoma. The observation that an inflammatory state is associated with an increased risk of IIN in sarcoma patients can be used prospectively to further investigate the relationship of inflammation and IIN. In addition, the easily accessible blood markers used in our study to predict IIN can be incorporated into clinical decision making

Early Reconstitution of Antibody Secreting Cells after Allogeneic Stem Cell Transplantation

Immune cell reconstitution after stem cell transplantation is allocated over several stages. Whereas cells mediating innate immunity recover rapidly, adaptive immune cells, including T and B cells, recover slowly over several months. In this study we investigated kinetics and reconstitution of de novo B cell formation in patients receiving CD3 and CD19 depleted haploidentical stem cell transplantation with additional in vivo T cell depletion with monoclonal anti-CD3 antibody. This model enables a detailed in vivo evaluation of hierarchy and attribution of defined lymphocyte populations without skewing by mTOR- or NFAT-inhibitors. As expected CD3+ T cells and their subsets had delayed reconstitution (<100 cells/μL at day +90). Well defined CD19+ B lymphocytes of naïve and memory phenotype were detected at day +60. Remarkably, we observed a very early reconstitution of antibody-secreting cells (ASC) at day +14. These ASC carried the HLA-haplotype of the donor and secreted the isotypes IgM and IgA more prevalent than IgG. They correlated with a population of CD19− CD27− CD38low/+ CD138− cells. Of note, reconstitution of this ASC occurred without detectable circulating T cells and before increase of BAFF or other B cell stimulating factors. In summary, we describe a rapid reconstitution of peripheral blood ASC after CD3 and CD19 depleted haploidentical stem cell transplantation, far preceding detection of naïve and memory type B cells. Incidence before T cell reconstitution and spontaneous secretion of immunoglobulins allocate these early ASC to innate immunity, eventually maintaining natural antibody levels

Controversial Role of the Immune Checkpoint OX40L Expression on Platelets in Breast Cancer Progression

In conventional T cells, OX40 has been identified as a major costimulating receptor augmenting survival and clonal expansion of effector and memory T cell populations. In regulatory T cells, (Treg) OX40 signaling suppresses cellular activity and differentiation. However, clinical trials investigating OX40 agonists to enhance anti-tumor immunity, showed only limited success so far. Here we show that platelets from breast cancer patients express relevant levels of OX40L and platelet OX40L (pOX40L) inversely correlates with platelet-expressed immune checkpoint molecules GITRL (pGITRL) and TACI (pTACI). While high expression of pOX40L correlates with T and NK cell activation, elevated pOX40L levels identify patients with higher tumor grades, the occurrence of metastases, and shorter recurrence-free survival (RFS). Of note, OX40 mRNA levels in breast cancer correlate with enhanced expression of anti-apoptotic, immune-suppressive, and tumor-promoting mRNA gene signatures. Our data suggest that OX40L on platelets might play counteracting roles in cancer and anti-tumor immunity. Since pOX40L reflects disease relapse better than the routinely used predictive markers CA15-3, CEA, and LDH, it could serve as a novel biomarker for refractory disease in breast cancer