Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

Radiosensitizing Favors Response to Peptide Receptor Radionuclide Therapy in Patients With Highly Proliferative Neuroendocrine Malignancies: Preliminary Evidence From a Clinical Pilot Study.

AIM/INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) represents a cornerstone of treatment regimens for patients with low proliferative neuroendocrine tumors (NETs). However, in patients experiencing somatostatin receptor-positive NET with higher proliferation rates, a value and potential therapeutic benefit of PRRT as part of multimodal treatment approaches and potentially with addition of radiosensitizing agents has not yet been established. PATIENTS AND METHODS: In this study, 20 patients with histologically confirmed gastroenteropancreatic (GEP) NET with proliferation rates (Ki67) between 15% and 55% were treated either with PRRT only (n = 10) or with a combination therapy (n = 10) comprising PRRT and capecitabine/temozolomide (CAP/TEM) for at least 2 consecutive cycles. RESULTS: Disease control rate in patients treated with PRRT alone was 60% (40% stable disease and 20% partial response). Strikingly, in patients treated with PRRT in combination with radiosensitization (CAP/TEM), the disease control rate was 90% (20% stable disease and 70% partial response). The median progression-free survival in the PRRT only group was 12 months, whereas the median progression-free survival in the PRRT + CAP/TEM group was 26 months and has not been yet reached for all patients in the group during the observation period. The median disease-specific survival for patients with PRRT alone was 51 months, whereas this end point was not yet reached in the PRRT + CAP/TEM group. Moreover, the PRRT + CAP/TEM group showed a significantly higher reduction of SSTR-PET-based metabolic tumor volume and chromogranin A levels compared with the PRRT only group. Importantly, adverse events of all grades did not differ between both groups. CONCLUSIONS: PRRT + CAP/TEM represents a highly promising and well-tolerated therapeutic regimen for patients experiencing somatostatin receptor-positive NET with higher (Ki67 ≥ 15%) proliferation rate. Prospective randomized clinical trials are warranted.

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness3-7. While small-molecule drugs capable of eliminating senescent cells (known as 'senolytics') partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective. As an alternative approach, we have developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and previously showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis8. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, a single administration of a low dose of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

Myasthenia gravis as initial presentation of a pancreatic neuroendocrine tumor: A case report.

Myasthenia gravis (MG) is a heterogeneous autoimmune disease, which is characterized by a postsynaptic neuromuscular transmission defect, with antibodies directly targeting the acetylcholine receptor (AChR) or other structural proteins of the neuromuscular junction. The majority of MG cases are associated with thymic pathologies, including thymoma, thyroiditis, autoimmune diseases or malignant hematologic neoplasia. The present study reported a rare case of AChR-positive and late-onset ocular MG, which rapidly progressed to a generalized myasthenic syndrome as an initial presentation of a pancreatic neuroendocrine neoplasia (pNEN). Following complete surgical resection of the pNEN, the myasthenic syndrome was improved and the anti-AChR antibody titers were reduced. It has been reported that MG is a paraneoplastic syndrome in thymic neoplasms and less common in hematologic malignancies. However, currently, only few cases of MG as initial presentation of a solid tumor, and more particular of a neuroendocrine neoplasm, have been reported in the literature. In conclusion, surveillance for extrathymic solid malignancies in newly diagnosed patients with MG could promote the early diagnosis of associated tumor diseases.

Diagnostic Approaches for Neuroendocrine Neoplasms of Unknown Primary (NEN-UPs) and Their Prognostic Relevance-A Retrospective, Long-Term Single-Center Experience.

Neuroendocrine neoplasms (NENs) represent a rare and heterogenous group of tumors with predominantly gastroenteropancreatic or pulmonary origin. Despite numerous diagnostic efforts, the primary tumor site remains unknown in up to 20% of the patients diagnosed with NEN. In this subgroup of NEN patients, a standard diagnostic algorithm has not yet been integrated into clinical routine. Of note, an undetermined primary tumor site in NENs is associated with an impaired clinical outcome by at least "formally" limiting treatment options exclusively approved for NENs of a certain histological origin. In this retrospective study, a patient cohort of 113 patients initially diagnosed with NEN of unknown primary (NEN-UP) was analyzed. In 13 patients (11.5%) a primary tumor site could be identified subsequently, amongst others, by performing somatostatin receptor (SSTR)-PET-based imaging, which was irrespective of the initial clinical or demographic features. Diagnostic work-up and therapeutic regimens did not differ significantly between patients with an identified or unidentified primary tumor site; only a detailed immunohistochemical assessment providing additional information on the tumor origin proved to be significantly associated with the detection of a primary tumor site. Our study revealed that a profound diagnostic work-up, particularly including SSTR-PET-based imaging, leads to additional treatment options, finally resulting in significantly improved clinical outcomes for patients with NEN-UPs.

NOTCH3 missense mutations as predictor of long-term response to gemcitabine in a patient with epithelioid hemangioendothelioma.

PURPOSE: Epithelioid hemangioendothelioma (EHE) as a very rare malignant vascular tumor belongs to the heterogenous group of soft-tissue sarcomas. Depending on the clinical course of the disease, interdisciplinary treatment concepts are required, including surgery, radiotherapy and systemic cancer therapy. However, due to its uncommonness, standard treatment options are lacking so far, especially in advanced disease with distant metastases. METHODS AND RESULTS: Here we report on an unusual case of a patient with metastasized EHE showing long-term response to second line treatment with gemcitabine over almost 2 decades. Cancer genome sequencing of the patient's tumor tissue detected a NOTCH3 missense mutation which could provide an explanation for these clinical findings. NOTCH3 is known to be a mediator of resistance towards gemcitabine-based cancer treatment, at least in pancreatic cancer and non-small cell lung cancer. CONCLUSION: The observation that this missense mutation of NOTCH3 is associated with an increased response to treatment with gemcitabine in EHE can be used prospectively to assess NOTCH3 as potential biomarker for predicting therapy response to gemcitabine.

Treatment modalities favoring outcome in well-differentiated neuroendocrine tumors G3.

Introduction: Neuroendocrine neoplasms (NEN) are a rare and heterogenous group of tumors arising from neuroendocrine cells in multiple organs. Neuroendocrine tumors (NET) G3 encompass a small subgroup accounting for less than 10% of all neuroendocrine neoplasms. In contrast to NET G1 and G2 as well as neuroendocrine carcinomas (NEC), in NET G3 data on treatment and patient outcomes are still limited. Especially in a metastasized tumor stage, the role of surgery, peptide receptor radionucleotide therapy (PRRT), and systemic chemotherapy is not clearly defined. Methods: In this real-life cohort, we consecutively analyzed clinical outcome in NET G3 patients receiving different diagnostic and treatment. Results and discussion: We found that even metastasized NET G3 patients undergoing surgery, or receiving radiation, somatostatin analogues (SSA), and PRRT showed a clear survival benefit. Interestingly, all treatment regimen were superior to classical chemotherapeutic agents. In addition, somatostatin receptor (SSTR) PET-CT, FDG PET-CT, and repetitive biopsies were shown to be useful diagnostic and prognostic tools in NET G3. Our study demonstrates that patients with highly proliferative NET G3 might benefit from less aggressive treatment modalities commonly used in low proliferative NEN.

Acquired von Willebrand syndrome is common in infants with systemic-to-pulmonary shunts: Retrospective case-series.

Background: Although acquired von Willebrand syndrome (aVWS) has been described in congenital heart disease before, anatomical features leading to aVWS with characteristic reduction or loss of high molecular weight von Willebrand multimers (HMWM) are not well known. This study assesses the prevalence and effects of aVWS in infants with systemic-to-pulmonary shunts (SPS). Methods: This retrospective single-center study analyzes diagnostic data of infants with complex congenital heart defects requiring palliation with SPS. During the study period between 12/15-01/17 fifteen consecutive patients were eligible for analysis. Results of von Willebrand factor antigen (VWF:Ag), collagen binding activity (VWF:CB) and von Willebrand factor multimer analysis were included. Results: In all 15 patients with SPS an aVWS could be found. Blood samples were collected between 5 and 257 days after shunt implantation (median 64 days). None of the patients demonstrated increased bleeding in everyday life. However, 6 out of 15 patients (40%) showed postoperative bleeding complications after SPS implantation. Following shunt excision multimeric pattern normalized in 8 of 10 (80%) patients studied. Conclusions: This study shows that in patients undergoing SPS implantation aVWS might emerge. Pathogenesis can be explained by shear stress resulting from turbulent flow within the shunt. Knowledge of aVWS existence is important for the consideration of replacement therapy with von Willebrand factor containing products and antifibrinolytic treatment in bleeding situations. Implementation of methods for rapid aVWS detection is required to achieve differentiated hemostatic therapy and reduce the risk of complications caused by empiric replacement therapy.

B7-H3-targeting Fc-optimized antibody for induction of NK cell reactivity against sarcoma.

Natural killer (NK) cells largely contribute to antibody-dependent cellular cytotoxicity (ADCC), a central factor for success of monoclonal antibodies (mAbs) treatment of cancer. The B7 family member B7-H3 (CD276) recently receives intense interest as a novel promising target antigen for immunotherapy. B7-H3 is highly expressed in many tumor entities, whereas expression on healthy tissues is rather limited. We here studied expression of B7-H3 in sarcoma, and found substantial levels to be expressed in various bone and soft-tissue sarcoma subtypes. To date, only few immunotherapeutic options for treatment of sarcomas that are limited to a minority of patients are available. We here used a B7-H3 mAb to generate chimeric mAbs containing either a wildtype Fc-part (8H8_WT) or a variant Fc part with amino-acid substitutions (S239D/I332E) to increase affinity for CD16 expressing NK cells (8H8_SDIE). In comparative studies we found that 8H8_SDIE triggers profound NK cell functions such as activation, degranulation, secretion of IFNγ and release of NK effector molecules, resulting in potent lysis of different sarcoma cells and primary sarcoma cells derived from patients. Our findings emphasize the potential of 8H8_SDIE as novel compound for treatment of sarcomas, particularly since B7-H3 is expressed in bone and soft-tissue sarcoma independent of their subtype.

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.

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.

BCR::ABL1 tyrosine kinase inhibitors hamper the therapeutic efficacy of blinatumomab in vitro.

PURPOSE: Acute B-lymphoblastic leukemia (B-ALL) is a malignant disease characterized by accumulation of clonal immature lymphocytes in the bone marrow and peripheral blood. The approval of BCR::ABL1 tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib and ponatinib marked a milestone in targeted therapy only for a subset of patients carrying the translocation t(9;22)(q34;q11). Immunotherapy with the bispecific antibody (bsAb) blinatumomab targeting CD19xCD3 revolutionized treatment of all B-ALL cases. The combination of both TKI and bsAb, so-called "dual targeting", is currently under clinical investigation, although TKI might influence T cell effects. METHODS: We here investigated the combination of different TKI and blinatumomab in BCR::ABL1+ and BCR::ABL1- B-ALL cell lines and primary samples regarding T cell proliferation, differentiation, cytokine release and killing of tumor cells. RESULTS: In vitro analysis revealed profound reduction of T cell proliferation, differentiation, cytokine release and killing of tumor cells upon application of BCR::ABL1 TKI with blinatumomab. Inhibition was more pronounced with dasatinib and ponatinib compared to nilotinib and imatinib. T cell signalling after CD3 stimulation was impaired by TKI mirrored by inhibition of LCK phosphorylation. This known off-target effect might influence the efficacy of bsAb therapy when combined with BCR::ABL1 TKI. CONCLUSION: In conclusion, we propose that nilotinib and imatinib might also be suitable substances for combination with blinatumomab and suggest evaluation in clinical trials.

Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies.

T cell-based immunotherapy, for example, with T cell-recruiting bispecific antibody (bsAb), has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions are still rare. Several tumor immune evasion mechanisms have been reported to counteract efficiency of T cell-engaging therapeutics. Platelets largely affect cancer pathophysiology by mediating tumor invasion, metastasis, and immune evasion. On treatment of patients in a clinical trial with a PSMA×CD3 bsAb (NCT04104607), we observed profound treatment-associated platelet activation, mirrored by a decrease of total platelet count. On modeling the treatment setting, we found that platelet activation significantly reduced bsAb-mediated CD4+ and CD8+ T-cell reactivity as revealed by impaired T-cell degranulation, secretion of perforin, and ultimately, inhibition of target cell lysis. This effect occurred in a transforming growth factor beta (TGF-ß)-dependent manner and was not restricted to PSMA×CD3 bsAb, but rather observed with various CD3-directed bispecific constructs, including the approved CD19×CD3 bsAb blinatumomab. BsAb-mediated T-cell reactivity could be restored by platelet inhibition and specifically by blocking the TGF-ß axis. Together, our findings demonstrate that platelets undermine the efficacy of T cell-recruiting bsAb and identify modulation of platelet function as a means to reinforce the effectiveness of bsAb treatment.

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.

Identification of CD105 (endoglin) as novel risk marker in CLL.

Several genetic and clinical markers are established as prognostic factors in chronic lymphocytic leukemia (CLL). However, additional markers are needed for risk stratification. Flow cytometric analysis is a mainstay of CLL diagnostics, thus identification of novel prognostic surface markers can improve risk assessment without increasing burden for patients and physicians. Furthermore, surface molecules preferentially expressed in high-risk cases could serve as therapeutic targets for immunotherapy. CD105 (endoglin) is a TGF-beta coreceptor and activates endothelial cells in healthy tissues and cancer. In addition, it is expressed on healthy hematopoietic precursors as well as lymphoid and myeloid leukemias. In acute myeloid leukemia (AML), a CD105 antibody is successfully applied in clinical studies. In CLL, mRNA expression of the CD105 gene ENG reportedly correlates with other risk factors but failed to show significant correlation with overall survival. However, CD105 protein expression in CLL has never been studied. We here analyzed CD105 surface expression on CLL cells from 71 patients by flow cytometry and report for the first time that substantial levels of CD105 are detectable on CLL cells in 70.4% of patients. Using receiver operating characteristics, we established a cutoff of 5.99% positive cells to distinguish between low and high CD105 levels, the latter correlating with decreased time to first treatment and overall survival. High CD105 expression further correlates with CD38 expression. Our study identified membrane expression of CD105 as a potential risk marker and therapeutic target in high-risk CLL. However, multivariant analyses of large cohorts should be performed in confirmatory studies.

Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer.

Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5ß1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1Adj.), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.

Immunoprofiling of 4-1BB Expression Predicts Outcome in Chronic Lymphocytic Leukemia (CLL).

Recent success of novel therapies has improved treatment of chronic lymphocytic leukemia (CLL) patients, but most of them still require several treatment regimes. To improve treatment choice, prognostic markers suitable for prediction of disease outcome are required. Several molecular/genetic markers have been established, but accessibility for the entirety of all patients is limited. We here evaluated the relevance of GITR/4-1BB as well as their ligands for the prognosis of CLL patients. Surface expression of GITR/GITRL and 4-1BB/4-1BBL was correlated with established prognostic markers. Next, we separated our patient population according to GITR/GITRL and 4-1BB/4-1BBL expression in groups with high/low expression levels and performed Kaplan-Meier analyses. Interestingly, no correlation was observed with the defined prognostic markers. Whereas no significant difference between high and low expression of GITR, GITRL and 4-1BBL was observed, high 4-1BB levels on leukemic cells were associated with significantly shorter survival. Thereby we identify 4-1BB as prognostic marker for CLL.

DNAM-1/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis.

DNAM-1 is reportedly expressed on cytotoxic T and NK cells and, upon interaction with its ligands CD112 and CD155, plays an important role in tumor immunosurveillance. It has also been reported to be functionally expressed by myeloid cells, but expression and function on malignant cells of the myeloid lineage have not been studied so far. Here we analyzed expression of DNAM-1 in leukemic cells of acute myeloid leukemia (AML) patients. We found substantial levels of DNAM-1 to be expressed on leukemic blasts in 48 of 62 (> 75%) patients. Interaction of DNAM-1 with its ligands CD112 and CD155 induced release of the immunomodulatory cytokines IL-6, IL-8 IL-10 and TNF-α by AML cells and DNAM-1 expression correlated with a more differentiated phenotype. Multivariate analysis did not show any association of DNAM-1 positivity with established risk factors, but expression was significantly associated with clinical disease course: patients with high DNAM-1 surface levels had significantly longer progression-free and overall survival compared to DNAM-1low patients, independently whether patients had undergone allogenic stem cell transplantation or not. Together, our findings unravel a functional role of DNAM-1 in AML pathophysiology and identify DNAM-1 as a potential novel prognostic maker in AML.

Significance and clinical impact of routinely tested urinary ethyl glucuronide after liver transplantation - development of a risk score.

Alcohol abuse after liver transplantation can seriously impact graft and patient survival. However, to date, there is no defined standard procedure to identify patients consuming alcohol after liver transplantation. The aim of this study was to analyze the diagnostic value and clinical impact of routinely measured urinary ethyl glucuronide (uEtG) - a metabolite of ethanol - in patients after liver transplantation. Data of 362 consecutive patients after liver transplantation who visited the University Hospital of Tuebingen for outpatient follow-up were analyzed. Forty-eight patients (13%) displayed positive uEtG results. The uEtG positive group contained significantly more patients with pretransplant alcoholic liver disease. However, two thirds of the uEtG positive patients had no history of pretransplant alcoholic liver disease. Several clinical parameters were significantly associated with positive uEtG. In order to enable a more cost-effective application of uEtG in the future, a clinical risk score was developed (specificity 0.95). In conclusion, routine testing for uEtG reveals a considerable percentage of patients practicing alcohol intake after liver transplantation. Application of our proposed risk score could help focusing uEtG testing on patients at risk.

Regulation of Platelet-Derived ADAM17: A Biomarker Approach for Breast Cancer?

Tumor progression and metastasis are critically dependent on the tumor microenvironment. A disintegrin and metalloproteinase 17 (ADAM17) is associated with shedding of several substrates involved in tumor progression and known to be expressed by platelets of healthy donors and patients with solid tumors. Here, we report that platelet-derived ADAM17 (pADAM17) is regulated upon platelet activation of breast cancer patients, but not of healthy individuals. The observed downregulation of pADAM17 on platelets of cancer patients correlated with clinical parameters related to tumor progression including tumor stage and the occurrence of metastasis. Our data identify an association between platelet activation, modulation of platelet-derived ADAM17, and metastasis. In conclusion, we demonstrate that further development of pADAM17 as a liquid biomarker is warranted for monitoring disease progression in breast cancer.