Vascular endothelial cells: heterogeneity and targeting approaches

Forming the inner layer of the vascular system, endothelial cells (ECs) facilitate a multitude of crucial physiological processes throughout the body. Vascular ECs enable the vessel wall passage of nutrients and diffusion of oxygen from the blood into adjacent cellular structures. ECs regulate vascular tone and blood coagulation as well as adhesion and transmigration of circulating cells. The multitude of EC functions is reflected by tremendous cellular diversity. Vascular ECs can form extremely tight barriers, thereby restricting the passage of xenobiotics or immune cell invasion, whereas, in other organ systems, the endothelial layer is fenestrated (e.g., glomeruli in the kidney), or discontinuous (e.g., liver sinusoids) and less dense to allow for rapid molecular exchange. ECs not only differ between organs or vascular systems, they also change along the vascular tree and specialized subpopulations of ECs can be found within the capillaries of a single organ. Molecular tools that enable selective vascular targeting are helpful to experimentally dissect the role of distinct EC populations, to improve molecular imaging and pave the way for novel treatment options for vascular diseases. This review provides an overview of endothelial diversity and highlights the most successful methods for selective targeting of distinct EC subpopulations

The role of B cell antigen receptors in mantle cell lymphoma

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and secondary resistance to currently available therapies in most cases. Therefore, despite recent advances in the treatment of this disease, it is still considered to be incurable in the majority of cases. MCL B cells retain their B cell antigen receptor (BCR) expression during and after neoplastic transformation. BCRs in MCL show distinct patterns of antigen selection and ongoing BCR signaling. However, little is known about the involved antigens and the mechanisms leading to lymphomagenesis and lymphoma progression in MCL. Recent preclinical and clinical studies have established a crucial role of the BCR and the potential of inhibiting its signaling in this disease. This has established the B cell antigen receptor signaling cascade as a very promising therapeutic target to improve outcome in MCL alone or in combination with chemo-immunotherapy in recent years

Alterations of peripheral blood T cell subsets following donor lymphocyte infusion in patients after allogeneic stem cell transplantation

Donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) is an established method to enhance the Graft-versus-Leukemia (GvL) effect. However, alterations of cellular subsets in the peripheral blood of DLI recipients have not been studied. We investigated the changes in lymphocyte subpopulations in 16 patients receiving DLI after successful alloSCT. Up to three DLIs were applied in escalating doses, prophylactically for relapse prevention in high-risk disease (n = 5), preemptively for mixed chimerism and/or a molecular relapse/persistence (n = 8), or as part of treatment for hematological relapse (n = 3). We used immunophenotyping to measure the absolute numbers of CD4+, CD8+, NK, and CD56+ T cells and their respective subsets in patients’ peripheral blood one day before DLI (d-1) and compared the results at day + 1 and + 7 post DLI to the values before DLI. After the administration of 1 × 106 CD3+ cells/kg body weight, we observed an overall increase in the CD8+ and CD56+ T cell counts. We determined significant changes between day − 1 compared to day + 1 and day + 7 in memory and activated CD8+ subsets and CD56+ T cells. Applying a higher dose of DLI (5 × 106 CD3+ cells/kg) led to a significant increase in the overall counts and subsets of CD8+, CD4+, and NK cells. In conclusion, serial immune phenotyping in the peripheral blood of DLI recipients revealed significant changes in immune effector cells, in particular for various CD8+ T cell subtypes, indicating proliferation and differentiation

Granulomatous dermatitis: a rare pitfall in lymphoma staging with [18F]FDG-PET/CT

A 36-year-old male with anaplastic large T cell lymphoma (A; nodal manifestations in the left iliac and left inguinal region, arrow) who had received six cycles of chemotherapy (brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) presented for restaging prior to autologous stem cell transplantation. A few days earlier, the patient had noticed multiple new tender subcutaneous nodules, and erythemato-squamous, polymorphous, partially atrophic plaques all over his body (B1). [18F]FDG-positron emission tomography/computed tomography (PET/CT) showed complete metabolic response of primary lymphoma manifestations but revealed intense tracer accumulation in the disseminated subcutaneous nodules (B, axial image B2). Besides cutaneous involvement by T cell lymphoma, differential diagnoses included cutaneous sarcoidosis and pityriasis rosea. Biopsy of a subcutaneous nodule revealed no evidence of malignancy but granulomatous inflammation (B3) most consistent with reactive granulomatous dermatitis. After initiation of prednisone therapy, all (sub-)cutaneous lesions quickly resolved, and the patient was eligible for stem cell transplantation. Follow-up [18F]FDG-PET/CT demonstrated only residual tracer uptake of some lesions and a sustained complete lymphoma response (C). Reactive granulomatous dermatitis is a very rare skin disease with only several hundred cases reported worldwide so far [1], most commonly associated with autoimmune disorders such as rheumatoid arthritis. Furthermore, it has been associated with hematologic malignancies, including — in approximately 3% of cases — (B cell) lymphoma [1,2,3]. To our knowledge, this is one of the very first cases of granulomatous dermatitis in anaplastic large T cell lymphoma [4], and the first visualization of granulomatous dermatitis by [18F]FDG-PET/CT mimicking cutaneous lymphoma manifestations

Predictive preoperative clinical score for patients with liver-only oligometastatic colorectal cancer

BACKGROUND: Resection of liver metastases from colorectal cancer (CRC) in the oligometastatic stage improves survival and is a potentially curative treatment. Thus, predictive scores that reliably identify those patients who especially benefit from surgery are essential. PATIENTS AND METHODS: In this multicenter analysis, 512 patients had undergone surgery for liver metastases from CRC. We investigated distinct cancer-specific risk factors that are routinely available in clinical practice and developed a predictive preoperative score using a training cohort (TC), which was thereafter tested in a validation cohort (VC). RESULTS: Inflammatory response to the tumor, a right-sided primary tumor, multiple liver metastases, and node-positive primary tumor were significant adverse variables for overall survival (OS). Patients were stratified in five groups according to the cumulative score given by the presence of these risk factors. Median OS for patients without risk factors was 133.8 months [95% confidence interval (CI) 81.2-not reached (nr)] in the TC and was not reached in the VC. OS decreased significantly for each subsequent group with increasing number of risk factors. Median OS was significantly shorter (P < 0.0001) for patients presenting all four risk factors: 14.3 months (95% CI 10.5 months-nr) in the TC and 16.6 months (95% CI 14.6 months-nr) in the VC. CONCLUSIONS: Including easily obtainable variables, this preoperative score identifies oligometastatic CRC patients with prolonged survival rates that may be cured, and harbors potential to be implemented in daily clinical practice