Computed tomography textural analysis for the differentiation of chronic lymphocytic leukemia and diffuse large B cell lymphoma of Richter syndrome.

OBJECTIVE: To test the hypothesis that both indolent and aggressive chronic lymphocytic leukemia (CLL) can be differentiated from diffuse large B cell lymphoma (DLBCL) of Richter syndrome (RS) by CT texture analysis (CTTA) of involved lymph nodes. MATERIAL AND METHODS: We retrospectively included 52 patients with indolent CLL (26/52), aggressive CLL (8/52), and DLBCL of RS (18/52), who underwent standardized contrast-enhanced CT. In main lymphoma tissue, VOIs were generated from which CTTA features including first-, second-, and higher-order textural features were extracted. CTTA features were compared between the entire CLL group, the indolent CLL subtype, the aggressive CLL subtype, and DLBCL using a Kruskal-Wallis test. All p values were adjusted after the Bonferroni correction. ROC analyses for significant CTTA features were performed to determine cut-off values for differentiation between the groups. RESULTS: Compared with DLBCL of RS, CTTA of the entire CLL group showed significant differences of entropy heterogeneity (p < 0.001), mean intensity (p < 0.001), mean average (p = 0.02), and number non-uniformity gray-level dependence matrix (NGLDM) (p = 0.03). Indolent CLL significantly differed for entropy (p < 0.001), uniformity of heterogeneity (p = 0.02), mean intensity (p < 0.001), and mean average (p = 0.01). Aggressive CLL showed significant differences in mean intensity (p = 0.04). For differentiation between CLL and DLBCL of RS, cut-off values for mean intensity and entropy of heterogeneity were defined (e.g., 6.63 for entropy heterogeneity [aggressive CLL vs. DLBCL]; sensitivity 0.78; specificity 0.63). CONCLUSIONS: CTTA features of ultrastructure and vascularization significantly differ in CLL compared with that in DLBCL of Richter syndrome, allowing complementary to visual features for noninvasive differentiation by contrast-enhanced CT. KEY POINTS: • Richter transformation of CLL into DLBCL results in structural changes in lymph node architecture and vascularization that can be detected by CTTA. • First-order CT textural features including intensity and heterogeneity significantly differ between both indolent CLL and aggressive CLL and DLBCL of Richter syndrome. • CT texture analysis allows for noninvasive detection of Richter syndrome which is of prognostic value.

Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Acute and chronic graft-vs.-host disease (aGvHD and cGvHD) are major complications after allogeneic hematopoietic cell transplantation (HCT) leading to substantial morbidity and mortality. This retrospective single-center study analyzes incidence, therapy, and outcome of GvHD in n = 721 patients ≥18 years having received allogeneic HCT 2004-2013 with a special focus on steroid refractory GvHD. Acute (n = 355/49.2%) and chronic (n = 269/37.3%) GvHD were mainly treated by steroids in first-line therapy. The proportion of steroid refractory aGvHD and cGvHD was 35.7% and 31.4%, respectively. As there is no standard therapy for steroid refractory GvHD, a range of different agents was used. In aGvHD, the overall response rate (ORR) of steroid refractory GvHD to second-line treatment was 27.4%. Mycophenolate mofetil (MMF) and mTOR inhibitors led to superior response rates (ORR 50.0% and 53.3%, respectively). In steroid refractory cGvHD therapy, ORR was 44.4%. Use of calcineurin inhibitors (CNI; n = 11/45.5%), MMF (n = 18/50.0%), mTOR inhibitors (n = 10/60.0%), and extracorporeal photophoresis (ECP; n = 16/56.3%) showed ORR above average. Targeted therapies lead to responses in 7.7% (n = 13). This data may help to improve the design of future prospective clinical studies in GvHD.

[Differential diagnosis of hypereosinophilia]. / Differenzialdiagnose der Hypereosinophilie.

Eosinophilia is defined as an elevated absolute number of eosinophilic leukocytes in peripheral blood or tissue. Its absolute number also defines the grade of eosinophilia. The main causes are allergic (including drug side effects) and infectious triggers but malignant and autoimmune diseases can also result in eosinophilia. Severe eosinophilia with the number of eosinophils >5000/µl are mostly caused by myeloproliferative disorders, eosinophilic granulomatosis with polyangiitis or during tissue migration in parasitic tissue infections. Hypereosinophilic syndrome is defined as eosinophilia with >1500 eosinophils/µl and a duration of more than 6 months by exclusion of parasitic infections, allergies or other causes of tissue eosinophilia with end-organ damage. For the diagnosis of a persistent eosinophilia a detailed medical history and physical examination should be followed by early organ screening, infection diagnostics especially for helminth infections and hematological laboratory analyses including bone marrow investigations.

Manipulating Surface States of III-V Nanowires with Uniaxial Stress.

III-V compound semiconductors are indispensable materials for today's high-end electronic and optoelectronic devices and are being explored for next-generation transistor logic and quantum technologies. III-V surfaces and interfaces play the leading role in determining device performance, and therefore, methods to control their electronic properties have been developed. Typically, surface passivation studies demonstrated how to limit the density of surface states. Strain has been widely used to improve the electronic transport properties and optoelectronic properties of III-Vs, but the potential of this technology to modify the surface properties still remains to be explored. Here we show that uniaxial stress induces a shift in the energy of the surface states of III-V nanowires, modifying their electronic properties. We demonstrate this phenomenon by modulating the conductivity of InAs nanowires over 4 orders of magnitude with axial strain ranging between -2.5% in compression and 2.1% in tension. The band bending at the surface of the nanostructure is modified from accumulation to depletion reversibly and reproducibly. We provide evidence of this physical effect using a combination of electrical transport measurement, Raman spectroscopy, band-structure modeling, and technology computer aided design (TCAD) simulations. With this methodology, the deformation potentials for the surface states are quantified. These results reveal that strain technology can be used to shift surface states away from energy ranges in which device performance is negatively affected and represent a novel route to engineer the electronic properties of III-V devices.

[Allogeneic stem cell transplantation : An option for autoimmune diseases?] / Allogene hämatopoetische Stammzelltransplantation : Eine Option bei Autoimmunerkrankungen?

According to experimental animal models and experiences of patients with coexisting autoimmune diseases, allogeneic stem cell transplantation has the potential to reestablish and maintain immunological tolerance. On the other hand, it is associated with significant treatment related mortality and may induce diverse immunological diseases by graft-versus-host reaction. Other than with severe aplastic anemia, it is not an established therapy for autoimmune diseases; it is under investigation in clinical trials and might be considered in severe, refractory immune cytopenia.

[Autologous stem cell transplantation in systemic sclerosis]. / Autologe Stammzelltransplantation bei systemischer Sklerose.

Autologous hematopoietic stem cell transplantation (HSCT) is a very effective treatment option for patients with severe systemic sclerosis (SSc). In addition to various case series two randomized controlled trials could prove its superiority over intense cyclophosphamide pulse therapy. Nevertheless, HSCT is associated with a treatment-related mortality of approximately 10 %; therefore, further studies should be carried out to reduce the toxicity of HSCT by adaptation of the therapy regimen and the option of HSCT should be made available earlier to patients with a high risk of mortality. The mechanism of action of HSCT is still poorly understood. While profibrotic cytokines or even autoantibodies hardly appear to be influenced by the treatment, alterations to regulatory T­cells may play a role. Further improvement of transplantation regimens as well as a better understanding of the underlying pathogenetic principles and mechanisms of action should be the aim of further studies on HSCT.

Study of GeSn based heterostructures: towards optimized group IV MQW LEDs.

We present results on CVD growth and electro-optical characterization of Ge(0.92)Sn(0.08)/Ge p-i-n heterostructure diodes. The suitability of Ge as barriers for direct bandgap GeSn active layers in different LED geometries, such as double heterostructures and multi quantum wells is discussed based on electroluminescence data. Theoretical calculations by effective mass and 6 band k∙p method reveal low barrier heights for this specific structure. Best configurations offer only a maximum barrier height for electrons of about 40 meV at the Γ point at room temperature (e.g. 300 K), evidently insufficient for proper light emitting devices. An alternative solution using SiGeSn as barrier material is introduced, which provides appropriate band alignment for both electrons and holes resulting in efficient confinement in direct bandgap GeSn wells. Finally, epitaxial growth of such a complete SiGeSn/GeSn/SiGeSn double heterostructure including doping is shown.

Noninfectious Generalized Bronchiolitis in the Setting of Allogeneic Stem Cell Transplantation: A Potential Mimic of Lower Respiratory Tract Infection.

RATIONALE AND OBJECTIVES: To describe a little-known therapy-related small-airway phenomenon presumably caused by mucosal irritation in patients undergoing allogeneic stem cell transplantation (allo-SCT). MATERIALS AND METHODS: Retrospective database search at our institution identified 739 hematologic patients who underwent chemotherapy + allo-SCT between September 2004 and March 2014. After infectious pulmonary complications were excluded, 75 patients (female = 24; male = 51; median age = 47 years) with signs of generalized bronchiolitis (GB) on chest high-resolution computed tomography were identified. Computed tomography (CT) was performed proximate to chemotherapy onset; 92% had follow-up CT (mean, 1.9 weeks). The presence of centrilobular nodules, bronchial wall thickening (BWT), tree-in-bud (distributed diffuse vs. focal), ground-glass opacity, airspace opacification, luminal impactions, and air trapping was correlated with occurrence and duration of oral mucositis and therapy characteristics. Intensity of tree-in-bud and centrilobular nodules was graded absent (grade = 0), moderate (grade = 1), or marked (grade = 2). RESULTS: Overall incidence of GB among allo-SCT patients was 10.14%. GB was diagnosed at the time point of transplantation with a mean duration of CT findings of 4 weeks (±2.7). Tree-in-bud (17% [grade 2] and 83% [grade 1]) and BWT were present in 100% of the patients. Centrilobular nodules diffusely distributed were found in 45.5% of patients (20% [grade 2], 24% [grade 1], and 56% [none]). Air trapping and mosaic pattern were found in 13% and 16% of the patients, respectively. Resolution of GB was spontaneous. GB and its severity correlated with the temporal course and grade of oral mucositis; frequency and degree were not significantly influenced by the chemotherapy regimen. The incidence of GB in high-resolution computed tomography was statistically and significantly higher in patients with oral mucositis (P < 0.035). CONCLUSIONS: GB is frequent during chemotherapy for allo-SCT and is characterized by an even distribution of tree-in-bud, BWT, centrilobular nodules, mild clinical symptoms, and spontaneous resolution.

[Endocrine abnormalities in a young patient with metastatic cancer - case 3/2013]. / Endokrine Veränderungen bei einem jungen Patienten mit metastasiertem Tumorleiden - Fall 3/2013.

HISTORY AND ADMISSION FINDINGS: We report on a 24-year-old male patient who presented with worsening of the general condition and abdominal pain. INVESTIGATIONS: On physical examination, gynecomastia was noted. Laboratory tests showed manifest hyperthyroidism. The beta-hCG levels were markedly increased. By ultrasound, the thyroid gland was hyperperfused without thyroid nodules. Several large echo mixed lesions were found in the liver. The testes appeared normal. DIAGNOSIS: In light of the typical laboratory findings, a non-seminomatous extragonadal germ cell tumor was diagnosed. Hyperthyroidism was most probably HCG induced. TREATMENT AND COURSE: Initially the patient was treated with thyreostatic drugs. After initiation of chemotherapy and a marked decrease in beta-hCG, thyreostatic therapy could be terminated. CONCLUSIONS: Germ cell tumors may cause an increase in beta-hCG concentration. By cross-reacting with the TSH-receptor this could induce hyperthyroidism. Germ cell tumors are therefore a rare differential diagnosis of hyperthyreoidism.

HRCT findings in idiopathic pneumonia syndrome with documentation of the disease course.

OBJECTIVE: To analyze extent and patterns of lung involvement in patients with idiopathic pneumonia syndrome (IPS) following allogeneic stem cell transplantation (SCT), and demonstrate their course during therapy. METHODS: 14 consecutive patients (age 29-64 years, mean 46.2 years) who experienced IPS after allogeneic SCT (as defined by current guidelines of NIH) were treated with either steroids (n = 5), or steroids and the TNF-α blocker etanercept in more severe cases (n = 9). CT-scans obtained before, during and after IPS were evaluated retrospectively. Quantification of pulmonary involvement was performed by visual estimation. Surveillance time ranged from 21 to 914 days with a total of 99 CT-scans (2-12 CT-scans per patient) obtained. RESULTS: IPS was mainly confined to the central lung regions (71%) with a bilateral and symmetric distribution (71%). Ground-glass opacity (93%) was the prominent CT-morphologic correlate, whereas concomitant consolidation of lung areas (noted in 43% of patients at the time of maximum infiltrates) only occurred in severe courses of IPS (p<0.01). Favourable courses (50%) showed an earlier peak with respect to extent and CT-attenuation of IPS infiltrates (p<0.01) followed by a rapid decline (median IPS duration 8 days) whereas a significantly more protracted course was observed in severe (unfavorable) cases (median IPS duration 52 days, p = 0.01). The death rate in the first and the latter groups (all of the severe cases receiving TNF blockage) was 0% and 43%, respectively. Pulmonary sequelae were recorded in almost all patients during follow-up with fibrotic residues. CONCLUSION: HRCT-features of IPS are non-specific, but predictable. Response monitoring in IPS can be well accomplished via HRCT and the course of pulmonary infiltrates heralds patient's outcome.

Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL).

Natural killer (NK) cells play an important role in the immunosurveillance of hematopoietic malignancies. Their reactivity is influenced by activating and inhibitory signals mediated by tumor-expressed ligands for NK receptors. Many members of the tumor necrosis factor (TNF) family modulate differentiation, proliferation, activation and death of both tumor and immune effector cells. The TNF receptor family member glucocorticoid-induced TNFR-related protein (GITR) stimulates anti-tumor immunity in mice, but available data indicate that GITR may mediate different effects in mice and men and impairs the reactivity of human NK cells. Here, we comprehensively studied the expression and function of GITR ligand (GITRL) in leukemia. Among the different leukemia entities, pronounced expression of GITRL on leukemic cells was observed in chronic lymphocytic leukemia (CLL), and the GITR receptor was expressed at significantly higher levels on NK cells of CLL patients compared with healthy controls. Upon GITR-GITRL interaction, signaling via GITRL into the leukemia cells induced the release of interleukin (IL)-6, IL-8 and TNF, which act as growth and survival factors for CLL cells. In addition, GITRL impaired both direct and Rituximab-induced degranulation, cytotoxicity and interferon-γ production of NK cells, which could be restored by GITR blocking antibodies. Thus, GITRL may contribute to disease pathophysiology and resistance to direct and Rituximab-induced NK reactivity in CLL.

Immune reconstitution after haploidentical hematopoietic cell transplantation: impact of reduced intensity conditioning and CD3/CD19 depleted grafts.

Haploidentical hematopoietic cell transplantation (HHCT) using CD34 selected grafts is complicated by slow engraftment and immune reconstitution. Engraftment and immune reconstitution might be improved using CD3/CD19-depleted grafts and reduced intensity conditioning (RIC). We report on 28 patients after HHCT with CD3/CD19-depleted grafts using RIC, which were prospectively evaluated for engraftment and immune reconstitution. Engraftment was rapid with full chimerism reached on day +15 after HHCT. T-cell reconstitution was delayed with a median of 205 CD3+ cells/µl, 70 CD3+CD4+ cells/µl and 66 CD3+ CD8+ cells/µl on day +100, respectively. A skewed T-cell receptor-Vß repertoire with oligoclonal T-cell expansions to day +100 and normalization after day +200 was observed. B-cell reconstitution was slow with a median of 100 CD19+ CD20+ cells/µl on day +150. Natural killer (NK) cell engraftment was fast reaching normal values on day +20. An increased natural cytotoxicity receptor and NKG2A, but decreased NKG2D and KIR expressions were observed on NK cells until day +100. We observed a positive impact of donor lymphocyte infusions on immune reconstitution. In conclusion, after HHCT, using CD3/CD19-depleted grafts and RIC, T- and B-cell reconstitution is delayed, whereas NK-cell reconstitution occurs early and fast.

Dendritic cells in cancer vaccines.

Dendritic cells (DC) are recognized as the most potent antigen-presenting cells with the ability to stimulate naive resting T cells and to initiate primary immune responses. Encouraging results in vaccination studies in animal models and the development of protocols to generate sufficient numbers of human DC for clinical application have led to attempts to verify the feasibility and efficacy of this approach in patients in the context of Phase I/II vaccination trials. This review aims to present a concise overview of the current knowledge in DC development and biology and describes the recent data of the first published DC-based vaccination studies. These preliminary trials indicate that immunotherapies utilizing DC-presenting tumor-associated antigens can safely be administered to patients with cancer and induce significant immunologic and clinical responses.

The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes.

The epithelial mucin MUC1 is overexpressed on the cell surface of many epithelial malignancies as well as on some B-cell lymphomas and multiple myelomas. Recently, we identified two HLA-A2-restricted T-cell epitopes derived from the MUC1 protein. To further extend the potential application of these peptides, we analyzed the expression of MUC1 on blast cells from patients with acute myelogenous leukemia (AML; n = 43) and several other hematological malignancies including acute lymphoblastic leukemia (n = 24), chronic lymphocytic leukemia (n = 36), hairy cell leukemia (n = 9), follicular lymphoma (n = 7), and multiple myeloma (n = 12). Using reverse transcription-PCR and MUC1-specific monoclonal antibodies, MUC1 expression was found in 67% of AML samples and 92% of myeloma samples. To analyze the presentation of MUC1 peptides by primary AML blasts, we induced MUC1-specific CTLs in vitro using peptide-pulsed dendritic cells from HLA-A2+ healthy donors as antigen-presenting cells. These CTLs efficiently lysed in an antigen-specific and HLA-A2-restricted manner not only target cells pulsed with the antigenic peptide but also tumor cell lines including multiple myeloma cells and primary AML blasts that constitutively expressed both MUC1 and HLA-A2. The specificity of the CTLs was confirmed in a cold target inhibition assay. Our data demonstrate that MUC1-derived peptides are tumor antigens in AML and several other hematological malignancies that could potentially be used for immunotherapeutic approaches.

Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells.

Vaccination of patients with cancer using dendritic cells (DCs) was shown to be effective for B-cell lymphoma and malignant melanoma. Here we provide evidence that patients with advanced breast and ovarian cancer can be efficiently vaccinated with autologous DCs pulsed with HER-2/neu- or MUC1-derived peptides. Ten patients were included in this pilot study. The DC vaccinations were well tolerated with no side effects. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood using both intracellular IFN-gamma staining and (51)Cr-release assays. The major CTL response in vivo was induced with the HER-2/neu-derived E75 and the MUC1-derived M1.2 peptide, which lasted for more than 6 months, suggesting that these peptides might be immunodominant. In addition, in one patient vaccinated with the MUC1-derived peptides, CEA- and MAGE-3 peptide-specific T-cell responses were detected after several vaccinations. In a second patient immunized with the HER-2/neu peptides, MUC1-specific T lymphocytes were induced after 7 immunizations, suggesting that antigen spreading in vivo might occur after successful immunization with a single tumor antigen. Our results show that vaccination of DCs pulsed with a single tumor antigen may induce immunologic responses in patients with breast and ovarian cancer. This study may be relevant to the design of future clinical trials of other peptide-based vaccines.