Neutrophil to lymphocyte ratio associated with prognosis of lung cancer

Purpose. Many studies recently focus on complicated and expensive genomic tests, but the prognostic values of biochemical markers which are easily obtained in clinics are largely overlooked and without further exploration. This study assesses the association of neutrophil-lymphocyte-ratio (NLR) with prognosis of lung cancer patients. Methods. In 1032 patients with histologically confirmed lung cancer, the association of pretreatment NLR values with overall survival (OS) was evaluated using a Cox proportional hazards model and the temporal relationship of longitudinal NLR was assessed using a mixed effects model. Results. Compared to the patients with a low pretreatment NLR value, those with elevated NLR exhibited a statistically significant worse OS with a hazard ratio (HR) of 1.50 (P < 0.0001) after adjusting for age, gender, race, smoking status, drinking status, tumor stage, tumor grade, histology, and treatments. A significant trend of increasing HRs along with increasing NLR values was observed. The increased risk of death conferred by pretreatment NLR values reached a peak level around 2 years after diagnosis. Moreover, in longitudinal analysis, we observed a trend of dramatically increased NLR values in patients who died during follow-up, but stable NLR values in those who were still alive, with a significant interaction of death-alive status with follow-up time (P < 0.0001). Conclusions. Elevated NLR is a potential biomarker to identify lung cancer patients with poor prognosis and should be validated in a future clinical trial (AU)

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Neutrophil to lymphocyte ratio associated with prognosis of lung cancer.

PURPOSE: Many studies recently focus on complicated and expensive genomic tests, but the prognostic values of biochemical markers which are easily obtained in clinics are largely overlooked and without further exploration. This study assesses the association of neutrophil-lymphocyte-ratio (NLR) with prognosis of lung cancer patients. METHODS: In 1032 patients with histologically confirmed lung cancer, the association of pretreatment NLR values with overall survival (OS) was evaluated using a Cox proportional hazards model and the temporal relationship of longitudinal NLR was assessed using a mixed effects model. RESULTS: Compared to the patients with a low pretreatment NLR value, those with elevated NLR exhibited a statistically significant worse OS with a hazard ratio (HR) of 1.50 (P < 0.0001) after adjusting for age, gender, race, smoking status, drinking status, tumor stage, tumor grade, histology, and treatments. A significant trend of increasing HRs along with increasing NLR values was observed. The increased risk of death conferred by pretreatment NLR values reached a peak level around 2 years after diagnosis. Moreover, in longitudinal analysis, we observed a trend of dramatically increased NLR values in patients who died during follow-up, but stable NLR values in those who were still alive, with a significant interaction of death-alive status with follow-up time (P < 0.0001). CONCLUSIONS: Elevated NLR is a potential biomarker to identify lung cancer patients with poor prognosis and should be validated in a future clinical trial.

Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin.

Cancer stem cells or tumour-propagating cells (TPCs) have been identified for a number of cancers, but data pertaining to their existence in lymphoma so far remain elusive. We show for the first time that a small subset of cells purified from human anaplastic lymphoma kinase (ALK)-positive and -negative, anaplastic large cell lymphoma cell lines and primary patient tumours using the side population (SP) technique have serial tumour-propagating capacity both in vitro and in vivo; they give rise to both themselves and the bulk tumour population as well as supporting growth of the latter through the production of soluble factors. In vivo serial dilution assays utilising a variety of model systems inclusive of human cell lines, primary human tumours and nucleophosmin (NPM)-ALK-induced murine tumours demonstrate the TPC frequency to vary from as many as 1/54 to 1/1336 tumour cells. In addition, the SP cells express higher levels of pluripotency-associated transcription factors and are enriched for a gene expression profile consistent with early thymic progenitors. Finally, our data show that the SP cells express higher levels of the NPM-ALK oncogene and are sensitive to an ALK inhibitor.

Transient retinal artery occlusion during phacoemulsification cataract surgery.

PURPOSE: Transient retinal artery occlusion (TRAO) is a potentially underdiagnosed cause of immediate 'pad off' visual loss following phacoemulsification cataract surgery under sub-Tenon's anaesthesia. METHODS: We describe a series of three patients presenting with enigmatic 'pad off' visual loss following phacoemulsification surgery, each diagnosed with TRAO. We describe the variable clinical presentation, illustrate the value of optical coherence tomography (OCT) imaging in establishing the diagnosis, and present the final visual outcomes. RESULTS: Clinical findings alone may be subtle and inadequate in localising the pathology in patients with TRAO. Cross-comparison of superior and inferior macula OCT profiles in branch-pattern arterial occlusion-and between healthy and affected eyes in central-pattern arteriolar occlusion-is critical in clinching the diagnosis. The typical evolution of OCT appearance is acute-phase inner retinal thickening/oedema and hyperreflectivity followed by progressive, late-phase inner retinal atrophy. Visual acuity may recover but central scotomas, and defects in colour perception may persist. CONCLUSION: The diagnosis of TRAO is challenging; delayed presentation may resolve fundal and retinal angiographic abnormalities. OCT may be the only imaging modality that can provide objective evidence of TRAO. Meticulous comparison/segmentation of OCT images is therefore mandatory in patients presenting with acute post-operative visual loss to exclude TRAO.

Leptin receptor in childhood acute leukemias.

Ob-R receptor is encoded by db gene and belongs to class I cytokine receptors family. Its expression was observed in hematopoietic CD34+ stem cells, erythropoietic, myeloid and lymphoblastic lineages cell lines and in human leukemic blast cells in lymphomas, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML). The studies on human bone marrow cells show that JAK/STAT pathway plays a substantial role in signal transduction in young bone marrow cells. The aim of the study was to examine the relationship between leptin receptor expression and the proliferation of neoplastic hematopoietic cells in bone marrow. The study was performed in a total of 57 children of both sexes aged 3 months to 16 years. A group of 46 patients with acute leukemia involved 25 children with ALLB, 11 children with ALLT and 10 children with ANNL. The control group consisted of 11 non-obese children with non-malignant hematological disturbances. The tests were performed on bone marrow samples. The assessments of membrane expression of Ob-R and the antigens determining the phenotype of bone marrow cells were performed using a flow cytometry method. In acute lymphoblastic leukemia, a significant decrease of Ob-R expression on leukemic blasts was observed in comparison with respective populations of normal bone marrow cells. Also in progenitor cells populations a significant decrease of CD34+Ob-R+w ALLT and ALLB was observed in comparison with the cells from normal bone marrow. No statistically significant differences in the percentage of Ob-R+ cells in ANNL bone marrow and in control bone marrow were observed.

Implementation and experimental results of 4D tumor tracking using robotic couch.

PURPOSE: This study presents the implementation and experimental results of a novel technique for 4D tumor tracking using a commercially available and commonly used treatment couch and evaluates the tumor tracking accuracy in clinical settings. METHODS: Commercially available couch is capable of positioning the patient accurately; however, currently there is no provision for compensating physiological movement using the treatment couch in real-time. In this paper, a real-time couch tracking control technique is presented together with experimental results in tumor motion compensation in four dimensions (superior-inferior, lateral, anterior-posterior, and time). To implement real-time couch motion for tracking, a novel control system for the treatment couch was developed. The primary functional requirements for this novel technique were: (a) the treatment couch should maintain all previous∕normal features for patient setup and positioning, (b) the new control system should be used as a parallel system when tumor tracking would be deployed, and (c) tracking could be performed in a single direction and∕or concurrently in all three directions of the couch motion (longitudinal, lateral, and vertical). To the authors' best knowledge, the implementation of such technique to a regular treatment couch for tumor tracking has not been reported so far. To evaluate the performance of the tracking couch, we investigated the mechanical characteristics of the system such as system positioning resolution, repeatability, accuracy, and tracking performance. Performance of the tracking system was evaluated using dosimetric test as an endpoint. To investigate the accuracy of real-time tracking in the clinical setting, the existing clinical treatment couch was replaced with our experimental couch and the linear accelerator was used to deliver 3D conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) treatment plans with and without tracking. The results of radiation dose distribution from these two sets of experiments were compared and presented here. RESULTS: The mechanical accuracies were 0.12, 0.14, and 0.18 mm in X, Y, and Z directions. The repeatability of the desired motion was within ±0.2 mm. The differences of central axis dose between the 3D-CRT stationary plan and two tracking plans with different motion trajectories were 0.21% and 1.19%. The absolute dose differences of both 3D tracking plans comparing to the stationary plan were 1.09% and 1.20%. Comparing the stationary IMRT plan with the tracking IMRT plan, it was observed that the central axis dose difference was -0.87% and the absolute difference of both IMRT plans was 0.55%. CONCLUSIONS: The experimental results revealed that the treatment couch could be successfully used for real-time tumor tracking with a high level of accuracy. It was demonstrated that 4D tumor tracking was feasible using existing couch with implementation of appropriate tracking methodology and with modifications in the control system.

SU-E-J-04: Initial Experience with 4D-CBCT for Lung Cancer: Physician Verification of Computed Shifts Remains Necessary.

PURPOSE: Four-dimensional cone-beam CT (4D-CBCT) is a novel imaging technique used to guide treatment setup for patients with pulmonary lesions by providing additional information about tumor motion at the time of treatment. This study aimed to evaluate the efficacy of the 4D-CBCT capability in ensuring accurate patient setup during SBRT. METHODS: Twelve patients with pulmonary lesions were imaged pre-treatment with Elekta XVI4.5 using the Symmetry protocol resulting in a respiratory correlated 4D-CBCT. Reconstruction produced 10 phased-based and one average 3DCT image set. Patient shifts were derived from contour-based(mask) registration driven by the weighted average of shifts from each phased CT(4D shifts). Physicians reviewed registration and manually adjusted shifts based on visual registration. We exported the average 3DCT to MIM Vista Software 5.1.1 in reference volume coordinates and manually fused to the reference CT. All manual fusions were contour-based registrations performed by a single observer. No rotations were permitted in manual fusion to mimic clinical procedure. Translational 3D shifts from manual fusion were compared to 4D(automatic registration) shifts and final physician-corrected shifts. RESULTS: Mean differences between 4D and 3D shifts in lateral, longitudinal, and vertical directions were 1.07mm, 5.92mm, and 1.43mm, respectively. Mean differences between physician-corrected and 3D shifts were 1.41mm, 4.83mm, and 1.61mm. Differences between 4D shifts and 3D shifts increased with increasing tumor motion. One patient had consistently large longitudinal differences between 4D and 3D shifts (mean=3.0cm). Further review revealed poor 4D registration(via mask and clipbox) on the XVI system which was corrected by physician adjustment prior to treatment. CONCLUSIONS: 4D-CBCT is a valuable imaging tool in patient setup. Physician review of contour-based registration is imperative in preventing a geometrical miss. Caution must be employed in tumors that exhibit a large degree of motion. Further research is necessary in determining functional limits of the 4D-CBCT system.

SU-E-J-12: Initial Clinical Experiences in Using 4D-CBCT as Image Guidance for Lung SBRT.

PURPOSE: The authors started to use Symmetry 4D-CBCT as image guidance for lung SBRT in August 2011. Here the authors present the initial clinical experiences with this novel image guidance technique. METHODS: In total 118 4D-CBCT scans have been acquired for 17 lung patients among which 15 received SBRT and the other 2 received hypofractionated treatments. 4D-CBCT scans are acquired with Elekta XVI 4.5 usingSymmetry, a procedure module in XVI that acquires 4D-CBCT, registers daily images to reference 3D-CT and generates shifts for patient setup. RESULTS: Typical thoracic 4D-CBCT scans with Symmetry take 3 minutes with a 200 degree gantry rotation. Symmetry automatically sorts images into 10 phases based on automatic detection of diaphragm position. Then Symmetry generates two independent intensity-based registrations, one according to a pre-defined large volume of interest including the tumor, surrounding tissues and bony structures, the other only according to an expanded target volume. The registrations are obtained by registering each phase image to the reference image and averaging across all phases in a time-weighted manner. Eventually Symmetry provides users the freedom to pick either one of the two registrations, a compromise, or a manual tuning. Compared to regular 3D-CBCT, 4D-CBCT enables physicians to visually place the moving target in the center of PTV, greatly reducing the probability of missing target due to respiratory motion, thus enables possible reduction in PTV margin. 4D-CBCT also provides the ability to repeatedly evaluate the quality of ITV. It is possible that ITV does not fully cover the tumor motion due to a low quality 4D-CT simulation for a patient with difficulties in regular breathing. CONCLUSIONS: 4D-CBCT is a superior image guidance technique for lung SBRT treatments for its ability to visualize moving target. It provides physicians more confidence in tumor targeting and ability to repeatedly evaluate ITV quality during the treatment course.

Regulatory T cells and immunodeficiency in mycosis fungoides and Sézary syndrome.

Cutaneous T-cell lymphoma (CTCL) is the term for diseases characterized by primary accumulation of malignant T cells in the skin. Patients with the two predominant clinical forms of CTCL called mycosis fungoides (MF) and Sézary syndrome (SS) characteristically develop severe immunodeficiency during disease progression and consequently patients with advanced disease frequently die of infections and not from the tumor burden. For decades, it has been suspected that the malignant T cells actively drive the evolving immunodeficiency to avoid antitumor immunity, yet, the underlying mechanisms remain unclear. The identification of a subset of highly immunosuppressive regulatory T cells (Tregs) triggered a variety of studies investigating if MF and SS are malignant proliferations of Tregs but seemingly discordant findings have been reported. Here, we review the literature to clarify the role of Tregs in MF and SS and discuss the potential mechanisms driving the immunodeficiency.

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA.

The mechanisms of malignant cell transformation mediated by the oncogenic anaplastic lymphoma kinase (ALK) tyrosine kinase remain only partially understood. In this study, we report that T-cell lymphoma (TCL) cells carrying the nucleophosmin (NPM)/ALK fusion protein (ALK+ TCL) strongly express hypoxia-induced factor 1α (HIF1α) mRNA, even under normoxic conditions, and markedly upregulate HIF1α protein expression under hypoxia. HIF1α expression is strictly dependent on the expression and enzymatic activity of NPM/ALK, as shown in BaF3 cells transfected with wild-type NPM/ALK and kinase-inactive NPM/ALK K210R mutant and by the inhibition of the NPM/ALK function in ALK+ TCL cells by a small-molecule ALK inhibitor. NPM/ALK induces HIF1α expression by upregulating its gene transcription through its key signal transmitter signal transducer and activator of transcription 3 (STAT3), which binds to the HIF1α gene promoter as shown by the chromatin immunoprecipitation assay and is required for HIF1α gene expression as demonstrated by its small interfering RNA-mediated depletion. In turn, depletion of HIF1α increases mammalian target of rapamycin complex 1 activation, cell growth and proliferation and decreases vascular endothelial growth factor synthesis. These results identify a novel cell-transforming property of NPM/ALK, namely its ability to induce the expression of HIF1α, a protein with an important role in carcinogenesis. These results also provide another rationale to therapeutically target NPM/ALK and STAT3 in ALK+ TCL.

Sublingual immunotherapy in asthma does not influence lymphocyte sensitivity to Fas stimulation.

BACKGROUND: The resistance of T lymphocytes to Fas-mediated apoptosis is an important feature of atopic asthma. The only effective causative treatment of atopic diseases is immunotherapy. Clinical efficacy of sublingual immunotherapy (SLIT) has been already proven, but there is still limited number of studies on its influence on lymphocytes function. OBJECTIVES: The aim of the study was to evaluate whether SLIT could restore the sensitivity of asthmatic T cells to undergo Fas-mediated apoptosis. MATERIAL AND METHODS: Peripheral blood was collected from 12 patients aged 8 ±2 years suffering from atopic asthma and undergoing sublingual specific immunotherapy. To evaluate sensitivity to Fas-mediated apoptosis, the blood was transmitted to sterile tubes and mixed with purified monoclonal antibody anti-CD95. After incubation, leukocytes were stained with Annexin V, propidium iodide, and monoclonal antibody against CD2 conjugated with phycoerythrin-cyanin 5.1, and then analyzed with flow cytometry. The procedure was repeated for each patient after 12 months of SLIT. - RESULTS: Stimulation with anti-CD95 of T lymphocytes from patients with atopic asthma before treatment increased the number of early apoptotic cells (from 19.5 ±16.7% before stimulation to 26.6 ±16.7% Annexin V positive cells after stimulation). After one year of SLIT anti-CD95 still caused an increase of the early apoptotic cells ratio in the lymphocyte population (from 12.4 ±7.4% before stimulation to 24.7 ±15.4% Annexin V positive T cells after CD95 stimulation). Although an increasing trend could be observed, differences between the analyzed groups were not statistically significant. CONCLUSIONS: A year of SLIT does not change the sensitivity of T lymphocytes from peripheral blood of children suffering from atopic asthma to Fas-mediated apoptosis.

Leptin receptors.

Leptin or obesity receptor (Ob-R) is a member of class I cytokine receptor family. Ob-R, expressed in six isoforms, is the product of alternative RNA splicing of db gene. According to its structural differences, the receptor's isoforms are divided into three classes: long, short, and secretory isoforms. A long, fully active isoform of Ob-Rb is expressed mainly in the hypothalamus, where it takes part in energy homeostasis and in the regulation of secretory organs' activity. Ob-Rb is also present on all types of immune cells, involved in innate and adaptive immunity. Short leptin isoforms (Ob-Ra, Ob-Rc, Ob-Rd, and Ob-Re) that contain box 1 motif are able to bind JAK kinases (Janus kinases) as well as to activate some other signal transduction cascades. A soluble isoform (Ob-Re) can regulate serum leptin concentration and serve as a carrier protein delivering the hormone to its membrane receptors and is able to transduce the signal into the cell. JAK/STAT pathway plays the major role in leptin signal transduction through membrane receptors. Among all Ob-R isoforms, only full-length isoform (Ob-Rb) is able to fully transduce activation signal into the cell.

Decreased CD4+CD152+ T cell subset and its correlation with the level of antithyroid antibodies in children with chronic autoimmune thyroiditis.

OBJECTIVE: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is one of the basic antigens involved in immune responses regulation associated with autoimmune thyroid diseases. The aim of the study was to evaluate whether the surface expression of CTLA-4(CD152) on T cells is correlated with laboratory autoimmune markers in children with Hashimoto's disease. MATERIAL AND METHODS: Blood samples were obtained from 45 children with Hashimoto's thyroiditis of the mean age 14.8 ±2.35 years, and from 55 healthy age-matched children, free of allergic, immune and hematological disorders, and with a normal thyroid function. The anti-thyroid antibodies were measured with Microparticle Enzyme Immunoassay (AxSYM Anti-Tg, AxSYM Anti-TPO). The T cell phenotype was evaluated flow cytometery, with the use of monoclonal antibodies combination: CD4- FITC/ CD28 -PC5/ CD152 -PE and CD8 -FITC/ CD28 -PC5/ CD152 -PE. - RESULTS: The percentage of T cells with CD152 expression was significantly decreased in children with Hashimoto's thyroiditis compared with healthy controls (P<0.001). A significant negative correlation was found between the level of anti-thyroglobulin antibodies and the percentage of CD4+CD152+ T cells (r = -0.34; P<0.05). Anti-thyroperoxidase antibodies did not correlate with CD152 expression. CONCLUSIONS: In children with Hashimoto's thyroiditis, the number of CD4+CD152+ T cells is decreased and negatively correlates with the level of anti-thyroglobulin antibodies.

COX-2-dependent PGE(2) acts as a growth factor in mycosis fungoides (MF).

Cancer often originates from a site of persistent inflammation, and the mechanisms turning chronic inflammation into a driving force of carcinogenesis are intensely investigated. Cyclooxygenase-2 (COX-2) is an inducible key modulator of inflammation that carries out the rate-limiting step in prostaglandin synthesis. Aberrant COX-2 expression and prostaglandin E(2) (PGE(2)) production have been implicated in tumorigenesis. In this study we show that COX-2 is ectopically expressed in malignant T-cell lines from patients with cutaneous T-cell lymphoma (CTCL) as well as in situ in lymphocytic cells in 21 out of 22 patients suffering from mycosis fungoides (MF) in plaque or tumor stage. COX-2 is not expressed in lymphocytes of 11 patients with patch-stage MF, whereas sporadic COX-2 staining of stromal cells is observed in the majority of patients. COX-2 expression correlates with a constitutive production of PGE(2) in malignant T cells in vitro. These cells express prostaglandin receptors EP3 and EP4 and the receptor antagonist as well as small interfering RNA (siRNA) directed against COX-2, and specific COX-2 inhibitors strongly reduce their spontaneous proliferation. In conclusion, our data indicate that COX-2 mediated PGE(2) exerts an effect as a tumor growth factor in MF.