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  • 1
    Publication Date: 2018-06-14
    Description: HIV-1-infected cells expressing envelope glycoproteins (Env) in the CD4-bound conformation on their surfaces are targeted by antibody-dependent cellular cytotoxicity (ADCC) mediated by CD4-induced (CD4i) antibodies and sera from HIV-1-infected individuals (HIV + sera). By downregulating the surface expression of CD4, Nef prevents Env-CD4 interaction, thus protecting HIV-1-infected cells from ADCC. HIV-1 infectious molecular clones (IMCs) are widely used to measure ADCC. In order to facilitate the identification of infected cells and high-throughput ADCC analysis, reporter genes (e.g., the Renilla luciferase [LucR] gene) are often introduced into IMC constructs. We evaluated the susceptibility of HIV-1-infected CD4 + T lymphocytes to ADCC using a panel of parental IMCs and derivatives that expressed the LucR reporter gene, utilizing different molecular strategies, including one specifically designed to retain Nef expression. We found that in some of these constructs, Nef expression in CD4 + T cells was suboptimal, and consequently, CD4 downregulation was incomplete. CD4 molecules remaining on the cell surface resulted in the exposure of ADCC-mediating CD4i epitopes on Env and a dramatic increase in the susceptibility of the infected cells to ADCC. Strikingly, protection from ADCC was observed when cells were infected with the parental IMC, which exhibited strong CD4 downregulation. This discrepancy between the parental and Nef-impaired viruses was independent of the strains of Env expressed, but rather, it was correlated with the levels of CD4 surface expression. Overall, our results indicate that caution should be taken when selecting IMCs for ADCC measurements and that CD4 downregulation needs to be carefully monitored when drawing conclusions about the nature and magnitude of ADCC. IMPORTANCE In-depth understanding of the susceptibility of HIV-1-infected cells to ADCC might help establish correlates of vaccine protection and guide the development of HIV-1 vaccine strategies. Different ADCC assays have been developed, including those using infectious molecular clones (IMCs) carrying a LucR reporter gene that greatly facilitates large-scale quantitative analysis. We previously reported different molecular strategies for introducing LucR while maintaining Nef expression and function and, consequently, CD4 surface downregulation. Here, we demonstrate that utilizing IMCs that exhibit impaired Nef expression can have undesirable consequences due to incomplete CD4 downregulation. CD4 molecules remaining on the cell surface resulted in the exposure of ADCC-mediating CD4i epitopes on Env and a dramatic increase in the susceptibility of the infected cells to ADCC. Overall, our results indicate that CD4 downregulation needs to be carefully monitored when drawing conclusions about the nature and magnitude of ADCC.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 2
    Abstract: INTRODUCTION: Patients with small-cell lung cancer (SCLC) demonstrate an exception in the treatment of brain metastases (BM), because in patients with SCLC whole brain radiotherapy (WBRT) only is the preferred treatment modality. The purpose of this study was to develop a prognostic score for patients with brain metastases from SCLC treated with WBRT. PATIENTS AND METHODS: The present study was conducted utilizing a single-institution, previously described, retrospective database of patients with SCLC who were treated with WBRT (n = 221). Univariate and multivariate analyses were performed to generate the "brain metastases from SCLC score" (BMS score) based on favorable prognostic factors: Karnofsky performance status (KPS 〉 70), extracerebral disease status (stable disease/controlled), and time of appearance of BM (synchronous). Furthermore, the disease-specific graded prognostic assessment score as well as the recursive partitioning analysis (RPA) were performed and compared with the new BMS score by using the log-rank (Mantel-Cox) test. RESULTS: BMS score and RPA showed the most significant differences between classes (P 〈 .001). BMS score revealed a mean overall survival (OS) of 2.62 months in group I (0-1 points), 6.61 months in group II (2-3 points), and 12.31 months in group III (4 points). The BMS score also identified the group with the shortest survival (2.62 months in group I), and the numbers of patients in each group were most equally distributed with the BMS score. CONCLUSION: The new BMS score was more prognostic than the RPA and disease-specific graded prognostic assessment scores. The BMS score is easy to use and reflects known prognostic factors in contemporary patients with SCLC treated with WBRT. Future studies are necessary to validate these findings.
    Type of Publication: Journal article epub ahead of print
    PubMed ID: 29373273
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  • 3
    Abstract: OBJECTIVES: Patients with brain metastases from small-cell lung cancer (SCLC) who underwent prior prophylactic cranial irradiation (PCI) are often treated with a second course of whole brain radiation therapy (Re-WBRT) or stereotactic radiosurgery (SRS) for purposes of palliation in symptomatic patients, hope for increased life expectancy or even as an alternative to untolerated steroids. Up to date there is only limited data available regarding the effect of this treatment. This study examines outcomes in patients in a single institution who underwent cerebral re-irradiation after prior PCI. METHODS: We examined the medical records of 76 patients with brain metastases who had initially received PCI between 2008 and 2015 and were subsequently irradiated with a second course of cerebral radiotherapy. Patients underwent re-irradiation using either Re-WBRT (88%) or SRS (17%). The outcomes, including symptom palliation, radiation toxicity, and overall survival (OS) following re-irradiation were analyzed. Survival and correlations were calculated using log-rank, univariate, and multivariate Cox proportional hazards-ratio analyses. Treatment-related toxicity was classified according to CTCAE v4.0. RESULTS: Median OS of all patients was 3 months (range 0-12 months). Median OS after Re-WBRT was 3 months (range 0-12 months). Median OS after SRS was 5 months (range 0-12 months). Karnofsky performance status scale (KPS 〉/=50%) was significantly associated with improved OS in both univariate (HR 2772; p=0,009) and multivariate analyses (HR 2613; p=0,024) for patients receiving Re-WBRT. No unexpected toxicity was observed and the observed toxicity remained consistently low. Symptom palliation was achieved in 40% of symptomatic patients. CONCLUSIONS: In conclusion, cerebral re-irradiation after prior PCI is beneficial for symptom palliation and is associated with minimal side effects in patients with SCLC. Our survival data suggests that it is primarily useful in patients with adequate performance status.
    Type of Publication: Journal article published
    PubMed ID: 27794411
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  • 4
    Keywords: CELL LUNG-CANCER ; LONG-TERM ; PROGNOSTIC-FACTORS ; PHASE-II ; RECTAL-CANCER ; surgical resection ; STAGE-III THYMOMA ; ADJUVANT RADIATION-THERAPY ; MALIGNANT THYMOMA ; INVASIVE THYMOMA
    Abstract: Purpose The purpose of this study was to evaluate postoperative radiotherapy regarding outcome and toxicity in patients with thymic epithelial tumors (TET) after surgery. Materials and methods We retrospectively analyzed medical records of 41 patients with TET treated with postoperative radiotherapy at our institution between 1995 and 2012. The impact of prognostic factors (e.g., Masaoka stage, histological subtype) was investigated and radiation-related toxicity was assessed. Results Median age was 59.8 years and median follow-up was 61 months. In 24.4 %, TETs were associated with paraneoplastic syndromes. The 5-year overall survival (OS) was 89.5 % and the 5-year disease-free survival (DFS) was 88.9 %. Masaoka stage had a significant impact on OS (p = 0.007). Locally limited stages I + II had a 5-year OS of 100 % compared to 80 % for stage III and 66.7 % for stage IV. The 5-year DFS was excellent with 100 % for both WHO groups A/AB/B1 and B2, respectively, and significantly (p = 0.005) differed from B3/C-staged patients with a 5-year DFS of 63.6 %. Resection status, paraneoplastic association, radiation dose, or tumor size did not influence survival. There were no high-grade acute or late side effects caused by radiotherapy. Conclusion Masaoka stage has a significant impact on OS as WHO type has on DFS in patients with TETs after surgery and adjuvant irradiation. Postoperative radiotherapy with doses around 50 Gy is safe and not likely to cause high-grade toxicity. Further prospective trials are necessary to separate patient subgroups that benefit from radiotherapy from those that do not.
    Type of Publication: Journal article published
    PubMed ID: 25156510
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  • 5
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    Abstract: The purpose of this study was to evaluate prognostic factors associated with overall survival (OS) and neurological progression free survival (nPFS) in small-cell lung cancer (SCLC) patients with brain metastases who received whole-brain radiotherapy (WBRT). From 2003 to 2015, 229 SCLC patients diagnosed with brain metastases who received WBRT were analyzed retrospectively. In this cohort 219 patients (95%) received a total photon dose of 30 Gy in 10 fractions. The prognostic factors evaluated for OS and nPFS were: age, Karnofsky Performance Status (KPS), number of brain metastases, synchronous versus metachronous disease, initial response to chemotherapy, the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class and thoracic radiation. Median OS after WBRT was 6 months and the median nPFS after WBRT was 11 months. Patients with synchronous cerebral metastases had a significantly better median OS with 8 months compared to patients with metachronous metastases with a median survival of 3 months (p 〈 0.0001; HR 0.46; 95% CI 0.31-0.67). Based on RPA classification median survival after WBRT was 17 months in RPA class I, 7 months in class II and 3 months in class III (p 〈 0.0001). Karnofsky performance status scale (KPS 〈 70%) was significantly associated with OS in both univariate (HR 2.84; p 〈 0.001) and multivariate analyses (HR 2.56; p = 0.011). Further, metachronous brain metastases (HR 1.8; p 〈 0.001), initial response to first-line chemotherapy (HR 0.51, p 〈 0.001) and RPA class III (HR 2.74; p 〈 0.001) were significantly associated with OS in univariate analysis. In multivariate analysis metachronous disease (HR 1.89; p 〈 0.001) and initial response to chemotherapy (HR 0.61; p 〈 0.001) were further identified as significant prognostic factors. NPFS was negatively significantly influenced by poor KPS (HR 2.56; p = 0.011), higher number of brain metastases (HR 1.97; p = 0.02), and higher RPA class (HR 2.26; p = 0.03) in univariate analysis. In this series, the main prognostic factors associated with OS were performance status, time of appearance of intracranial disease (synchronous vs. metachronous), initial response to chemotherapy and higher RPA class. NPFS was negatively influenced by poor KPS, multiplicity of brain metastases, and higher RPA class in univariate analysis. For patients with low performance status, metachronous disease or RPA class III, WBRT should be weighed against supportive therapy with steroids alone or palliative chemotherapy.
    Type of Publication: Journal article published
    PubMed ID: 28560661
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  • 7
    Abstract: PURPOSE: Whole brain radiation therapy (WBRT) is historically the standard of care for patients with brain metastases (BM) from small-cell lung cancer (SCLC), although locally ablative treatments are the standard of care for patients with 1-4 BM from other solid tumors. The objective of this analysis was to find prognostic factors influencing overall survival (OS) and intracranial progression-free survival (iPFS) in SCLC patients with single BM (SBM) treated with WBRT. METHODS: A total of 52 patients were identified in the authors' cancer center database with histologically confirmed SCLC and contrast-enhanced magnet resonance imaging (MRI) or computed tomography (CT), which confirmed SBM between 2006 and 2015 and were therefore treated with WBRT. A Kaplan-Meier survival analysis was performed for OS analyses. The log-rank (Mantel-Cox) test was used to compare survival curves. Univariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS and iPFS. RESULTS: The median OS after WBRT was 5 months and the median iPFS after WBRT 16 months. Patients that received surgery prior to WBRT had a significantly longer median OS of 19 months compared to 5 months in the group receiving only WBRT (p = 0.03; HR 2.24; 95% confidence interval [CI] 1.06-4.73). Patients with synchronous disease had a significantly longer OS compared to patients with metachronous BM (6 months vs. 3 months, p = 0.005; HR 0.27; 95% CI 0.11-0.68). Univariate analysis for OS revealed a statistically significant effect for metachronous disease (HR 2.25; 95% CI 1.14-4.46; p = 0.019), initial response to first-line chemotherapy (HR 0.58; 95% CI 0.35-0.97; p = 0.04), and surgical resection (HR 0.36; 95% CI 0.15-0.88; p = 0.026). OS was significantly affected by metachronous disease in multivariate analysis (HR 2.20; 95% CI 1.09-4.45; p = 0.028). CONCLUSIONS: Univariate analysis revealed that surgery followed by WBRT can improve OS in patients with SBM in SCLC. Furthermore, synchronous disease and response to initial chemotherapy appeared to be major prognostic factors. Multivariate analysis revealed metachronous disease as a significantly negative prognostic factor on OS. The value of WBRT, stereotactic radiosurgery (SRS), or surgery alone or in combination for patients with a limited number of BM in SCLC should be evaluated in further prospective clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 29085978
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  • 8
    Abstract: BACKGROUND: In 2007, the European Organization for Research and Treatment of Cancer (EORTC) study (ClinicalTrials.gov identifier, NCT00016211) demonstrated a beneficial effect on overall survival (OS) with the use of prophylactic cranial irradiation (PCI) for extensive disease (ED) small-cell lung cancer (SCLC). Nevertheless, debate is ongoing regarding the role of PCI, because the patients in that trial did not undergo magnetic resonance imaging (MRI) of the brain before treatment. Also, a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with negative pretreatment brain MRI findings. MATERIALS AND METHODS: We examined the medical records of 136 patients with ED SCLC who had initially responded to chemotherapy and undergone PCI from 2007 to 2015. The outcomes, radiation toxicity, neurologic progression-free survival, and OS after PCI were analyzed. Survival and correlations were calculated using log-rank and univariate Cox proportional hazard ratio analyses. RESULTS: The median OS and the median neurologic progression-free survival after PCI was 12 and 19 months, respectively. No significant survival difference was seen for patients who had undergone MRI before PCI compared with patients who had undergone contrast-enhanced computed tomography (P = .20). Univariate analysis for OS did not show a statistically significant effect for known cofactors. CONCLUSION: In the present cohort, PCI was associated with improved survival compared with the PCI arm of the EORTC trial, with a nearly doubled median OS period. Also, the median OS was prolonged by 2 months compared with the irradiation arm of the Japanese trial.
    Type of Publication: Journal article published
    PubMed ID: 28027850
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  • 9
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; tumor ; CELL ; Germany ; LUNG ; THERAPY ; TOXICITY ; lung cancer ; LUNG-CANCER ; COHORT ; DISEASE ; HISTORY ; RISK ; radiation ; ASSOCIATION ; CONFORMAL RADIOTHERAPY ; AGE ; smoking ; chemotherapy ; LOCALIZATION ; PREDICTION ; ESCALATION ; ONCOLOGY ; small cell lung cancer ; REGRESSION ; development ; NSCLC ; RADIATION PNEUMONITIS ; MODALITY ; CONCURRENT CHEMOTHERAPY ; Dose-volume constraints
    Abstract: Purpose: To analyze the association of patient- and treatment-related factors with the onset of radiation pneumonitis in a homogeneously treated cohort of patients suffering from small cell Lung cancer (SCLC). Patients and Methods: 242 patients with SCLC staged as limited disease, who had been treated with chemotherapy and three-dimensional conformal radiotherapy, were retrospectively analyzed. Pneumonitis was defined by typical symptoms and radiographic findings and judged clinically relevant, if drug administration and hospitalization were necessary. Patient- (age, gender, smoking history, performance status, tumor Localization, benign lung disease) and treatment-related parameters (V-10-V-40, mean lung dose [MLD]) were analyzed using chi(2)-tests for categorical parameters and Logistic regression for continuous variables. Results: 33 patients (13.6%) developed a clinically relevant pneumonitis, of whom three patients died. ALL cases of pneumonitis developed within 120 days. None of the patient-related parameters correlated significantly with the onset of pneumonitis. Considering treatment-related parameters, a significant correlation of V-30 in regard to total lung and V-40 in regard to ipsilateral, contralateral and total Lung to the risk of pneumonitis was found. So, the estimated risk of a clinically relevant pneumonitis increased from 10% given a V-30 of 13% to 30% given a V-30 of 35%. In contrast, no significant correlation was found for V-10 and V-20 and only a trend for MLD. Conclusion: In this series, high-dose radiation volume parameters, i.e., V-30 and especially V-40, were identified as the most important factors for the development of radiation pneumonitis. Low-dose radiation volume parameters and clinical parameters played an inferior role in predicting the pneumonitis risk
    Type of Publication: Journal article published
    PubMed ID: 20165822
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  • 10
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