Frederic Carsten Schmeel

Adoptive Immunotherapy Strategies with Cytokine-Induced Killer (CIK) Cells in the Treatment of Hematological Malignancies

Cytokine-induced killer (CIK) cells are a heterogeneous population of immune effector cells that feature a mixed T- and Natural killer (NK) cell-like phenotype in their terminally-differentiated CD3+CD56+ subset. The easy availability, high proliferation rate and widely major histocompatibility complex (MHC)-unrestricted antitumor activity of CIK cells contribute to their particularly advantageous profile, making them an attractive approach for adoptive immunotherapy. CIK cells have shown considerable cytotoxicity against both solid tumors and hematological malignancies in vitro and in animal studies. Recently, initial clinical experiences demonstrated the feasibility and efficacy of CIK cell immunotherapy in cancer patients, even at advanced disease stages. Likewise, the clinical application of CIK cells in combination with standard therapeutic procedures revealed synergistic antitumor effects. In this report, we will focus our consideration on CIK cells in the treatment of hematological malignancies. We will give insight into the latest advances and future perspectives and outline the most prominent results obtained in 17 clinical studies. Overall, CIK cells demonstrated a crucial impact on the treatment of patients with hematological malignancies, as evidenced by complete remissions, prolonged survival durations and improved quality of life. However, up to now, the optimal application schedule eventually favoring their integration into clinical practice has still to be developed.

Cardiac Magnetic Resonance Reveals Signs of Subclinical Myocardial Inflammation in Asymptomatic HIV-Infected Patients.

Background—People living with chronic HIV infection are at an increased risk for cardiovascular disease. With this study, we aimed to determine the extent of cardiovascular involvement in asymptomatic HIV-infected patients by a comprehensive cardiac magnetic resonance (CMR) approach. Methods and Results—Asymptomatic patients with chronic HIV infection undergoing combination antiretroviral therapy (n=28) and control subjects (n=22) underwent CMR. HIV-infected patients were successfully controlled for the disease with a consistent plasma viremia of <200 copies/mL (mean CD4+-cell count, 475.1±307.9 cells/&mgr;L). CMR protocol allowed for the determination of cardiac function, myocardial inflammation, myocardial fibrosis, aortic stiffness, and pericardial fat volume. When compared with healthy controls, HIV-infected patients showed alterations in left ventricular function as demonstrated by a lower ejection fraction (60.9±7.1% versus 65.2±5.5%; P=0.023) and lower global peak systolic longitudinal and circumferential strain values (longitudinal strain, −17.7±3.4% versus −20.2±3.2%, circumferential strain, −21.2±4.6% versus −24.7±5.1%; P<0.001, respectively). CMR parameters indicating myocardial inflammation were elevated in HIV-infected patients (native T1 relaxation times, 1128.3±53.4 ms versus 1086.5±54.5 ms; P=0.009; relative T2 signal intensity ratio, 1.6±0.3 versus 1.4±0.3; P=0.046; early gadolinium enhancement ratio, 3.1±1.2 versus 2.1±0.6; P=0.003). Myocardial fibrosis, predominantly at the subepicardium of the midventricular and basal inferolateral wall, was prevalent in 82.1% of HIV-infected patients, but only in 27.3% of healthy controls (P<0.001). Conclusions—Comprehensive CMR revealed a high burden of cardiovascular disease in asymptomatic HIV-infected patients. Subclinical myocardial inflammation as detected by CMR may be a potential precursor of the increased cardiovascular morbidity and mortality observed in patients with chronic HIV infection.

Piceatannol exhibits selective toxicity to multiple myeloma cells and influences the Wnt/ beta‐catenin pathway

Aberrant activation of Wnt/β‐catenin signaling promotes development and progression of various malignant neoplasms. Recent studies observed that the Wnt pathway is constitutively active in myeloma cells and promotes an exaggerated proliferation. Thus, the Wnt signaling pathway might be an attractive therapeutic target for multiple myeloma. In this study, we identified piceatannol as an inhibitor of the Wnt/β‐catenin pathway and as a potent inducer of apoptosis in myeloma cells. Interestingly, healthy cells remained mainly unaffected. These results reveal a significant selective induction of apoptosis by piceatannol and suggest a significant in vivo effect against multiple myeloma. Copyright

Proton density fat fraction (PDFF) MRI for differentiation of benign and malignant vertebral lesions

ObjectivesTo investigate whether proton density fat fraction (PDFF) measurements using a six-echo modified Dixon sequence can help to differentiate between benign and malignant vertebral bone marrow lesions.MethodsSixty-six patients were prospectively enrolled in our study. In addition to conventional MRI at 3.0-Tesla including at least sagittal T2-weighted/spectral attenuated inversion recovery and T1-weighted sequences, all patients underwent a sagittal six-echo modified Dixon sequence of the spine. The mean PDFF was calculated using regions of interest and compared between vertebral lesions. A cut-off value of 6.40% in PDFF was determined by receiver operating characteristic curves and used to differentiate between malignant (< 6.40%) and benign (≥ 6.40%) vertebral lesions.ResultsThere were 77 benign and 44 malignant lesions. The PDFF of malignant lesions was statistically significant lower in comparison with benign lesions (p < 0.001) and normal vertebral bone marrow (p < 0.001). The areas under the curves (AUC) were 0.97 for differentiating benign from malignant lesions (p < 0.001) and 0.95 for differentiating acute vertebral fractures from malignant lesions (p < 0.001). This yielded a diagnostic accuracy of 96% in the differentiation of both benign lesions and acute vertebral fractures from malignancy.ConclusionPDFF derived from six-echo modified Dixon allows for differentiation between benign and malignant vertebral lesions with a high diagnostic accuracy.Key Points• Establishing a diagnosis of indeterminate vertebral lesions is a common clinical problem• Benign bone marrow processes may mimic the signal alterations observed in malignancy• PDFF differentiates between benign and malignant lesions with a high diagnostic accuracy• PDFF of non-neoplastic vertebral lesions is significantly higher than that of malignancy• PDFF from six-echo modified Dixon may help avoid potentially harmful bone biopsy

Revised PROPELLER for T2-weighted imaging of the prostate at 3 Tesla: impact on lesion detection and PI-RADS classification

PurposeTo evaluate revised PROPELLER (RevPROP) for T2-weighted imaging (T2WI) of the prostate as a substitute for turbo spin echo (TSE).Materials and methodsThree-Tesla MR images of 50 patients with 55 cancer-suspicious lesions were prospectively evaluated. Findings were correlated with histopathology after MRI-guided biopsy. T2 RevPROP, T2 TSE, diffusion-weighted imaging, dynamic contrast enhancement, and MR-spectroscopy were acquired. RevPROP was compared to TSE concerning PI-RADS scores, lesion size, lesion signal-intensity, lesion contrast, artefacts, and image quality.ResultsThere were 41 carcinomas in 55 cancer-suspicious lesions. RevPROP detected 41 of 41 carcinomas (100%) and 54 of 55 lesions (98.2%). TSE detected 39 of 41 carcinomas (95.1%) and 51 of 55 lesions (92.7%). RevPROP showed fewer artefacts and higher image quality (each p < 0.001). No differences were observed between single and overall PI-RADS scores based on RevPROP or TSE (p = 0.106 and p = 0.107). Lesion size was not different (p = 0.105). T2-signal intensity of lesions was higher and T2-contrast of lesions was lower on RevPROP (each p < 0.001).ConclusionFor prostate cancer detection RevPROP is superior to TSE with respect to motion robustness, image quality and detection rates of lesions. Therefore, RevPROP might be used as a substitute for T2WI.Key points• Revised PROPELLER can be used as a substitute for T2-weighted prostate imaging.• Revised PROPELLER detected more carcinomas and more suspicious lesions than TSE.• Revised PROPELLER showed fewer artefacts and better image quality compared to TSE.• There were no significant differences in PI-RADS scores between revised PROPELLER and TSE.• The lower T2-contrast of revised PROPELLER did not impair its diagnostic quality.

Proton density fat fraction (PDFF) MR imaging for differentiation of acute benign and neoplastic compression fractures of the spine

ObjectivesTo evaluate the diagnostic performance of proton density fat fraction (PDFF) magnetic resonance imaging (MRI) to differentiate between acute benign and neoplastic vertebral compression fractures (VCFs).MethodsFifty-seven consecutive patients with 46 acute benign and 41 malignant VCFs were prospectively enrolled in this institutional review board approved study and underwent routine clinical MRI with an additional six-echo modified Dixon sequence of the spine at a clinical 3.0-T scanner. All fractures were categorised as benign or malignant according to either direct bone biopsy or 6-month follow-up MRI. Intravertebral PDFF and PDFFratio (fracture PDFF/normal vertebrae PDFF) for benign and malignant VCFs were calculated using region-of-interest analysis and compared between both groups. Additional receiver operating characteristic and binary logistic regression analyses were performed.ResultsBoth PDFF and PDFFratio of malignant VCFs were significantly lower compared to acute benign VCFs [PDFF, 3.48 ± 3.30% vs 23.99 ± 11.86% (p < 0.001); PDFFratio, 0.09 ± 0.09 vs 0.49 ± 0.24 (p < 0.001)]. The areas under the curve were 0.98 for PDFF and 0.97 for PDFFratio, yielding an accuracy of 96% and 95% for differentiating between acute benign and malignant VCFs. PDFF remained as the only imaging-based variable to independently differentiate between acute benign and malignant VCFs on multivariate analysis (odds ratio, 0.454; p = 0.005).ConclusionsQuantitative assessment of PDFF derived from modified Dixon water-fat MRI has high diagnostic accuracy for the differentiation of acute benign and malignant vertebral compression fractures.Key Points• Chemical-shift-encoding based water-fat MRI can reliably assess vertebral bone marrow PDFF• PDFF is significantly higher in acute benign than in malignant VCFs• PDFF provides high accuracy for differentiating acute benign from malignant VCFs

Quantitative evaluation of T2* relaxation times for the differentiation of acute benign and malignant vertebral body fractures

OBJECTIVES The aim of this prospective study was to evaluate the diagnostic performance of T2*-weighted magnetic resonance imaging (MRI) to differentiate between acute benign and neoplastic vertebral compression fractures (VCFs). MATERIALS AND METHODS Thirty-seven consecutive patients with a total of 52 VCFs were prospectively enrolled in this IRB approved study. All VCFs were categorized as either benign or malignant according to direct bone biopsy and histopathologic confirmation. In addition to routine clinical spine MRI including at least sagittal T1-weighted, T2-weighted and T2 spectral attenuated inversion recovery (SPAIR)-weighted sequences, all patients underwent an additional sagittal six-echo modified Dixon gradient-echo sequence of the spine at 3.0-T. Intravertebral T2* and T2*ratio (fracture T2*/normal vertebrae T2*) for acute benign and malignant VCFs were calculated using region-of-interest analysis and compared between both groups. Additional receiver operating characteristic analyses were performed. Five healthy subjects were scanned three times to determine the short-term reproducibility of vertebral T2* measurements. RESULTS There were 27 acute benign and 25 malignant VCFs. Both T2* and T2*ratio of malignant VCFs were significantly higher compared to acute benign VCFs (T2*, 30 ± 11 vs. 19 ± 11 ms [p = 0.001]; T2*ratio, 2.9 ± 1.6 vs. 1.2 ± 0.7 [p < 0.001]). The areas under the curve were 0.77 for T2* and 0.88 for T2*ratio, yielding an accuracy of 73% and 89% for distinguishing acute benign from malignant VCFs. The root mean square absolute precision error was 0.44 ms as a measure for the T2* short-term reproducibility. CONCLUSION Quantitative assessment of vertebral bone marrow T2* relaxation times provides good diagnostic accuracy for the differentiation of acute benign and malignant VCFs.

Prophylactically applied Hydrofilm polyurethane film dressings reduce radiation dermatitis in adjuvant radiation therapy of breast cancer patients

Abstract Purpose: Radiation-induced skin injury represents one of the most common side effects in breast cancer patients receiving adjuvant whole-breast radiotherapy. Numerous systemic and topical treatments have been studied in the prevention and management of radiation-induced skin injury without providing sustainable treatment strategies. While superficial barrier-forming skin products such as dressings are the standard of care in wound care management, their utilization as preventive treatment approach in radiotherapy has barely attracted attention. Methods: In this prospective, intra-patient randomized study, Hydrofilm polyurethane film dressings were applied prophylactically to either the medial or lateral breast half of 62 patients with breast cancer undergoing adjuvant radiation therapy following breast conserving surgery. The breast half contralateral to the film dressing was concurrently treated with 5% urea lotion as control skin care. Maximum severity of radiation dermatitis was assessed using RTOG/EORTC toxicity scores, photospectrometric erythema measurements and patient-assessed modified RISRAS scale. Results: In the Hydrofilm compartments, mean maximum RTOG/EORTC radiation dermatitis severity grades were significantly reduced from 1.33 to 0.35 and photospectrometric measurements showed significantly reduced erythema severity, as compared to the control compartments, with an overall response rate of 89.3%. Hydrofilm completely prevented moist desquamation and significantly reduced patients’ subjective experience of itching and pain. Conclusion: The obtained results along with a favorable cost–benefit ratio and an easy and quick application suggest a prophylactic application of Hydrofilm in adjuvant radiotherapy of breast cancer patients to reduce or even prevent radiation dermatitis.