α-Particle-induced DNA damage tracks in peripheral blood mononuclear cells of [223Ra]RaCl2-treated prostate cancer patients.

PURPOSE: One therapy option for prostate cancer patients with bone metastases is the use of [223Ra]RaCl2. The α-emitter 223Ra creates DNA damage tracks along α-particle trajectories (α-tracks) in exposed cells that can be revealed by immunofluorescent staining of γ-H2AX+53BP1 DNA double-strand break markers. We investigated the time- and absorbed dose-dependency of the number of α-tracks in peripheral blood mononuclear cells (PBMCs) of patients undergoing their first therapy with [223Ra]RaCl2. METHODS: Multiple blood samples from nine prostate cancer patients were collected before and after administration of [223Ra]RaCl2, up to 4 weeks after treatment. γ-H2AX- and 53BP1-positive α-tracks were microscopically quantified in isolated and immuno-stained PBMCs. RESULTS: The absorbed doses to the blood were less than 6 mGy up to 4 h after administration and maximally 16 mGy in total. Up to 4 h after administration, the α-track frequency was significantly increased relative to baseline and correlated with the absorbed dose to the blood in the dose range < 3 mGy. In most of the late samples (24 h - 4 weeks after administration), the α-track frequency remained elevated. CONCLUSION: The γ-H2AX+53BP1 assay is a potent method for detection of α-particle-induced DNA damages during treatment with or after accidental incorporation of radionuclides even at low absorbed doses. It may serve as a biomarker discriminating α- from ß-emitters based on damage geometry.

Improved cancer detection in Waldeyer's tonsillar ring by 68Ga-FAPI PET/CT imaging.

PURPOSE: In cancer of unknown primary (CUP), positron emission tomography/computed tomography (PET/CT) with the glucose analog [18F]FDG represents the standard imaging approach for localization of the malignant primary. Frequently, however, [18F]FDG PET/CT cannot precisely distinguish between small occult tumors and chronic inflammation, especially in Waldeyer's tonsillar ring. To improve the accuracy for detecting primary tumors in the Waldeyer's tonsillar ring, the novel PET tracer [68Ga]Ga-FAPI-4 for specific imaging of fibroblast activation protein (FAP) expression was used as a more specific target for cancer imaging. METHODS: Eight patients with suspicion of a malignant tumor in Waldeyer's tonsillar ring or a CUP syndrome were examined. PET/CT scans with [18F]-FDG and [68Ga]Ga-FAPI-4 were performed for pre-operative tumor localization. After surgical resection, histopathological and immunohistochemical results were compared to PET/CT findings. RESULTS: Histopathology revealed a palatine or lingual tonsil carcinoma in all patients. In case of lymph node metastases smaller than 7 mm in size, the [18F]FDG PET/CT detection rate of cervical lymph node metastases was higher than that of [68Ga]FAPI PET/CT, while both tracers identified the primary tumors in all eight cases. The size of the primary and the lymph node metastases was directly correlated to the respective FAP expression, as detected by immunohistochemistry. The mean SUVmax for the primary tumors was 21.29 ± 7.97 for 18F-FDG and 16.06 ± 6.29 for 68Ga-FAPI, respectively (p = 0.2). The mean SUVmax for the healthy contralateral tonsils was 8.38 ± 2.45 for [18F]FDG and 3.55 ± 0.47 for [68Ga]FAPI (p < 0.001). The SUVmax ratio of [68Ga]FAPI was significantly different from [18F] FDG (p = 0.03). Mean TBRmax for the [68Ga]Ga-FAPI-4 tracer was markedly higher in comparison to [18F]FDG (10.90 vs. 4.11). CONCLUSION: Non-invasive imaging of FAP expression by [68Ga]FAPI PET/CT resulted in a better visual detection of the malignant primary in CUP, as compared to [18F]FDG imaging. However, the detection rate of lymph node metastases was inferior, presumably due to low FAP expression in small metastases. Nevertheless, by offering a detection method for primary tumors with the potential of lower false positive rates and thus avoiding biopsies, patients with CUP syndrome may benefit from [68Ga]FAPI PET/CT imaging.

[Diagnostics in osteology]. / Diagnostik in der Osteologie.

Clinical diagnostics in metabolic bone diseases cover a broad spectrum of conventional and state of the art methods ranging from the medical history and clinical examination to molecular imaging. Patient treatment is carried out in an interdisciplinary team due to the multiple interactions of bone with other organ systems. Diagnosis of osteoporosis is supported by high level national guidelines. A paradigm shift concerning the clinical relevance of bone mineral density measurement renders this now to be a strong risk factor rather than a diagnostic parameter, while strengthening the value of other clinical factors for risk assessment. The impact of parameters for muscle mass, structure and function is steadily increasing in all age groups. In order to identify underlying diseases that influence bone metabolism a panel of general laboratory diagnostic parameters is recommended. Markers for bone formation and resorption and specific parameters for the regulation of calcium and phosphate metabolism should be evaluated by specialists because they require diligence in preanalytics and experience in interpretation. Genetic diagnosis is well established for rare bone diseases while diagnostic panels are not yet available for routine diagnostics in polygenetic diseases such as osteoporosis. Conventional radiology is still very important to identify, e. g. fractures, osteolytic and osteoblastic lesions and extraosseous calcifications; however tomography-based methods which combine, e. g. scintigraphy or positron emission technologies with anatomical imaging are of increasing significance. Clinical diagnostics in osteology require profound knowledge and are subject to a dynamic evolution.

Decision making for osteoporotic treatment using FRAX or DVO risk algorithms in a clinical setting.

OBJECTIVES: To evaluate the therapy decisive clinical risk factors (CRFs) in tools provided by WHO (WHO-FRAX) and the Head Osteology Organization of Germany (DVO) in a clinical setting, and, the degree of agreement between them. METHODS: Three hundred subjects, 40 to 88 years of age, were consecutively referred for an evaluation of osteoporosis-related fracture risk, and therapy was possibly recommended. The evaluation used the 12 CRFs in the FRAX tool and the 21 CRFs in the DVO tool. We analyzed the degree of agreement and the strength of the CRFs in determining the therapy decision. RESULTS: Before evaluation, 52 (17.3%) of the patients took anti-osteoporotic medication. The FRAX tool indicated 36 (12.0%) patients suggested for treatment when hip density was included as a CRF, whereas the DVO tool indicated 80 (26.7%) and 91(30.3%), depending on bone density site. The pre- and post-test results agreed poorly to fair, whereas agreement was poor to good within both models and using the plain T-score to define the therapy intervention threshold. CONCLUSIONS: CRFs with debatable evidence reached significant influence on therapy decision. A considerably divergent number of patients were identified as treatment candidates, deserving further investigation to confirm the usefulness of some CRFs.

Thyroglobulin fluctuations in patients with iodine-refractory differentiated thyroid carcinoma on lenvatinib treatment - initial experience.

Tyrosine kinase inhibitors (TKI) have shown clinical effectiveness in iodine-refractory differentiated thyroid cancer (DTC). The corresponding role of serum thyroglobulin (Tg) in iodine-refractory DTC has not been investigated yet. 9 patients (3 female, 61 ± 8y) with progressive iodine-refractory DTC starting on lenvatinib were considered. Tumor restaging was performed every 2-3 months including contrast-enhanced computed tomography (CT, RECIST 1.1). Serum Tg was measured and compared to imaging findings. After treatment initiation, serum Tg levels dropped in all patients with a median reduction of 86.2%. During long-term follow-up (median, 25.2 months), fluctuations in Tg could be observed in 8/9 subjects. According to RECIST, 6/9 subjects achieved a partial response or stable disease with the remaining 3/9 experiencing progressive disease (2/3 with Tg levels rising above baseline). All of the patients with disease progression presented with a preceding continuous rise in serum Tg, whereas tumor marker oscillations in the subjects with controlled disease were only intermittent. Initiation of lenvatinib in iodine-refractory DTC patients is associated with a significant reduction in serum Tg levels as a marker of treatment response. In the course of treatment, transient Tg oscillations are a frequent phenomenon that may not necessarily reflect morphologic tumor progression.

Prognostic Value of Serum Tumor Markers in Medullary Thyroid Cancer Patients Undergoing Vandetanib Treatment.

Tyrosine kinase inhibitors (TKIs) such as vandetanib have shown clinical effectiveness in advanced medullary thyroid cancer (MTC). During TKI treatment, fluctuations in the tumor markers carcinoembryonic antigen (CEA) and calcitonin (CTN) are frequently observed. Their role for treatment monitoring and the decision-making process has not been fully elucidated yet.Twenty-one patients (male, 16, female, 5; mean age, 49 ±â€Š13 years) with progressive MTC receiving vandetanib (300 mg orally per day) were considered. Tumor restaging was performed every 3 months including contrast-enhanced computed tomography (CT). Response was assessed according to recent criteria (Response Evaluation Criteria in Solid Tumors, RECIST 1.1). Additionally, CEA and CTN were measured at the day of CT imaging and alterations observed in tumor markers were compared to respective imaging findings (partial response, PR; stable disease, SD; progressive disease, PD).During long-term follow-up (510 ±â€Š350 days [range, 97-1140 days]), CTN and CEA levels initially dropped in 71.4% and 61.9% of the patients followed by fluctuations in serum marker levels. A rise in CTN ≥39.5% between 2 subsequent measurements (defined by ROC analysis) had a sensitivity of 70.6% and a specificity of 83.2% in predicting PD with an accuracy of 82.0% (area under the curve (AUC), 0.76). Oscillations in CEA levels were not predictive for PD.Whereas tumor marker fluctuations in MTC patients undergoing TKI treatment are a frequent phenomenon, a significant rise in CTN ≥40% turns out to as an early indicator of tumor progression.

Surgery for endomyocardial fibrosis revisited.

OBJECTIVE: To identify life expectancy after surgery for endomyocardial fibrosis (EMF) and the events that influence it. METHODS: Eighty-three patients with EMF underwent endocardial decortication and atrioventricular valve replacement or repair, between December 1977 and December 1997. There were 66 (79.6%) female and 17 (20.4%) male patients, ranging in age from 4 to 59 years (mean, 31). Thirty-seven (44.5%) had biventricular disease, 34 (41.0%) had disease of the right ventricle alone and 12 (14.5%) had EMF confined to the left ventricle. All were in functional class III or IV (New York Heart Association classification). RESULTS: Sixty-eight (81.9%) patients survived the operation and were followed up for periods ranging from 2 months to 17 years. The total follow-up time was 6290 patient/months (mean, 92 months). There were 15 late deaths, but in six, the cause was not related to the underlying disease. Four (5.8%) patients presented recurrence of the fibrosis and were reoperated on and in six (8.8%), EMF appeared in the other ventricle. Five (7.3%) patients were reoperated on to replace either a valve prosthesis or a native valve which had been preserved during the first procedure. Only 24 (45%) of the 53 surviving patients are in functional class I or II. The actuarial probability of survival at 17 years, including operative mortality, was 55%. CONCLUSION: Surgical treatment of EMF should be considered a palliative procedure because surgery does not alter the progressive nature of the disease. However, surgical therapy is recommended for patients with EMF and heart failure as it is their only hope of survival.