Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA.

PURPOSE: The fibroblast activation protein (FAP) is an emerging target for molecular imaging and therapy in cancer. OncoFAP is a novel small organic ligand for FAP with very high affinity. In this translational study, we establish [68Ga]Ga-OncoFAP-DOTAGA (68Ga-OncoFAP) radiolabeling, benchmark its properties in preclinical imaging, and evaluate its application in clinical PET scanning. METHODS: 68Ga-OncoFAP was synthesized in a cassette-based fully automated labeling module. Lipophilicity, affinity, and serum stability of 68Ga-OncoFAP were assessed by determining logD7.4, IC50 values, and radiochemical purity. 68Ga-OncoFAP tumor uptake and imaging properties were assessed in preclinical dynamic PET/MRI in murine subcutaneous tumor models. Finally, biodistribution and uptake in a variety of tumor types were analyzed in 12 patients based on individual clinical indications that received 163 ± 50 MBq 68Ga-OncoFAP combined with PET/CT and PET/MRI. RESULTS: 68Ga-OncoFAP radiosynthesis was accomplished with high radiochemical yields. Affinity for FAP, lipophilicity, and stability of 68Ga-OncoFAP measured are ideally suited for PET imaging. PET and gamma counting-based biodistribution demonstrated beneficial tracer kinetics and high uptake in murine FAP-expressing tumor models with high tumor-to-blood ratios of 8.6 ± 5.1 at 1 h and 38.1 ± 33.1 at 3 h p.i. Clinical 68Ga-OncoFAP-PET/CT and PET/MRI demonstrated favorable biodistribution and kinetics with high and reliable uptake in primary cancers (SUVmax 12.3 ± 2.3), lymph nodes (SUVmax 9.7 ± 8.3), and distant metastases (SUVmax up to 20.0). CONCLUSION: Favorable radiochemical properties, rapid clearance from organs and soft tissues, and intense tumor uptake validate 68Ga-OncoFAP as a powerful alternative to currently available FAP tracers.

[Flat epithelial atypia]. / Flache epitheliale Atypie.

According to the WHO, flat epithelial atypia (FEA) is defined as a neoplastic epithelial proliferation of ductal type in either a single or in multiple terminal duct lobular unit(s) limited to the periphery of the ductules in a clinging growth pattern. The atypical cells may form between one and several layers of epithelial cells that show low grade cytologic atypia. FEA most often presents as mammographic microcalcifications, which are typically round (secretory type and psammomatous calcification in an eosinophilic matrix, so-called ossifying calcifications). Clinical relevance is dependent on whether the lesion appears in isolation or whether it is an excision biopsy or a minimally invasive biopsy. Currently available data suggest that the risk of subsequent breast carcinoma in the ipsilateral breast is very low following the diagnosis of FEA. The differential diagnosis should include atypical ductal hyperplasia, low-grade clinging ductal carcinoma in situ, blunt duct adenosis and apocrine metaplasia.

[Immunohistochemistry in breast pathology: differential diagnosis of epithelial breast lesions]. / Immunhistochemie in der Mammapathologie: Zur Differenzialdiagnose epithelialer Mammaläsionen.

Proliferative epithelial breast lesions include a wide variety of benign hyperplastic and noninvasive neoplastic lesions, as well as invasive carcinomas. Mammographically these lesions may show microcalcifications, architectural distortions or mass lesions. The task of the pathologist begins with a preoperative diagnosis by means of minimally invasive biopsy. His diagnosis forms the basis for not only the radiological-pathological correlation diagnosis, but also for the management of benign proliferative breast disease lesions, as well as therapeutic decisions in the case of malignant lesions.In daily practice, immunohistochemistry is the method of choice for clarifying difficult cases. The aim of this chapter is to describe the relevant markers in breast pathology and to provide an algorithmic approach to different proliferative breast disease lesions.

Rates of presurgical underestimation of breast cancer after standardized assessment of breast calcifications.

PURPOSE: To determine the frequency of histopathological underestimation of breast cancer after vacuum-assisted biopsy (VAB) in standardized assessment of breast calcifications compared to postsurgical diagnosis. MATERIALS AND METHODS: The retrospective study included acquired data of 506 consecutively examined women, who underwent VAB for the assessment of pure calcifications after standardized digital mammographic and sonographic imaging. 119/506 (24.5 %) women underwent further surgical procedures: 37 women had a surgical diagnostic excision biopsy, 82 women a surgical procedure based on a therapeutic concept. Presurgical results of VAB were compared with the postsurgical histopathological reports. RESULTS: In 91/119 women (76.5 %) the final histology was malignant. The rate of ductal carcinoma in situ (DCIS) was 79.1 % (72/91) and the rate of invasive carcinoma was 20.9 % (19/91). In 9/37 women with diagnostic excision biopsy, the presurgical status of benign or uncertain changed to a postsurgical diagnosis of malignant (24.3 %). In eight cases underestimation included DCIS (21.6 %) and in one case invasive cancer (2.7 %). Seven of the nine underestimated cases (77.8 %) resulted from excision biopsy of atypical epithelial proliferation of ductal type (AEPDT, positive predictive value 30.4 % (7/23)). After surgery due to DCIS in 7/71 women invasive breast cancer was diagnosed (9.9 %). In 11/82 women with oncological surgery, invasive cancer was already diagnosed by VAB. CONCLUSION: Underestimation of invasive cancer in terms of presurgical DCIS diagnosis can be minimized by the standardized assessment protocol to about 10 %. Underestimation of DCIS is mainly related to presurgical diagnosis of AEPDT. KEY POINTS: • The standardized use of digital mammographic and sonographic imaging prior to vacuum-assisted biopsy is suitable for minimizing underestimation of invasive breast cancer. AEPDT represents a high risk diagnosis for underestimation of DCIS.

Minimal invasive biopsy results of "uncertain malignant potential" in digital mammography screening: high prevalence but also high predictive value for malignancy.

PURPOSE: To evaluate the rate, the histological spectrum and the positive predictive value (PPV) for malignancy of minimally invasive biopsies with "uncertain malignant potential (B3)" in digital mammography screening. METHODS AND MATERIALS: Consecutive data of 37,178 participants of one digital unit of the German screening program were included. RESULTS: The B 3 rate was 15.1 % (148 / 979). The frequencies of lesion subtypes were as follows: atypical epithelial proliferation of ductal type (AEPDT) 35.1 % (52 / 148), radial scar (RS) 28.4 % (42 / 148), papillary lesions (PAP) 20.3 % (30 / 148), lobular carcinoma in situ 8.8 % (13 / 148), flat epithelial atypia 5.4 % (8 / 148), and mucocele-like lesions 2.0 % (3 / 148). The PPV for malignancy in surgical excisions was overall 0.28 (25 / 91); in detail 0.40 (19 / 47) for AEPDT, 0.20 (5 / 25) for RS, 0.08 (1 / 12) for PAP. CONCLUSION: Despite a higher B 3 rate of minimally invasive biopsies with "uncertain malignant potential" in digital screening, the benign surgical biopsy rate is not disproportionally increased compared with analog screening programs. Together with defined management protocols, this results in an increased cancer detection rate per screening participant with surgical excision.

Expression patterns of angiogenic and lymphangiogenic factors in ductal breast carcinoma in situ.

The objective of this study was to investigate expression of various growth factors associated with angiogenesis and lymphangiogenesis and of their receptors in ductal carcinomas in situ of the breast (DCIS). We studied protein expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF)-A, endothelin (ET)-1, and VEGF-C, and their receptors bFGF-R1, Flt-1, KDR, ET(A)R, ET(B)R, and Flt-4 immunohistochemically in 200 DCIS (pure DCIS: n=96; DCIS adjacent to an invasive component: n=104) using self-constructed tissue microarrays. Basic fibroblast growth factor-R1, VEGF-C, Flt-4, and ET(A)R were expressed in the tumour cells in the majority of cases, whereas bFGF and Flt-1 expression was rarely observed. VEGF-A, KDR, ET-1, and ET(B)R were variably expressed. The findings of VEGF-C and its receptor Flt-4 as lymphangiogenic factors being expressed in tumour cells of nearly all DCIS lesions and the observed expression of various angiogenic growth factors in most DCIS suggest that in situ carcinomas are capable of inducing angiogenesis and lymphangiogenesis. Moreover, we found a higher angiogenic activity in pure DCIS as compared to DCIS with concomitant invasive carcinoma. This association of angiogenic factors with pure DCIS was considerably more pronounced in the subgroup of non-high-grade DCIS (n=103) as compared with high-grade DCIS (n=94). Determination of these angiogenic markers may therefore facilitate discrimination between biologically different subgroups of DCIS and could help to identify a particularly angiogenic subset with a potentially higher probability of recurrence or of progression to invasiveness. For these DCIS, targeting angiogenesis may represent a feasible therapeutic approach for prevention of progression of DCIS to invasion.

Expression of endothelin-A-receptor predicts unfavourable response to neoadjuvant chemotherapy in locally advanced breast cancer.

Endothelin-1 (ET-1) and its receptors (ETAR and ETBR), referred to as the endothelin (ET) axis, are overexpressed in breast carcinomas and appear to influence tumour growth and progression. The objective of this study was to determine the effect of expression of the ET axis in breast carcinomas on response to cytotoxic chemotherapy. The study included 44 patients with locally advanced breast cancer participating in a prospective phase III study evaluating high-dose neoadjuvant chemotherapy of epirubicin and cyclophosphamide. Expression of ET-1, ETAR and ETBR was determined by semiquantitative immunohistochemical analysis of breast cancer tissue from prechemotherapy tru-cut biopsies. Immunohistochemical staining was positive for ET-1 in 61.5%, for ETAR in 35% and for ETBR in 35.9% of breast carcinomas. Pathological response to chemotherapy was significantly decreased in ETAR-positive patients (P=0.002). In total, 50% of ETAR-positive patients as compared to 7.7% of ETAR-negative patients attained pathologically 'no change'. Logistic regression confirmed ETAR as an independent predictive marker for pathological response (P=0.009). These data indicate that increased expression of ETAR in breast carcinomas is associated with resistance to chemotherapy. Determination of ETAR status may serve as a predictive marker for identifying patients less likely to be responsive to conventional chemotherapy.

Abordaje psicoterapéutico en el marco de la medida judicial para menores / Psychotherapeutic approach Waits the Framework of judiciary measures for ominors

El tratamiento ambulatorio es una de las medidas que pueden imponer los jueces a los menores con conductas delictivas. Este artículo propone una reflexión sobre la aplicación de estos tratamientos, partiendo de la experiencia de un programa de salud mental cuya finalidad es atender a adolescentes y jóvenes denunciados a la justicia. Se analiza como abordar cuestiones como la motivación y al vinculación frente a la imposición de la medida, su focalización y desarrollo, así como la necesidad del trabajo interdisciplinar con los equipos de Justicia Juvenil para realizarlos (AU)

One of the measures which can be imposed by Spanish juvenile courts on delinquent minors is an outpatient treatment. This paper is a reflection on the application of this kind of treatmens in a mental health service for adolescents vhoy have been reported to the juvenile justice sustem. Several relevant issues involved in theses treatments such as personal motivation and bondung facing the imposition of the mesasure, psychodynamic focus and develpment, and the need for an interdisciplinary approach, ate all examined in this paper (AU)