[en] Purpose: High-dose-rate (HDR) brachytherapy of human lung cancer is well established, however fractionation schemes and dosages are based mainly on experience. The aim of this investigation was to study the effects of different doses of HDR iridium-192 on normal human bronchial epithelium in three-dimensional miniorgans of the human bronchial wall. Methods and Materials: Forty-eight biopsies from normal bronchi were cultivated for 14 days and exposed at random to different doses of HDR iridium 192 (0 Gy, 30 Gy, 45 Gy, 60 Gy, or 75 Gy). Cell viability was assessed immediately after irradiation, after 4 or 18 days by fluorescent staining, and cell damage of the culture was analyzed by light microscopy. Lactate dehydrogenase (LDH) was measured in the supernatant for 4 days. Results: There was no histologically apparent tissue damage regardless of the irradiation dose. The number of nonvital cells increased in irradiated miniorgans depending on the dose used (p < 0.05 at 75 Gy). This effect occurred early and was less pronounced with time. LDH measurements showed an increase only in the first 24 hours. Conclusions: Our results confirm that normal bronchial epithelium has a high tolerance to early epithelial damage by irradiation. This model of human bronchial miniorgans is useful for further studies of the effects of irradiation on human bronchi

[en] Despite improved biochemical recurrence-free survival rates by the use of immediate adjuvant radiotherapy (RT) in patients with locally advanced prostate cancer, disagreement about the need and timing of RT remains. From 2005-2009, 94 patients presenting with a stage pT3a N0 and microscopic positive resection margin were retrospectively analyzed after radical prostatectomy. Special attention was given to patients' outcome, the frequency of additive RT, and its efficacy. Median follow-up was 80 months. A total of 71 patients had a negative postoperative prostate-specific antigen (PSA) level (<0.07 ng/ml). Thirty-six of them did not experience any PSA relapse (subgroup 1). Fourteen of them received additive RT and during follow-up all 36 patients remained PSA negative. Of 71 initially PSA-negative patients, 35 had a biochemical relapse (subgroup 2); 28 patients underwent salvage RT. The median PSA value before salvage RT was 0.24 ng/ml and was subsequently negative (<0.07 ng/ml) in 23 patients after RT. Of the entire cohort, 23 patients had persisting PSA after surgery (subgroup 3). Of these, 18 patients received salvage RT at a median PSA level of 0.4 ng/ml. One patient in subgroup 1, 5 patients in subgroup 2, and 9 patients in subgroup 3 had ongoing androgen deprivation therapy. The present study of 94 pT3a N0 R1 prostate cancer patients provides insight into medical care of this patient cohort and underlines the need for additive RT for the majority of patients to achieve long-term biochemical control. Although immediate adjuvant RT was applied with restraint (20 %), during the observation period 60 of 94 patients (63.8 %) received RT - highlighting the need of postoperative treatment. (orig.)

[en] ["6"8Ga]PSMA-HBED-CC ("6"8Ga-PSMA) is a novel and promising tracer for highly sensitive combined integrated positron emission tomography and X-ray computed tomography (PET/CT) diagnosis of recurrent prostate cancer (PCA). Our aim was to assess the sensitivity, specificity, positive and negative predictive value (PPV/NPV), and accuracy per lesion, as well as the positive predictive value per patient of "6"8Ga-PSMA PET/CT using post-lymphadenectomy histology as a standard, and to compare these values to those obtained in a patient collective scanned using "1"8F-Fluoroethylcholine ("1"8FEC) PET/CT. Thirty eight patients had "1"8FEC and 28 patients had "6"8Ga-PSMA. We performed a pelvic and/or retroperitoneal lymphadenectomy, if necessary supplemented by resection of locally recurrent lesions in accordance with imaging results. In 30/38 "1"8FEC and 23/28 "6"8Ga-PSMA patients ≥1 focus of PCA was identified in postsurgical histology, leading to a per-patient PPV of 78.9 % for "1"8FEC and 82.1 % for "6"8Ga-PSMA. In "1"8FEC and "6"8Ga-PSMA patients, a total of 378 and 308 lymph nodes and local lesions were removed, respectively. For "1"8FEC and "6"8for Ga-PSMA, the respective sensitivity (95 % confidence interval) was 71.2 % (64.5-79.6 %) and 86.9 % (75.8-94.2 %), specificity was 86.9 % (82.3-90.6 %) and 93.1 % (89.2-95.9 %), PPV was 67.3 % (57.7-75.9 %) and 75.7 % (64.0-98.5 %), NPV was 88.8 % (84.4-92.3 %) and 96.6 % (93.5-98.5 %), and accuracy was 82.5 % (78.3-86.8 %) and 91.9 % (88.7 %-95.1 %). In the present series Ga-PSMA PET/CT shows a better performance than FEC PET/CT with a significantly higher NPV and accuracy for the detection of locoregional recurrent and/or metastatic lesions prior to salvage lymphadenectomy. (orig.)

[en] The inter-alpha-trypsin inhibitors (ITI) are a family of plasma protease inhibitors, assembled from a light chain – bikunin, encoded by AMBP – and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5), contributing to extracellular matrix stability by covalent linkage to hyaluronan. So far, ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis. We systematically investigated differential gene expression of the ITIH gene family, as well as AMBP and the interacting partner TNFAIP6 in 13 different human tumor entities (of breast, endometrium, ovary, cervix, stomach, small intestine, colon, rectum, lung, thyroid, prostate, kidney, and pancreas) using cDNA dot blot analysis (Cancer Profiling Array, CPA), semiquantitative RT-PCR and immunohistochemistry. We found that ITIH genes are clearly downregulated in multiple human solid tumors, including breast, colon and lung cancer. Thus, ITIH genes may represent a family of putative tumor suppressor genes that should be analyzed in greater detail in the future. For an initial detailed analysis we chose ITIH2 expression in human breast cancer. Loss of ITIH2 expression in 70% of cases (n = 50, CPA) could be confirmed by real-time PCR in an additional set of breast cancers (n = 36). Next we studied ITIH2 expression on the protein level by analyzing a comprehensive tissue micro array including 185 invasive breast cancer specimens. We found a strong correlation (p < 0.001) between ITIH2 expression and estrogen receptor (ER) expression indicating that ER may be involved in the regulation of this ECM molecule. Altogether, this is the first systematic analysis on the differential expression of ITIH genes in human cancer, showing frequent downregulation that may be associated with initiation and/or progression of these malignancies

[en] Plasminogen activator inhibitor 1 (PAI-1) overexpression is an important prognostic and predictive biomarker in human breast cancer. SERBP1, a protein that is supposed to regulate the stability of PAI-1 mRNA, may play a role in gynaecological cancers as well, since upregulation of SERBP1 was described in ovarian cancer recently. This is the first study to present a systematic characterisation of SERBP1 expression in human breast cancer and normal breast tissue at both the mRNA and the protein level. Using semiquantitative realtime PCR we analysed SERBP1 expression in different normal human tissues (n = 25), and in matched pairs of normal (n = 7) and cancerous breast tissues (n = 7). SERBP1 protein expression was analysed in two independent cohorts on tissue microarrays (TMAs), an initial evaluation set, consisting of 193 breast carcinomas and 48 normal breast tissues, and a second large validation set, consisting of 605 breast carcinomas. In addition, a collection of benign (n = 2) and malignant (n = 6) mammary cell lines as well as breast carcinoma lysates (n = 16) were investigated for SERBP1 expression by Western blot analysis. Furthermore, applying non-radioisotopic in situ hybridisation a subset of normal (n = 10) and cancerous (n = 10) breast tissue specimens from the initial TMA were analysed for SERBP1 mRNA expression. SERBP1 is not differentially expressed in breast carcinoma compared to normal breast tissue, both at the RNA and protein level. However, recurrence-free survival analysis showed a significant correlation (P = 0.008) between abundant SERBP1 expression in breast carcinoma and favourable prognosis. Interestingly, overall survival analysis also displayed a tendency (P = 0.09) towards favourable prognosis when SERBP1 was overexpressed in breast cancer. The RNA-binding protein SERBP1 is abundantly expressed in human breast cancer and may represent a novel breast tumour marker with prognostic significance. Its potential involvement in the plasminogen activator protease cascade warrants further investigation