Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial.

PURPOSE: To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS: From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. RESULTS: Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. CONCLUSION: Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.

Combined PET/MRI improves diagnostic accuracy in patients with prostate cancer: a prospective diagnostic trial.

PURPOSE: The pretherapeutic assessment of prostate cancer is challenging and still holds the risk of over- or undertreatment. This prospective trial investigates positron emission tomography (PET) with [(18)F]fluoroethylcholine (FEC) combined with endorectal magnetic resonance imaging (MRI) for the assessment of primary prostate cancer. EXPERIMENTAL DESIGN: Patients with prostate cancer based on needle biopsy findings, scheduled for radical prostatectomy, were assessed by FEC-PET and MRI in identical positioning. After prostatectomy, imaging results were compared with histologic whole-mount sections, and the PET/MRI lesion-based semiquantitative FEC uptake was compared with biopsy Gleason scores and postoperative histology. RESULTS: PET/MRI showed a patient-based sensitivity of 95% (36/38; 95% confidence interval (CI), 82%-99%). The analysis of 128 prostate lesions demonstrated a sensitivity/specificity/positive predictive value/negative predictive value/accuracy of 67%/35%/59%/44%/54% (P = 0.8295) for MRI and 85%/45%/68%/69%/68% (P = 0.0021) for PET, which increased to 84%/80%/85%/78%/82% (P < 0.0001) by combined FEC-PET/MRI in lesions >5 mm (n = 98). For lesions in patients with Gleason >6 tumors (n = 43), MRI and PET achieved 73%/31%/71%/33%/60% (P = 1.0000) and 90%/62%/84%/73%/81% (P = 0.0010), which were improved to 87%/92%/96%/75%/88% (P < 0.0001) by combined PET/MRI. Applying semiquantitative PET analysis, carcinomas with Gleason scores >6 were distinguished from those with Gleason ≤ 6 with a specificity of 90% and a positive predictive value of 83% (P = 0.0011; needle biopsy 71%/60%, P = 0.1071). CONCLUSIONS: In a prospective diagnostic trial setting, combined FEC-PET/MRI achieved very high sensitivity in the detection of the dominant malignant lesion of the prostate, and markedly improved upon PET or MRI alone. Noninvasive Gleason score assessment was more precise than needle biopsy in this patient cohort. Hence, FEC-PET/MRI merits further investigation in trials of randomized, multiarm design.

Testis cancer cells have a genetic determination for a high sensitivity to apoptosis inducing stimuli.

OBJECTIVE: The effect of cytotoxic therapy in testicular tumors (TGCT) has been shown to be mediated mainly by the induction of apoptosis. So far, it is not known which genes play a role for this inherent sensitivity to apoptosis inducing drugs. The aim of this study was to investigate the differential gene expression of apoptosis regulating genes in testicular tumors and in normal testis tissue using a quantitative method. As a premature S-phase entry was shown to induce apoptosis, genes controlling the G1/S-phase checkpoint were also investigated. MATERIAL AND METHODS: Gene expression levels of a representative subset of 19 genes involved in apoptosis and cell cycle control were investigated in vivo in 19 TGCTs using real-time quantitative PCR. Measurements were performed in tumor tissues of both tumor entities, seminomatous and non-seminomatous tumors (SGCT and NSGCT), and in corresponding biopsies from the unaffected site of the resected testis. RESULTS: There was an up-regulation of genes that play a role in facilitating apoptosis, such as FasL, TRAIL, and Bax in both tumor entities. Genes inhibiting apoptosis, such as Bcl-2 were predominantly down-regulated. Regarding cell cycle regulators, a gene expression profile was found that corresponds to a premature S phase entry and subsequent apoptosis induction. CONCLUSION: This study for the first time identified in vivo a panel of genes that give TGCT an inherent sensitivity to apoptotic stimuli after exposure to DNA damaging agents. Studies on these genes in therapy-refractory cancers should provide further insight into the mechanisms of chemotherapy resistance. Furthermore, these genes are promising targets for a future targeted therapy of testis cancer.

Apoptosis: a key effector mechanism of lymphocyte action in human nonseminomatous testicular carcinoma?

OBJECTIVE: To correlate the number of tumour-infiltrating T lymphocytes (TILs) with the extent of apoptosis in testicular germ cell tumours, as TILs are considered to be a favourable prognostic factor of human testicular tumours, especially of seminomas, but the mechanism by which TIL contribute to an improved outcome is unclear. MATERIALS AND METHODS: Tissue samples from 47 patients with nonseminomatous germ cell tumour (NSGCT) and 15 with seminomatous GCT were investigated immunohistochemically for lymphocyte infiltration and apoptosis. The apoptotic index (AI) was assessed in various categories (DNA condensation and fragmentation) using in-situ end-labelling to identify typical apoptotic DNA strand breaks, and nuclear staining to identify typical apoptotic morphology. RESULTS: In seminomatous GCT there was no correlation between the number of TILs and any AI. In NSGCT there was only a relationship between lymphoid infiltration and those AIs showing morphological criteria of apoptosis in a small subgroup of NSGCT, i.e. metastasized embryonal cell carcinomas. Only 1.2% (AI, chromatin condensation) and 0.8% (AI, fragmentation and condensation) of all tumour cells showed these features of apoptosis. The overall AI in NSGCT was 7.9%. CONCLUSIONS: TILs do not seem to induce apoptosis in testicular tumours. Embryonal cell carcinomas might be susceptible to lymphocyte attack, resulting in apoptosis of the tumour cell. The mechanisms of interaction between lymphocytes and testis tumour cells need further investigation.

Imaging studies in the diagnosis of urogenital trauma.

UNLABELLED: Polytraumatized patients often present with urological injuries. After hemodynamic stability is maintained urologists are consulted to evaluate diagnostic and therapeutic interventions. The following article describes how to handle the work-up of patients with injuries to specific urogenital organs: the importance of clinical examination, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), angiography as well as organ-specific radiologic studies such as intravenous pyelography or cystography are discussed. CONCLUSION: Even though injuries to the urogenital tract are rarely initially life--threatening, a fast, reliable and adequate diagnostic algorithm has to be established to avoid any delay of specific treatment. Urologists should be familiar with the indications, range and accuracy of these procedures in the diagnosis of urogenital trauma.

Comparative analysis of different apoptosis detection methods in human testicular cancer.

In situ end-labeling (ISEL) of internucleosomal 3' DNA strand breaks and the morphological proof of nuclear chromatin condensation are two widely used methods to investigate and quantify apoptosis. However, it is still unclear whether both processes are linked with each other and if quantifying apoptosis by both methods leads to comparable results. Therefore, internucleosomal DNA fragmentation and chromatin condensation were measured simultaneously on double-fluorescence-labeled sections of 62 testicular tumors (47 nonseminomatous tumors and 15 seminomas) using immunofluorescence microscopy. Different apoptotic indices (AI), based on DNA fragmentation and/or morphological criteria were determined. The AI were quantified. Morphologically obtained AI ranged between 1.99% for non-seminomatous tumors and 0.88% for seminomas. The detection of DNA fragmentation values ranged between 8.15% for non-seminomatous tumors and 2.70% for seminomas. Only about 30% of all apoptotic cells could be detected with the morphological method compared to 80% using ISEL in both tumor entities. Therefore, the equivalence of investigations using different apoptosis detection methods in human testicular cancer seems questionable.

Fas/Fas ligand system and apoptosis induction in testicular carcinoma.

BACKGROUND: Tumor-infiltrating, Fas ligand (FasL)-expressing lymphocytes are able to eliminate Fas-bearing tumor cells by apoptosis induction. Activated cytotoxic T-cells that express Fas may enter apoptosis in the presence of FasL tumor cells. To date, no studies of patients with testicular carcinoma have correlated the differential expression of Fas and FasL in both cell types with the corresponding apoptotic index (AI). METHODS: Fas and FasL were investigated immunohistochemically in paraffin embedded tissue sections from 25 patients with nonseminomatous testicular tumors. The percentages of positive cells and the ratios of Fas cells to FasL cells were correlated with the AI of tumor cells and lymphocytes, respectively, using Spearman correlations. RESULTS: No association was found between the rate of FasL positive cells and AI of the other cell type or between the rate of Fas positive cells and the AI of the same cell type. Ratios between Fas positive cells and FasL positive cells were not correlated with the AI; however, a significant positive correlation was found between the AI of tumor cells and the AI of lymphocytes. CONCLUSIONS: It seems unlikely that the Fas/FasL system is responsible for immune escape of the tumor in testicular carcinoma. Rather, the significant positive correlation between the AIs of tumor cells and lymphocytes implicate a previously unknown mechanism of apoptosis induction in both cell types.