Stefan C. Mueller

Positron emission tomography in the clinical staging of patients with Stage I and II testicular germ cell tumors.

OBJECTIVES To evaluate the accuracy of fluorodeoxyglucose positron emission tomography (PET) compared with computed tomography (CT) staging in patients with Stage I and II testicular germ cell tumors (GCTs). METHODS From January 1995 to July 1997, in 37 patients with clinical Stage (CS) I (n = 25) and CS II (n = 12) GCT (24 nonseminomas, 13 seminomas), PET and CT were compared in the initial staging. After PET, the patients with nonseminomatous GCT were staged surgically by retroperitoneal lymph node dissection and the patients with seminomatous GCT were followed up clinically. RESULTS Correct staging by PET was achieved in 34 of 37 patients compared with correct CT staging in 29 of 37 patients. Of 10 metastatic lesions, 7 and 4 were detected by PET and CT, respectively. PET did not show false-positive signals. PET was unable to detect vital cancer with a maximal diameter less than 0.5 cm or teratoma at any size. CONCLUSIONS PET was useful for detecting viable tumor in lesions that are visible on CT scan and, thus, it may omit false-positive CS II lesions. However, PET was not able to identify mature teratoma. In this study, PET did not improve the staging in patients with CS I tumor.

Noncancerous PTGS2 DNA fragments of apoptotic origin in sera of prostate cancer patients qualify as diagnostic and prognostic indicators

Our study was designed to evaluate Cell‐Free DNA in sera of prostate cancer (PCA) patients as a useful biomarker. Real‐time PCR was used to amplify a <200 bp PTGS2 DNA fragment that biochemically characterizes apoptosis and a larger >250 bp Reprimo DNA fragment that defines mostly other cell death entities. The apoptosis index (AI) expresses the ratio of PTGS2 to Reprimo DNA fragments. GSTP1 hypermethylation was assessed to evaluate the amount of tumor‐derived DNA. We analyzed serum of 216 patients (168 PCA; 5 incidental PCA; 42 benign prostatic hyperplasia (BPH); 11 healthy individuals). Distinctly elevated concentrations of PTGS2 fragments were detected in PCA compared to BPH and healthy individuals (median: 70.2, 10.5 and 7.1 ng/ml, respectively; p < 0.0001). The AI was significantly increased in PCA vs. BPH patients and healthy individuals (6.01 vs. 1.54 and 0.84 respectively; p = 0.002–0.0001). GSTP1 hypermethylation was only present in a small percentage (mean 1.92%) of circulating DNA. Concentrations of apoptotic PTGS2 fragments discriminated sensitively (88%) and specifically (64%) between BPH and PCA, whereas the AI was more specific (82%) but less sensitive (70%). The AI correlated with histological grading (p = 0.044). Kaplan–Meier analysis for a subset of 124 patients revealed a significant correlation between apoptotic PTGS2 fragments or the AI and PSA recurrence following radical prostatectomy (p = 0.0395–0.0482). In conclusion, circulating PTGS2 fragments of apoptotic origin and the AI are promising serum biomarkers for the diagnosis and prognosis of PCA. We suggest that cancer‐induced apoptosis of peripheral noncancerous tissues is relevant in many malignancies.

Cell-Free Circulating DNA: Diagnostic Value in Patients With Testicular Germ Cell Cancer

PURPOSE Increased levels of cell-free circulating DNA have been described in various malignancies as a diagnostic and prognostic biomarker. We analyzed the significance of cell-free DNA in patients with testicular cancer. MATERIALS AND METHODS Cell-free DNA was isolated from the serum of 74 patients with testicular cancer, including 39 with seminoma and 35 with nonseminoma, and 35 healthy individuals. Real-time polymerase chain reaction was used to quantify a 106, a 193 and a 384 actin-beta DNA fragment. DNA integrity is expressed as the ratio of large (193 or 384 bp) to short (106 bp) DNA fragments. RESULTS Actin-beta-106/193/384 fragment levels were significantly increased in patients with cancer compared to those in healthy individuals (each p <0.001). DNA integrity was significantly decreased in patients with cancer (p <0.001). Cell-free DNA fragment levels were not different when comparing patients with nonseminoma and seminoma (p >0.24). ROC analysis demonstrated that cell-free DNA levels distinguished patients with cancer from healthy individuals with 87% sensitivity and 97% specificity. Even in 31 patients in whom the established serum tumor markers alpha-fetoprotein, human chorionic gonadotropin, placental alkaline phosphatase and lactate dehydrogenase were normal cell-free DNA levels allowed us to distinguish between patients with cancer and healthy individuals with 84% sensitivity and 97% specificity. Cell-free DNA levels were more frequently increased in patients with clinical stage 3 than in patients with stage 1 or 2 disease (p <0.046). CONCLUSIONS Cell-free DNA levels are increased in patients with testicular cancer and they allow the accurate discrimination of healthy individuals. The high sensitivity of cell-free DNA could facilitate the management of testicular cancer, especially in patients with conventional tumor markers that are not increased.

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer.

Superantigens are potent activators of T lymphocytes; therefore, their characteristics can be exploited in diseases where immunomodulation is known to be effective. In this study, we evaluated a new approach for the intravesical therapy of superficial bladder cancer. We investigated in coculture experiments if staphylococcal enterotoxin B (SEB)–activated PBMCs are able to induce apoptosis in human transitional cell carcinoma (TCC) cells. Additionally, we tested the toxicity and efficacy of SEB dissolved in NaCl 0.9% administered intravesically once weekly for 6 weeks in a rat bladder cancer model. To validate the coculture in vitro findings, we evaluated tumor stage, grade, apoptotic cells in the urothelium and stroma of the bladder and infiltration of the bladder wall by lymphocytes, macrophages and mononuclear cells. Coculture experiments revealed that SEB‐activated PBMCs are able to kill TCC cells by inducing apoptosis. The intravesical toxicity study with a maximum dose of 100 μg/ml SEB demonstrated no side effects. In the intravesically SEB‐treated animals (10 μg/ml), only 3 tumors remained vs. 15 persisting tumors in the control group. The remaining tumors of the therapy group showed a significant amount of apoptosis and granulocytes, mainly in the urothelium, whereas no relevant apoptosis or infiltration of the bladder with lymphocytes or macrophages was found in the control group. These preclinical findings suggest that SEB might be an interesting candidate for further clinical evaluation.

Bladder cancer cells acquire competent mechanisms to escape Fas-mediated apoptosis and immune surveillance in the course of malignant transformation

Mechanisms of resistance against Fas-mediated cell killing have been reported in different malignancies. However, the biological response of immune escape mechanisms might depend on malignant transformation of cancer cells. In this study we investigated different mechanisms of immune escape in 2 well-differentiated low-grade (RT4 and RT112) and 2 poorly differentiated high-grade (T24 and TCCSUP) bladder cancer cell lines. Fas, the receptor of Fas-ligand, is expressed and shedded by human transitional bladder carcinoma cell lines RT4, RT112, T24 and TCCSUP. Cytotoxicity and apoptosis assays demonstrate that in spite of the Fas expression, poorly differentiated T24 and TCCSUP cells are insensitive towards either recombinant Fas-ligand or agonistic apoptosis-inducing monoclonal antibody against Fas. In poorly differentiated T24 and TCCSUP cell lines we were able to detect marked Fas-ligand protein by flow cytometry and Western blot analysis. In grade 1 RT4 and RT112 cells only minor expression of Fas-ligand possibly because of proteinase action. Fas-ligand mRNA translation or post-translational processing seems to be regulated differentially in the cancer cell lines depending on malignant transformation. In co-culture experiments we show that poorly differentiated cells can induce apoptosis and cell death in Jurkat cells and activated peripheral blood mononuclear cells. This in vitro study suggests that bladder cancer cells can take advantage of different mechanisms of immune evasion and become more competent in avoiding immune surveillance during transformation to higher-grade malignant disease.

Transrenal Ureter Occlusion with an Amplatzer Vascular Plug

The Amplatzer vascular plug has been used as an embolic device in a variety of cardiovascular interventions. The present report describes successful transrenal ureter occlusion with an Amplatzer plug inserted into an excised latex cover. The procedure led to immediate ureter occlusion in a patient with vesicovaginal fistula. Further investigation into the use of this technique for ureteral occlusion is warranted.

Distribution of neuropeptide Y-containing nerves in the neurogenic and non-neurogenic detrusor

To evaluate the role of neuropeptide Y in the detrusor of patients with neurogenic detrusor overactivity (NDO), as it has an important role in the neural regulation of the lower urinary tract by exerting differential effects on the release of cholinergic and adrenergic transmitters via autoinhibition and heterosynaptic interactions

A cohort compassionate-use program with cabazitaxel plus prednisone for patients with metastatic castration-resistant prostate cancer: Interim results.

172 Background: In the Phase III TROPIC trial ( NCT00417079 ), cabazitaxel/prednisone (CbzP) improved overall survival compared with mitoxantrone/prednisone in patients (pts) with mCRPC who had progressed on or after prior docetaxel (D) (HR 0.70; P < 0.0001). The survival benefit observed supported the establishment of 2 programs (based on local regulations): a compassionate use (CUP) and an early access program (EAP) ( NCT01254279 ). METHODS The aims of both programs are to provide drug to pts with mCRPC who may benefit from CbzP prior to commercial availability, and further evaluate CbzP safety profile. Total enrollment for both programs is targeted to be 1,600 pts from 250 centers in Europe, Asia, Latin America and Canada. Eligible pts will receive CbzP (25 mg/m2 Q3W plus oral prednisone 10 mg daily) until disease progression, death, unacceptable toxicity or physician/pt decision. RESULTS Baseline characteristics and safety data are available for the first 399 pts. Median age was 68 yrs (range 43-89); 90.2% were ECOG PS 0-1. Median cumulative dose of prior D was 675 mg/m2 (median 9 cycles). For pts whose disease progressed following D, the median time from last dose of D to progression was 4 months; 53.3% of pts experienced disease progression either during or < 3 months after D. 61% of pts had ≥ 2 metastatic sites; the most common were bone (93.2%) and regional lymph nodes (34.4%). A median of 4 cycles of CbzP was administered and 4 pts received ≥ 10 cycles. Median relative dose intensity was 99.2% (range 80.1-104.9). G-CSF was administered to 34.3% of pts in Cycle 1 (6.3% therapeutic, 26.6% prophylactic). Overall, 71.4% of pts experienced adverse events (AEs) (all grades) considered related to study drug. The most common Grade 3-4 AEs included neutropenia 11.3%, febrile neutropenia 6.3%, anemia 2.8%, fatigue 2%, neutropenic sepsis 1.8%, vomiting 1.3% and diarrhea 1%. 8 (2%) treatment-related deaths were reported. CONCLUSIONS The CUP/EAP programs provide additional safety data for CbzP in a routine clinical practice population of pts with mCRPC. Treatment with CbzP was tolerable, with a manageable toxicity profile consistent with the data reported for the TROPIC trial.