Treatment of cervix carcinoma FIGO IIIb with Photofrin II as a radiosensitizer: a case report.

Cervical cancer is the fourth-most common type of cancer and cause of death in women. Human papilloma virus (HPV) infection is responsible for over 90% of cervical cancers. The recommended treatment is multidisciplinary, consisting of a combination of surgery, chemotherapy, and radiation therapy. The standard treatment in advanced stages, such as FIGO IIIb, is radio-chemotherapy with overall 5-year survival of 32%. Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in both in vitro and in vivo tumor models, admitted for radiation therapy. We describe a patient with advanced cervical carcinoma (squamous cell) who contacted us for further therapy in 2003. Staging included a gynecological examination, colonoscopy, explorative laparotomy, biopsy and pelvic MRI. The explorative laparotomy showed enlarged pelvic and para-aortal lymph nodes. The histologic examination described tumor infiltrated, positive lymph nodes (Stage FIGO IIIb). Contrary to recommendations, the patient refused standard treatment with a combination of chemotherapy and radiotherapy, but accepted a combined treatment of Photofrin II as a radiosensitizer and a radiotherapy procedure. She underwent irradiation with a 50.4 + 14 Gy boost with fractionation of 1.8 Gy day-1 for 5 days per week; the boost was given with 2 Gy fractions. She was injected with a single intravenous dose in a slow infusion (30 min) of 1 mg kg-1 of Photofrin II 24 h prior to radiation therapy. A localized relapse in the cervix appeared after 30 months, and was resected by hysterectomy. The patient is still alive with no evidence of disease after 15 years.

[Urology in Munich celebrating its 80th anniversary : Memories of the establishment and development from an eyewitness]. / Die Münchner Urologie wird 80 Jahre alt : Erinnerungen eines Zeitzeugen zur Entstehungs- und Entwicklungsgeschichte.

The Department of Urology, Municipal Hospital, Thalkirchnerstr. 48, Munich (1938-1984) is justly reputed as one of the germ-cells of German Urology, not only by Prof. May's protagonism for an independent urology, but also by the multiple, especially technical innovations under the successors, which are fundamentals for the modern urology.

High immune response rates and decreased frequencies of regulatory T cells in metastatic renal cell carcinoma patients after tumor cell vaccination.

Our previously reported phase I clinical trial with the allogeneic gene-modified tumor cell line RCC-26/CD80/IL-2 showed that vaccination was well tolerated and feasible in metastatic renal cell carcinoma (RCC) patients. Substantial disease stabilization was observed in most patients despite a high tumor burden at study entry. To investigate alterations in immune responses that might contribute to this effect, we performed an extended immune monitoring that included analysis of reactivity against multiple antigens, cytokine/chemokine changes in serum and determination of the frequencies of immune suppressor cell populations, including natural regulatory T cells (nTregs) and myeloid-derived suppressor cell subsets (MDSCs). An overall immune response capacity to virus-derived control peptides was present in 100% of patients before vaccination. Vaccine-induced immune responses to tumor-associated antigens occurred in 75% of patients, demonstrating the potent immune stimulatory capacity of this generic vaccine. Furthermore, some patients reacted to peptide epitopes of antigens not expressed by the vaccine, showing that epitope-spreading occurred in vivo. Frequencies of nTregs and MDSCs were comparable to healthy donors at the beginning of study. A significant decrease of nTregs was detected after vaccination (p = 0.012). High immune response rates, decreased frequencies of nTregs and a mixed T helper 1/T helper 2 (T(H)1/T(H)2)-like cytokine pattern support the applicability of this RCC generic vaccine for use in combination therapies.

Phase 1 trial of allogeneic gene-modified tumor cell vaccine RCC-26/CD80/IL-2 in patients with metastatic renal cell carcinoma.

Preclinical studies showed that the allogeneic tumor cell line RCC-26 displayed natural immunogenic potential that was enhanced through expression of CD80 costimulatory molecules and secretion of interleukin-2. Here we report the study of RCC-26/CD80/IL-2 cells in a phase 1 vaccine trial of renal cell carcinoma patients with metastatic disease (mRCC). Fifteen patients of the HLA-A*0201 allotype, with at least one metastatic lesion, were included. Irradiated vaccine cells were applied in increasing doses of 2.5, 10, and 40 x 10(6) cells over 22 weeks. Primary study parameters included safety and toxicity. Sequential blood samples were analyzed by interferon-gamma enzyme-linked immunospot assays to detect tumor antigen-associated (TAA) effector cells. The vaccine was well tolerated and the designated vaccination course was completed in 9 of 15 patients. Neither vaccine-induced autoimmunity nor systemic side effects were observed. Delayed-type hypersensitivity skin reactions were detected in 11 of 12 evaluated patients and were particularly strong in patients with prolonged survival. In parallel, vaccine-induced immune responses against vaccine or overexpressed TAA were detected in 9 of 12 evaluated patients. No tumor regressions occurred according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria; however, median time to progression was 5.3 months and median survival was 15.6 months, indicating substantial disease stabilization. We conclude that vaccine use was safe and feasible in mRCC. Clinical benefits were limited in these patients with advanced disease; however, immune monitoring revealed vaccine-induced responses against multiple TAAs in the majority of study participants. These results suggest that this vaccine could be useful in combination therapies and/or minimal residual disease.

Photodynamic diagnosis of prostate cancer using 5-aminolevulinic acid--first clinical experiences.

OBJECTIVES: To study the feasibility of 5-aminolevulinic-acid (5-ALA)-induced photodynamic diagnosis (PDD) for the evaluation of the surgical margins (SMs) during radical prostatectomy (RP) in patients with prostate cancer (PCa). METHODS: A total of 18 patients with histologically confirmed PCa (Gleason score 4 to 8, prostate-specific antigen 1 to 20 ng/mL) underwent RP. Of the 18 patients, 16 received 5-ALA (20 mg/kg) orally 2 hours before RP, and 2 served as controls without any application of 5-ALA. To study the protoporphyrin IX (PPIX) accumulation after application of 5-ALA, all harvested specimens were investigated by fluorescence microscopy and spectroscopy. In 10 of 16 patients, PDD of the SMs and the prostate was performed during RP using an incoherent light source filtered for efficient fluorescence excitation. RESULTS: In all 16 patients, who had received 5-ALA fluorescence microscopy showed a selective accumulation of PPIX in the PCa cells, and only weak PPIX fluorescence could be detected in benign epithelial cells and none in the adjacent stroma. The 2 patients, who had not received 5-ALA had no PPIX fluorescence in the prostate. Of 10 patients, 8 demonstrated fluorescence-negative and histologically confirmed negative margins during PDD, and 1 each demonstrated a fluorescence-positive SM that was also confirmed by histologic examination and a positive SM that was not confirmed by PPD. CONCLUSIONS: This is the first report of PDD for PCa using 5-ALA. These initial results have demonstrated that PPIX is selectively enhanced in malignant tissue, an essential prerequisite of PDD. Additional studies are warranted to validate these preliminary data and the efficacy of PDD for PCa during RP.

Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma.

PURPOSE: The inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) participates in immune tolerance and tumor immune escape processes by degradation of the essential amino acid tryptophan and formation of toxic catabolites. Here, we analyzed the role of IDO in tumor growth and disease progression in patients with clear cell renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: Expression of IDO mRNA was analyzed by quantitative reverse transcription-PCR in 55 primary and 52 metastatic RCC, along with 32 normal kidneys. Western blot and immunohistochemistry analyses were used to semiquantitatively determine IDO proteins in a subset of tumor samples, in RCC cell lines, and microvessel endothelial cells. IDO expression was correlated with expression of the proliferation marker Ki67 in tumor cells and survival of patients with tumor. RESULTS: More than 75% of the clear cell RCC in comparison to normal kidney contained elevated levels of IDO mRNA, which correlated with their IDO protein content. Low IDO mRNA levels in primary tumors represented an unfavorable independent prognostic factor (hazard ratio, 3.8; P = 0.016). Unexpectedly, immunohistochemical analyses revealed that IDO is nearly exclusively expressed in endothelial cells of newly formed blood vessels and is virtually absent from tumor cells, although RCC cells could principally synthesize IDO as shown by in vitro stimulation with IFN-gamma. A highly significant inverse correlation between the density of IDO-positive microvessels and the content of proliferating Ki67-positive tumor cells in primary and metastatic clear cell RCC was found (P = 0.004). CONCLUSIONS: IDO in endothelial cells might limit the influx of tryptophan from the blood to the tumor or generate tumor-toxic metabolites, thus restricting tumor growth and contributing to survival.

Prognostic relevance of disseminated tumour cells in bone marrow of patients with transitional cell carcinoma.

OBJECTIVE: This prospective study is the first immunocytochemical investigation of the frequency and prognostic value of CK+ tumour cells in the bone marrow of patients with transitional cell carcinoma (TCC). METHODS: Bone marrow aspirates from 228 TCC patients were taken preoperatively. Cytospins were made and stained by immunocytochemistry using the monoclonal antibodies CK2 and A45-B/B3. 27 patients with no evidence of any malignant disease served as control group. RESULTS: CK+ tumour cells were detected in 28% (63/228) of the TCC patients. No CK+ cells (0/27) were detected in the control group. In multivariate analysis the detection of > or =3 CK+ cells in bone marrow was an independent prognostic factor (hazard ratio=2.7, p<0.05) in patients with T2-4 tumour classification. CONCLUSION: Disseminated CK+ cells play a role in the biology of tumour spread of TCC, and their immunocytochemical detection can be useful in assessing the prognosis of TCC patients with an invasive tumour.

Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder.

OBJECTIVES: Photodynamic diagnosis (PDD) using 5-aminolevulinic acid has proved to be a procedure with an outstanding sensitivity for the detection of transitional cell carcinoma of the bladder, in particular in the detection of flat urothelial lesions. We report on our clinical results with 875 patients (1713 PDD procedures) between March 1995 and March 2002. METHODS: A total of 1713 PDD procedures were done in 875 patients. Fluorescence imaging was performed 2 to 3 hours after instillation of 50 mL of a 3% solution of 5-aminolevulinic acid into the bladder by an incoherent light source. In total, specimens from 4630 lesions (2.7 lesions/PDD) were taken. RESULTS: In 34.8% of all biopsies, the histologic finding was malignant; 23.7% of these biopsies had been taken only because of positive fluorescence. In 28.5% of the positive biopsies, flat lesions had been identified. Also, 43.4% of carcinoma in situ and 30.7% of dysplasia II degrees were detected only by positive fluorescence. Of all tumor lesions, 92.0% were detected by PDD compared with 76.3% detected by white light endoscopy. CONCLUSIONS: PDD has proved to be an effective detection device for superficial bladder cancer.

Feasibility of photofrin II as a radiosensitizing agent in solid tumors--preliminary results.

BACKGROUND: Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in in vitro and in vivo tumor models. We aimed to investigate the feasibility of a clinical application of Photofrin II. MATERIAL AND METHODS: 12 patients were included in the study (7 unresectable solid tumors of the pelvic region, 3 malignant gliomas, 1 recurrent oropharyngeal cancer, 1 recurrent adenocarcinoma of the sphenoid sinus). The dose of ionizing irradiation was 30-50.4 Gy; a boost irradiation of 14 Gy was added for the pelvic region. All patients were intravenously injected with 1 mg/kg Photofrin II 24 h prior to the commencement of radiotherapy. Magnetic resonance imaging (MRI) controls and in some cases positron emission tomography (PET) were performed in short intervals. The mean follow-up was 12.9 months. RESULTS: No major adverse events were noted. Minor adverse events consisted of mild diarrhea, nausea and skin reactions. A complete remission was observed in 4/12 patients. A reduction in local tumor volume of >45% was achieved in 4/12 patients. Stable disease was observed in 4/12 patients. 1 patient showed local disease progression after 5 months. CONCLUSION: The early follow- up results are encouraging regarding the feasibility of the application of Photofrin II as a radiosensitizing agent.

High-level virtual reality simulator for endourologic procedures of lower urinary tract.

OBJECTIVES: To analyze the limitations of existing simulators for urologic techniques, and then test and evaluate a novel virtual reality (VR) simulator for endourologic procedures of the lower urinary tract. Surgical simulation using VR has the potential to have a tremendous impact on surgical training, testing, and certification. Endourologic procedures seem to be an ideal target for VR systems. METHODS: The URO-Trainer features genuine VR, obtained from digital video footage of more than 400 endourologic diagnostic and therapeutic procedures, as well as data from cross-sectional imaging. The software offers infinite random variations of the anatomy and pathologic features for diagnosis and surgical intervention. An advanced haptic force feedback is incorporated. Virtual cystoscopy and resection of bladder tumors were evaluated by 24 medical students and 12 residents at our department. RESULTS: The system was assessed by more than 150 international urologists with varying experience at different conventions and workshops from March 2003 to September 2004. Because of these evaluations and constant evolutions, the final version provides a genuine representation of endourologic procedures. Objective data are generated by a tutoring system that has documented evident teaching benefits for medical students and residents in cystoscopy and treatment of bladder tumors. CONCLUSIONS: The URO-Trainer represents the latest generation of endoscopy simulators. Authentic visual and haptic sensations, unlimited virtual cases, and an intelligent tutoring system make this modular system an important improvement in computer-based training and quality control in urology.

Integral spectrophotometric analysis of 5-aminolaevulinic acid-induced fluorescence cytology of the urinary bladder.

OBJECTIVE: To evaluate whether tumour cells can be detected in bladder lavage fluid samples by an objective spectrofluorometric method, as 5-aminolaevulinic acid (ALA)-induced fluorescence endoscopy (AFE) and cytology are promising valuable tools for detecting transitional cell carcinoma of the urinary bladder (TCCB). MATERIALS AND METHODS: After instilling ALA into the urinary bladder, lavage samples were collected and their sediments analysed spectroscopically under blue excitation at approximately 400 nm wavelength. During AFE, biopsies were taken. From 62 cases, 24 patients had a histologically confirmed TCCB (group A), 28 had a history of TCCB but no evidence of disease (group B) and 10 were negative for TCCB (group C). RESULTS: Lavage sediments of all patients fluoresced in the green spectral range, typical of cellular autofluorescence. Sediments of all patients of group A caused red fluorescence peaking at 635 nm, indicating protoporphyrin IX (PPIX). The PPIX signals derived from bleaching spectra were significantly different between benign and malignant findings (P = 0.001). There was another red fluorescence peak at approximately 620 nm; in 19 cases its intensity exceeded the intensity of the PPIX signal. CONCLUSIONS: Spectrofluorometric analysis of lavage sample sediments can be used to detect tumour-associated red fluorescence of PPIX in TCCB. Immediate significant and objective measurements are possible, which could be further automated for the rapid diagnosis of TCCB.

Frequency and prognostic relevance of disseminated tumor cells in bone marrow of patients with metastatic renal cell carcinoma.

BACKGROUND: The prognostic relevance of disseminated cytokeratin-positive (CK+) tumor cells in the bone marrow of patients with different types of carcinoma has been demonstrated in several studies. In this prospective study, the frequency and prognostic value of CK+ tumor cells was investigated in the bone marrow of 55 consecutive patients with metastatic renal cell carcinoma (M1 RCC) in comparison with 256 M0 RCC patients from a previous study. METHODS: Aspiration of bone marrow from the anterior iliac crest was performed immediately before tumor resection in RCC patients. Cytospins were made and stained by immunocytochemistry using the APAAP (alkaline phosphatase-antialkaline phosphatase) protocol and monoclonal antibodies CK2 and A45-B/B3. Twenty-seven patients with no evidence of any malignant disease served as a control group. RESULTS: CK+ tumor cells were detected in 42% (23 of 55 patients) of the M1 patients and 25% (63 of 256 patients) of the M0 patients (P <.01). No CK+ cells (0 of 27 patients) were detected in the control group. In the M1 group, CK- patients demonstrated a trend toward a better outcome compared with CK+ patients (log-rank test, P = .19). This difference was significant when applying a higher threshold (0-2 CK+ cells vs. > or = 3 CK+ cells; P <.05). On multivariate analysis, the detection of > or = 3 CK+ cells in the bone marrow was found to be an independent prognostic factor (P <.001). CONCLUSIONS: The results of the current study indicate that disseminated CK+ cells play a role in the biology of tumor spread of RCC, and that their immunocytochemical detection can be useful in assessing the prognosis of patients with M1 disease.

Photodynamic selectivity of 5-aminolevulinic acid to prostate cancer cells.

OBJECTIVE: To determine the selectivity of 5-aminolevulinic acid (5-ALA) as a photosensitizer to malignant prostatic cells in men undergoing radical retropubic prostatectomy. PATIENTS AND METHODS: Nineteen patients with localized prostate cancer were included in the study. Eighteen patients received 5-ALA and one patient did not receive it and was used as a control. The dose was 20mg /kg body weight, 15 patients received 5-ALA 4 hours before radical prostatectomy, two patients received it 2 hours before prostatectomy through a Ryle tube, and one patient received 5-ALA 12 hours before the operation. The removed prostates were examined for protoporphyrin IX (PpIX) fluorescence macroscopically, by fluorescence microscopy and by light microscopy. RESULTS: All carcinomas showed a clear evidence of PpIX-enrichment except in the control case. The enrichments were strong (++) in 15 cases and weak (+) in 3 cases. Two of those three cases were given 5-ALA two hours through a Ryle tube before excision of the prostate as well as the patient who was given 5-ALA 12 hours preoperatively. No PpIX enrichment was observed in the stroma of the prostate gland or in the benign tissue sections in any case (0/19). CONCLUSION: Oral 5-ALA is selectively concentrated in malignant cells of the prostate. This may lead to the clinical application of photodynamic therapy for localized prostate cancer.

[Examination of urine in the office]. / Effiziente Urindiagnostik in der Praxis. Uberlassen Sie das Feld nicht automatisch lhrer Helferin.

Urinalysis is a major basic examination that makes demands on the physician's knowledge and experience. The assessment of the color and smell already provide the doctor with important diagnostic information. For rapid orientation, test strips (pH, sugar, nitrite, bilirubin, protein, ketone bodies, urobilinogen, erythrocytes, leukocytes, etc.) and dip-slides (orientation for the presence of bacteria, semiquantitative determination) are available.

High power (80 W) potassium-titanyl-phosphate laser vaporization of the prostate in 66 high risk patients.

PURPOSE: Men with lower urinary tract symptoms secondary to benign prostatic hyperplasia who are at high cardiopulmonary risk or on oral anticoagulation are often denied surgical treatment. Potassium-titanyl-phosphate (KTP) laser vaporization at 80 W is a novel, rapidly emerging technique that promises instant hemostatic tissue ablation. We evaluated the merits of this procedure in patients at high risk and those on long-term anticoagulation. MATERIALS AND METHODS: The prospective study included 66 patients with severe lower urinary tract symptoms who underwent 80 W KTP laser vaporization of the prostate. All patients were at high cardiopulmonary risk, having presented with an American Society of Anesthesiology score of 3 or greater. Additionally, 29 patients were being treated with ongoing oral anticoagulant therapy (26) or had a severe bleeding disorder (3). RESULTS: In all 66 patients KTP laser vaporization was performed successfully. Mean preoperative prostate volume +/- SD was 49 +/- 30 ml and mean operative time was 49 +/- 19 minutes. No major complication occurred intraoperatively or postoperatively and no blood transfusion was required. Postoperatively 48 of 62 catheterized patients (77%) did not require irrigation. Average catheterization time was 1.8 +/- 1.4 days. Two patients required reoperation due to recurrent urinary retention. At 1, 3, 6 and 12 months mean urinary peak flow increased from 6.7 +/- 2 ml per second preoperatively to 18.5 +/- 9, 18.9 +/- 10, 19.2 +/- 8 and 21.6 +/- 7 ml per second, respectively. Mean International Prostate Symptom Score decreased from 20.2 +/- 6 to 11.7 +/- 7, 7.9 +/- 7, 6.9 +/- 5 and 6.5 +/- 4, respectively. CONCLUSIONS: Our initial experience indicates that 80 W KTP laser vaporization is a virtually bloodless and, hence, safe but effective treatment option in seriously ill patients or those on oral anticoagulants.

Durability of probes for interstitial laser coagulation: impact of power setting and probe design.

BACKGROUND AND PURPOSE: Interstitial laser coagulation (ILC) is a well-established treatment option for patients suffering from benign prostatic hyperplasia (BPH). The vulnerability of the current fibers adds to the high cost of the procedure. The objective was to study the impact of different time-power modes and novel probe designs on tissue effects and fiber durability. MATERIALS AND METHODS: Standardized interstitial laser (Nd:YAG) applications utilizing different fiber types and power settings were performed in vitro on fresh bovine liver in a fluid medium. The resulting effects on tissue coagulation were evaluated. Additionally, the durability of contemporary probes as well as novel designs was examined. RESULTS: High-intensity application protocols of 1750 J within 60 seconds were significantly (p < 0.001) more effective in coagulating tissue (4.22 cm3) than the 90 seconds (3.68 cm3) and 120 seconds (3.06 cm3) time-power modes but significantly (p < 0.001) decreased the durability of fibers. Prototype probes significantly improved durability (p < 0.001), whereas efficacy remained unchanged (p > 0.5). CONCLUSIONS: Using a laboratory model, we could demonstrate that high-intensity time-power settings are more effective in creating tissue coagulation in ILC. The resulting deterioration of the probes can be reduced by applying new fiber designs.

Experimental comparison of high power (80 W) potassium titanyl phosphate laser vaporization and transurethral resection of the prostate.

PURPOSE: Perioperative hemorrhage is still the major complication of standard transurethral prostate resection (TURP). Potassium titanyl phosphate (KTP) laser vaporization using 80 W is a novel technique that promises instant hemostatic tissue ablation. In this ex vivo investigation we compared the hemostatic properties of the 2 procedures. MATERIALS AND METHODS: Ex vivo, blood perfused porcine kidneys were used to verify the hemostatic efficacy of KTP laser vaporization and TURP-like tissue resection. Bleeding could be exactly quantified in relation to tissue ablation for the 2 techniques. In addition, specimens were examined microscopically. RESULTS: KTP laser vaporization demonstrated highly significantly decreased bleeding as compared to conventional tissue resection for a standardized ablation volume of 16 cm tissue (2.1 vs 23.3 ml per minute, p <0.0001). Tissue ablation was more rapid in the resection group (20 vs 100 seconds, p <0.001). Histological examinations revealed larger coagulation zones for the KTP group compared to conventional tissue resection (0.9 vs 0.6 mm, p <0.01). CONCLUSIONS: Ex vivo, 80 W KTP laser vaporization is a virtually bloodless ablative procedure, giving rise to hemostasis that is highly superior to conventional TURP-like tissue resection. However, the novel procedure is considerably more time-consuming.

Photodynamic therapy of prostate cancer by means of 5-aminolevulinic acid-induced protoporphyrin IX - in vivo experiments on the dunning rat tumor model.

OBJECTIVE: In order to expand the use of photodynamic therapy (PDT) in the treatment of prostate carcinoma (PCA), the aim of this study was to evaluate PDT by means of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPIX) in an in vivo tumor model. METHODS: The model used was the Dunning R3327 tumor. First of all, the pharmacokinetics and the localization of PPIX were obtained using fluorescence measurement techniques. Thereafter, PDT using 150 mg 5-ALA/kg b.w. i.v. was performed by homogenous irradiation of the photosensitized tumor (diode laser lambda = 633 nm). The tumors were resected 2 days post-PDT and the extent of the necrosis was determined histopathologically. RESULTS: The kinetics of PPIX fluorescence revealed a maximum intensity in the tumor tissue within 3 and 4.5 h post-application of 5-ALA. At this time, specific PPIX fluorescence could be localized selectively in the tumor cells. The PDT-induced necrosis (n = 18) was determined to be 94 +/- 12% (range 60-100%), while the necrosis of the controls (n = 12) differs significantly (p < 0.01), being less than 10%. CONCLUSION: These first in vivo results demonstrate the effective potential of 5-ALA-mediated PDT on PCA in an animal model.