[On the practice of therapy decision in locally limited prostate cancer: surgery vs. radiation-who benefits? : Allocation and results of a monocentric, cumulative long-term study]. / Zur Praxis der Therapieentscheidung beim lokal begrenzten Prostatakarzinom: Operation vs. Bestrahlung ­ wer profitiert? : Allokation und Ergebnisse einer unizentrischen, kumulativen Langzeitstudie.

AIM: The goal of this two-armed observational study was to map the clinical therapy effectiveness of radical prostatovesiculectomy (RPVE) and external beam radiation therapy (EBRT) in locally limited prostate cancer (PCA) in direct comparison over 20 years under clinical conditions. Retrospectively, the various variables and predictors for the individual therapy decision were identified, and the preference was to compared with studies on survival and recurrence characteristics. The presentation of toxicity was not the focus of this work. METHODOLOGY: In all, 743 patients from a single center were enrolled according to biopsy/staging chronologically in the sequence of the initial consultation after clarification and informed consent: 494 patients were in the RPVE arm and 249 patients in the EBRT arm. We used retrospective data analysis with univariate and multivariate comparisons in the alternative therapy arms. Multivariate logical regression models were developed to objectify the allocation process. Univariate processing of survival analyses, the comparison of tumor- and comorbidity-specific mortality rates was co-founded. RESULTS: Predictive variables for RPVE vs. EBRT therapy decision are significantly age, Gleason score, D'Amico index, Charlson index, prostate-specific antigen (PSA), and prostate volume. There was no significance level for the biopsy score. The age gap was in the median 67 (RPVE) and 73 (EBRT) years. Overall survival (n = 734, 20 years, all risks) in the RPVE arm was 56.8% (95% confidence interval [CI] 45.1-67.0%) and in the EBRT arm 19.2% (95%CI 9.2-31.8%). Comorbid risk was highly significantly (p < 0.0001) different (27.1% [95%CI 18.0-36.1%] in the RPVE arm, and 60.4% [95%CI 47.3-73.5%] in the EBRT arm). The risk of tumor-specific death at 16.2% (95%CI 8.1-24.4%) after RPVE and 20.5% (95%CI 11.7-29.3%) after EBRT was not significantly different (p = 0.2122, overlapping 95%CI). After stratification, a clear advantage can be demonstrated for the high-risk tumors after allocation to the RPVE arm. CONCLUSIONS: The complexity of the predictive variables of the PCA further complicates the individual therapy decision. According to our data, the higher D'Amico score, the rather low Charlson index, a high Gleason score and a higher organ volume speak for a valid therapy for RPVE.

[Modern nephrolithiasis in the complex setting of metaphylaxis : Latest epidemiological data and a nationwide survey in private practices]. / Die Nephrolithiasis im komplexen Metaphylaxesystem heute : Epidemiologische Daten zur Prävalenz und Resultate einer deutschlandweiten Praxisumfrage.

The focus of this work is on aspects of the current management of recurrent nephrolithiasis in private practices and outpatient departments in Germany. We wanted to make a contribution to the epidemiological discourse as well as for an instrument for the self-reflection and complex classification of urolithiasis in everyday practice by a first-time determination of population-based, age- and gender-based data based on the full recording of urological diagnoses and treatments in the federal accounting setting. The analysis of the taken positions in this representative practice survey prove to some extent information and experience deficits in the handling of complicated nephrolithiasis. Therefor more than 90% of the interviewees demand a structured practical training initiative. In this context, nearly 65% of practices also support the establishment of regional consultation hours. A majority strongly welcomes the establishment of a National Register of Urolithiasis, but nearly 40% are skeptical about defining pending framework conditions.

[Development and treatment of localized/systemic BCGitis : Retrospective studies in direct comparison to mitomycin C]. / Zur urogenitalen Klinik der lokalisierten/systemischen BCGitis : Retrospektive Untersuchungen im direkten Vergleich zu Mitomycin C.

Adjuvant therapy with different bacillus Calmette-Guérin (BCG) preparations is a well-established guideline-endorsed treatment for nonmuscle invasive bladder cancer (NMIBC). Our observational study demonstrates equality between BCG and mitomycin C (MMC) treatment based on the oncological outcome. However, there were significant toxicity differences with higher rates in the BCG treatment group. The potential adverse effects of BCG in terms of a BCGitis are controversially discussed regarding their occurrence. As such, we sought to retrospectively evaluate the incidence in 106 consecutive patients. The BCG group demonstrated minor adverse effects in 78.4% and major adverse effects in 43.3%-partially coincident. Moreover, the parallel MMC group showed in 34.7% respectively 1.4% adverse events-as expected distinctly lower. In the context of this clinical discussion, we refer to alternative treatment concepts. Our data show a high clinical relevance of the patient's primary comorbidity.

[Home blood pressure self-measurement in children and adolescents with renal replacement therapy]. / Häusliche Blutdruck-Selbstmessung bei Kindern und Jugendlichen mit Nierenersatztherapie.

BACKGROUND: Most patients with terminal renal failure show arterial hypertension. In addition to casual blood pressure measurements in the clinic, home blood pressure measurement is recommended for these patients to control arterial blood pressure. PATIENTS: The study was performed in children with hemodialysis (HD; n = 11), peritoneal dialysis (PD; n = 14) or after renal transplantation (NTX; n = 21) from one department of Pediatric Nephrology. We performed a retrospective analysis of home blood pressure values from patients' diaries. METHODS: The average number of blood pressure measurements per day and the mean blood pressure values were calculated from the blood pressure data documented during one month at home. Single measurements above the 95th percentile for height and gender were defined to be hypertensive and the frequency as percentage of all documented values was calculated. RESULTS: Four patients did not document any blood pressure values at home. The other patients documented an average of 2.3 measurements per day. Systolic hypertension was found in 7% of patients defined by home BP measurements compared to 30% defined by casual BP measurements. Prevalence of diastolic hypertension did not differ between both methods (35% vs. 46%). Mean home BP was significantly higher than values after HD and lower than values before HD. Mean clinic BP was significantly higher in PD-patients compared to home BP. Home and clinic blood pressure values did not differ in patients after renal transplantation. The mean percentage of hypertensive readings for systolic BP was 5 and for diastolic BP 39%. CONCLUSIONS: Blood pressure measurement at home is performed reliably by most children and adolescents with chronic renal failure and shows lower values than clinic BP in many patients. It is an important method for control of blood pressure and a valuable supplement to 24 h blood pressure monitoring.

Aluminium-induced granulomas after inaccurate intradermal hyposensitization injections of aluminium-adsorbed depot preparations.

BACKGROUND: The development of persistent subcutaneous nodules at the injection sites of aluminium-adsorbed hyposensitization solutions is rare. These nodules have been interpreted as a delayed, granulomatous hypersensitivity reaction to aluminium. We report for the first time a case of persistent intradermal granulomas that developed at the sites of inaccurate intradermal, instead of subcutaneous, hyposensitization injections. METHODS: An intradermal nodule was excised and processed for histopathology, scanning electron microscopy, and X-ray microanalysis. Intradermal and patch tests with aluminium hydroxide were performed. RESULTS: Histologically, the nodule presented a pattern of granulomatous inflammatory reaction surrounding foci of necrotic tissue. Scanning electron microscopy and X-ray microanalysis revealed deposits of aluminium within the granulomas. Patch tests with aluminium hydroxide were negative, and intradermal tests caused persistent intradermal granulomas. Subsequent hyposensitization therapy in our department with the usual subcutaneous injections of aluminium-adsorbed allergen extracts was well tolerated by the patient. CONCLUSIONS: Local toxic effects of aluminium may be crucial in the development of persistent intradermal injection-site granulomas. Such intradermal nodules may develop even if the subcutaneous route is well tolerated. We conclude that inaccurate intradermal injections of aluminium-containing solutions have to be strictly avoided.

Axilloscopy and endoscopic sentinel node detection in breast cancer patients.

BACKGROUND: Sentinel node biopsy is a promising technique that allows the axillary status of breast cancer patients to be predicted with high accuracy. Reducing false negative results remains a major challenge for the improvement of this procedure. Furthermore, new techniques are required to achieve axillary clearing with less morbidity in cases of unsuccessful mapping or multicentric carcinoma. We analyzed whether axilloscopy and endoscopic sentinel node biopsy is a feasible procedure for visualization of the axillary space and resection of the sentinel node using endoscopic techniques. METHODS: Following blue dye-guided lymphography and liposuction of the axillary fat, endoscopic axillary sentinel node biopsy was performed in 35 breast cancer patients. We then assessed the exposure of anatomical landmarks, the detection rate of the sentinel node, the false negative rate, and the accuracy of consecutive axillary clearing. RESULTS: In almost every case, an excellent anatomical orientation was achieved. The detection rate for the sentinel node was 83.3%. In one case, the sentinel node did not reflect the status of the residual axilla. A mean number of 17.1 lymph nodes was harvested at consecutive axillary clearing. CONCLUSIONS: Axilloscopy and endoscopic sentinel node biopsy, following liposuction of the axillary fat, is a feasible procedure that allows identification and minimally invasive resection of the sentinel node with high accuracy. The endoscopic approach might help to minimize the pitfalls of sentinel node biopsy by visualizing the axillary space. In future, it may become a technique that enables minimally invasive axillary clearing when complete lymphadenectomy is required.

Fluorescence diagnosis of endometriosis on the chorioallantoic membrane using 5-aminolaevulinic acid.

The chorioallantoic membrane (CAM) is a useful model for the fluorescence diagnosis of experimentally induced endometriosis. In our experimental setup 75.7% of the histologically examined tissue preparations were viable and only 24.3% showed signs of necrosis on the CAM after various periods of incubation. Best results were obtained when grafting to the CAM was performed between days 7 and 9 and when implants were left on the CAM for 3-5 days (P < 0.05). We were able to demonstrate that 5-aminolaevulinic acid (ALA) is stored selectively in ectopic endometrium. The subsequent fluorescence of the endometrium shows a rapid increase that reaches a peak after 10-14 h which can be clearly differentiated from the weaker fluorescence of grafted normal peritoneum and fimbriae (P < 0.01).

DNA-Based Vaccination Primes Tumor-Rejecting T-Cell Responses.

DNA-based vaccination efficiently primes MHC-restricted T-cell responses. This technique specifically stimulates MHC-II-restricted CD4(+) T-cell responses and MHC-I-restricted CD8(+) T-cell responses against "strong" (immunodominant) or "weak" (subdominant or cryptic) epitopes of intracellular, secreted or membrane-associated protein antigens. In many experimental systems, T-cell-mediated effector functions have the potential to control tumor growth. In particular MHC-I-restricted cytotoxic T lymphocytes (CTL) can reject tumors. This has been shown using either defined tumor-associated antigens (TAA), or viral antigens containing well-defined, MHC-binding and CTL-stimulating epitopes that are expressed by transfected tumor cells.

Serum p53 autoantibodies in patients with minimal lesions of ductal carcinoma in situ of the breast.

Five of 43 patients (11.6%) with ductal carcinoma in situ of the breast presented with p53 autoantibodies at diagnosis. Three seropositive patients demonstrated tumour sizes of < or = 5 mm. There was no association of p53 autoantibody status with age, clinical presentation, histological subtype, tumour size, grading, p53 immunohistochemistry or hormone receptor status.

[Endoscopic axillary lymph node excision--results of a pilot study]. / Die endoskopisch axilläre Lymphonodektomie--Ergebnisse einer Pilotstudie.

OBJECTIVE: Assessment of axillary nodal status with reduced shoulder-arm-morbidity remains a major challenge for primary surgery of breast cancer patients. In a pilot study endoscopic axillary lymph node dissection was evaluated. MATERIAL AND METHODS: In 30 breast cancer patients axillary lymphadenectomy was performed after liposuction using an endoscopic approach. During a learning phase of 15 cases an open revision was routinely carried out. Later complete endoscopic lymph node dissection was performed. The exposition of anatomical landmarks, the number of resected lymph nodes, postoperative lymphorrhea, histopathological signs of traumatisation were assessed as well as intra and postoperative complications. RESULTS: In any case we found excellent exposure of anatomical landmarks. Following a learning curve of 15 cases the average number of resected lymph nodes was equal to the average number of lymph nodes resected with conventional techniques (18.2 vs. 18.4, median 17 vs 18). Minimal intraoperative complications were observed. Postoperative lymphorrhea and seroma rate were not remarkably reduced in comparison with open procedures. CONCLUSIONS: Our study demonstrates, that endoscopic lymph node dissection may be performed with a low complication rate and with identical accuracy as achieved by open techniques.

SiMa, a new neuroblastoma cell line combining poor prognostic cytogenetic markers with high adrenergic differentiation.

We describe the establishment and characterization of a new neuroblastoma (Nb) cell line, SiMa, carrying the major recurrent chromosome changes associated with poor prognosis Nb, including amplification of N-MYC by formation of double minutes (dmin), der(1)t(1;17)(p35;q12) and der(22)t(17;22)(q22;p13), and loss of chromosome 11, documented at both initiation and late passage. In contrast to these cytogenetic stigmata of poor prognosis, analysis of catecholamine synthesis by high pressure liquid chromatography (HPLC) measurement revealed an advanced degree of adrenergic differentiation with high rates of 3,4-Dihydroxyphenylalanine (DOPA), noradrenaline, homovanillic acid (HVA), and vanillylmandelic acid (VMA) production. Contrastingly advanced differentiation and poor prognostic genetic markers combine to render SiMa a unique instrument for investigating the pathology and therapy of Nb.

Laparoscopic management of ovarian tumors.

BACKGROUND: Laparoscopy can be used with minimal operative morbidity to evaluate adnexal masses. We report our experience with the endoscopic approach to the diagnosis and treatment of ovarian tumors. In particular, we describe 11 patients who incidentally underwent laparoscopy and in whom the ovarian masses were found to be malignant. METHODS: Between September 1994 and September 1996, 292 patients with 316 ovarian tumors were treated laparoscopically in the Department of Obstetrics-Gynaecology, University of Ulm. We assessed vaginal ultrasonography, clinical assessment, the tumor marker CA 12-5, and the intraoperative low-power magnification for their value in predicting the final diagnosis in all laparoscopically treated ovarian tumors. RESULTS: From a total of 292 patients with ovarian tumors, 11 were diagnosed, intraoperatively or after final histologic examination, as having a malignant or borderline ovarian tumor. All applied pre- and intraoperative diagnostic procedures were by themselves too unreliable to exclude early stages of ovarian carcinoma exactly. CONCLUSIONS: On the basis of the present findings, we are tempted to conclude that laparoscopic surgery is justified in the management of ovarian tumors. Even with an accurate preoperative selection of suitable patients for laparoscopic surgery, the presence of an undetected ovarian carcinoma cannot be entirely excluded.

Routes of plasmid DNA vaccination that prime murine humoral and cellular immune responses.

Induction of humoral and MHC (major histocompatibility complex)-I-restricted, cytotoxic T lymphocyte (CTL) responses of Balb/c mice to the small hepatitis B surface antigen (HBsAg) were studied with a protein antigen or a DNA vaccine. Different routes were used to deliver the HBsAg-encoding plasmid DNA or the recombinant HBsAg particles: different doses of expression plasmid DNA (10 micrograms or 100 micrograms per mouse) or of recombinant HBsAg lipoprotein particles were injected into different (normal or regenerating) muscles (m. tibialis anterior and m. quadriceps), into subcutaneous tissue (at the base of the tail), into the peritoneal cavity, or intravenously (into the tail vein). At different time points post-vaccination, the induction of HBsAg specific, MHC-I-restricted CD8+ T cells and of serum antibodies to HBsAg was monitored. The data show that the intramuscular and subcutaneous but not the intravenous and intraperitoneal injection of 'naked' DNA efficiently and reliably primes cellular and humoral immune responses. In contrast, recombinant HBsAg particles injected by all four routes (without adjuvants) efficiently primed specific humoral and CTL responses. These data demonstrate that the choice of routes to deliver 'naked' plasmid DNA for obtaining efficacious immunogenicity of the expressed antigen is restricted.

T cell-mediated, IFN-gamma-facilitated rejection of murine B16 melanomas.

The murine melanoma cell line B16.F10 (H-2b) was used to study specific T cell responses that reject tumors. Stable B16 transfectants were established that express viral Ags, either the hepatitis B surface Ag (HBsAg) or the large tumor Ag (T-Ag) of SV40. B16 cells and their transfected sublines were CD40+ CD44+ but expressed no (or low levels of the) costimulator molecules CD154 (CD40L), CD48, CD54, CD80, and CD86. Surface expression of MHC class I (Kb, Db) and class II (I-Ab) molecules by B16 cells was low, but strikingly up-regulated by IFN-gamma. CD95 (Fas) and CD95 ligand (CD95L (FasL)) were "spontaneously" expressed by B16 cells growing in vitro in serum-free medium; these markers were strikingly up-regulated by IFN-gamma. B16 cells coexpressing CD95 and CD95L were irreversibly programmed for apoptosis. In vitro, noninduced B16 transfectants stimulated a specific IFN-gamma release response, but no cytolytic response (in a 4-h assay) in MHC class I-restricted CTL; in contrast, IFN-gamma-induced B16 targets were efficiently and specifically lysed by CTL. In vivo, B16 transfectants were specifically rejected by DNA-vaccinated syngeneic hosts through a T-dependent immune effector mechanism. The tumors showed evidence of massive apoptosis in vivo during the rejection process. The data suggest that CTL-derived IFN-gamma enhances an intrinsic suicide mechanism of these tumor cells in addition to facilitating lytic interactions of effectors with tumor targets.

Ascorbic acid stimulates DOPA synthesis and tyrosine hydroxylase gene expression in the human neuroblastoma cell line SK-N-SH.

Ascorbic acid is well known to induce noradrenaline synthesis in sympathetic nervous cells. In a series of experiments we found that incubation of the neuroblastoma cell line SK-N-SH with ascorbic acid (100-500 microM) for 2 h results in a significantly enhanced synthesis of 3,4-dihydroxyphenylalanine (DOPA) and dopamine. Additionally, cDNA-polymerase chain reaction (cDNA-PCR) analysis of relative mRNA levels corresponding to the enzymes involved in catecholamine synthesis revealed a 3-fold increase of tyrosine hydroxylase gene expression after 5 days of incubation with ascorbic acid (200 microM), whereas expression of dopamine-beta-hydroxylase was found to be unaltered. In summary the data give evidence that ascorbic acid leads to enhanced DOPA production in SK-N-SH cells by two different mechanisms: at the metabolic level after short-term incubation and by increasing the tyrosine hydroxylase gene expression after long-term incubation. Based on these data we suppose that enhancement of DOPA synthesis by ascorbic acid may be useful in the treatment of early Parkinson's disease.

MRI of histologically confirmed mammary carcinoma: clinical relevance of diagnostic procedures for detection of multifocal or contralateral secondary carcinoma.

PURPOSE: MR mammography (MRM) is a sensitive diagnostic method for the detection of mammary carcinomas. The present study evaluates whether MRM can yield additional relevant data in cases of histologically confirmed mammary carcinoma. METHOD: Thirty-four patients with histologically confirmed mammary carcinoma were examined at MRM using a T1-weighted GE sequence and a T2-weighted SE sequence. Morphologic criteria and the dynamic contrast medium behavior of the tumors were evaluated. RESULTS: MRM showed a 100% sensitivity and diagnostic accuracy in the detection of mammary carcinomas. Additionally, three unexpected contralateral carcinomas were discovered. In 26 patients, there was a multifocal or multicentric tumor process. In 24 patients, peritumoral edema was visualized, which corresponded histologically in 21 patients with lymphangiosis and in 3 with an inflammatory peritumoral reaction. CONCLUSION: Because of its high sensitivity in the diagnosis of multifocal disease and of contralateral carcinomas, MRM would seem to represent a useful addition to preoperative diagnostic procedures. The potential benefit to the patient and its cost efficiency, however, remain to be clarified.

Stress protein (hsp73)-mediated, TAP-independent processing of endogenous, truncated SV40 large T antigen for Db-restricted peptide presentation.

Transporter associated with antigen processing (TAP)-competent and TAP-deficient cell lines were transfected with expression plasmids encoding either the wild-type (wt) large tumor antigen (T-Ag) of SV40, or a truncated cytoplasmic variant (cT-Ag) of this viral protein. Stable expression of comparable levels of both forms of the viral protein was observed in different transfectants. The truncated cT-Ag variant, but not the wtT-Ag was stably associated with the constitutively expressed, cytosolic heat shock protein (hsp)73 chaperone. Two Db-binding peptides and one Kb-binding peptide of T-Ag were presented to cytotoxic T lymphocyte lines (CTLL) by TAP-competent transfectants expressing either wtT-Ag or cT-Ag. TAP-deficient transfectants expressing the wtT-Ag did not present any of these epitopes to CTLL. In contrast, TAP-deficient transfectants expressing the truncated hsp73-associated cT-Ag, presented the two Db-binding epitopes, but not the Kb-binding T-Ag epitope to CTLL. Regurgitation of peptides by transfectants was not detectable. The described data indicate that a pool of post-Golgi Db molecules is available for 2-3 h in TAP-deficient transfectants for loading with peptides released during endolysosomal processing of hsp73-associated, endogenous antigen.

Targeting an anti-viral CD8+ T cell response to a growing tumor facilitates its rejection.

We demonstrate in a murine model that targeting an anti-viral T cell response to a growing tumor facilitates priming of a tumor-associated antigen (TAA)-specific, rejecting T cell response. Murine P815 mastocytoma cells grow aggressively in a syngeneic host. Transfected P815/S cells (expressing the hepatitis B surface antigen, HBsAg) also grow as subcutaneous tumors, but occasional 'spontaneous' rejections after transient growth are observed. Growth of P815/S tumors (but not of P815 tumors) is efficiently suppressed by a CD8+ cytotoxic T lymphocyte (CTL)-dependent immune mechanism in mice primed to HBsAg by DNA-immunization. In hosts immunized against HBsAg by DNA vaccination, HBsAg-specific CTL are generated. This specific CTL reactivity was targeted to s.c.-growing P815 tumors by intra tumor injections of either HBsAg-encoding plasmid DNA or viable P815/S cells; this treatment led to tumor rejection in 70-80% of the tumor-bearing animals. All rejecting animals showed a CD8+ CTL-dependent resistance to subsequent challenges by native, non-transfected P815 tumors. Targeting an established anti-viral ('strong') CTL response to a growing tumor hence is an efficient strategy to facilitate priming of a rejecting CTL response against ('weak') TAA in this system.

DNA vaccination primes MHC class I-restricted, simian virus 40 large tumor antigen-specific CTL in H-2d mice that reject syngeneic tumors.

We investigated the stimulation of a MHC class I-restricted response of CTL to the SV40 large tumor Ag (T-Ag) by different vaccination strategies in H-2d and H-2b mice. Immunization with plasmid DNA or exogenous T-Ag, or infection with SV40, primed CTL to T-Ag in H-2b mice; these three different types of Ag delivery primed T-Ag-specific CTL populations with similar epitope/restriction specificities. In H-2d mice, i.m. immunization with plasmid DNA, but neither immunization with exogenous protein Ag nor SV40 infection, primed CTL to T-Ag. T-Ag-specific H-2d CTL were primed by DNA-based immunization in vivo, expressed the CD4-CD8+ phenotype, and were L(d)-restricted. In H-2d (DBA/2) mice, T-Ag-specific immune responses primed by plasmid DNA injection, but not those primed by exogenous T-Ag or SV40 infection, mediated CD8+ CTL-dependent rejection of T-Ag-expressing P815/T tumor grafts. The data indicate that immunization by plasmid DNA injection is an efficient strategy to induce class I-restricted CTL responses against oncogene-encoded Ags of low immunogenicity that mediate tumor rejection.