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Purpose In testicular neoplasms, the interrelationship of elevations of the novel serum tumor marker microRNA-371a-3p (M371) and traditional markers with other clinical features is still incompletely understood. The present study evaluated marker expression rates in relation to various other clinical parameters. Methods The following data were retrospectively registered from 641 consecutive patients with testicular neoplasms: histology, such as seminoma (n = 365), nonseminoma (n = 179), benign tumor (n = 79), other malignant tumor (n = 18); patients age (years); clinical stage (CS1, CS2a/b, CS2c, CS3); and preoperative elevation of beta HCG, AFP, LDH, M371 (yes/no). Descriptive statistical methods were employed with comparisons of various subgroups to disclose associations of marker expression rates with age, histology and CS, and of age with histology. Results The histologic subgroups revealed significantly different expression rates of tumor markers. M371 performed best with expression rates of 82.69% and 93.58% in seminoma and in nonseminoma, respectively. In germ cell tumors, all markers had significantly higher expression rates in metastasized stages than in localized disease. All markers except LDH have significantly higher expression rates in younger than in older patients. Nonseminoma is most prevalent in the youngest age category, seminoma predominates in patients > 40 years, other malignancies were restricted to patients > 50 years. Conclusion The study documented significant associations of serum marker expression rates with histology, age and clinical staging, with highest rates in nonseminomas, young age and advanced clinical stages. M371 showed significantly higher expression rates than other markers suggesting its superior clinical usefulness.

The role of primary tumour size (TS) in the clinical course of testicular tumours is incompletely understood. We retrospectively evaluated 641 consecutive patients with testicular neoplasms with regard to TS, histology, clinical stage (CS), serum tumour marker (STM) expression and patient age using descriptive statistical methods. TS ≤ 10 mm was encountered in 13.6% of cases. Median TS of 10 mm, 30 mm, 35 mm, and 53 mm were found in benign tumours, seminomas, nonseminomas, and other malignant tumours, respectively. In cases with TS ≤ 10 mm, 50.6% had benign tumours. Upon receiver operating characteristics analysis, TS of > 16 mm revealed 81.5% sensitivity and 81.0% specificity for detecting malignancy. In subcentimeter germ cell tumours (GCTs), 97.7% of cases had CS1, and CS1 frequency dropped with increasing TS. Expression rates of all STMs significantly increased with TS. MicroRNA-371a-3p (M371) serum levels had higher expression rates than classical STMs, with a rate of 44.1% in subcentimeter GCTs. In all, TS is a biologically relevant factor owing to its significant associations with CS, STM expression rates and histology. Importantly, 50% of subcentimeter testicular neoplasms are of benign nature, and M371 outperforms the classical markers even in subcentimeter tumours.

The testis represents one place where the progenitor of vitamin D is converted into its active form. Loss of one testis was suggested to result in reduced vitamin D serum levels. Vitamin D deficiency would represent a significant health problem in the long-term course of patients with testicular germ cell tumors (GCTs) since most of them survive. The purpose of this study was to look to the serum 25(OH)-Vitamin D (25OHD) levels in patients with GCTs before and after orchiectomy. A total of 177 GCT patients underwent measurements of serum 25OHD levels, thereof 83 with preoperative measurements and 94 with measurements at six particular time-points from immediate postoperatively to24 months. Longitudinal assessments of 25OHD serum levels were performed in individual patients with repeated measurements. A second analysis involved patient cohorts with measurements at six postoperative time-points. Serum levels of patients were also compared with 2 control groups, one consisting of 84 patients with non-neoplastic testicular diseases and another with 237 patients with non-neoplastic urologic diseases. We also looked to associations of 25OHD levels with levels of testosterone, follicle stimulating hormone (FSH), age, histology of GCT and season. Descriptive statistical methods were employed to compare groups and to analyze changes over time.Normal serum levels of 25OHD were found in 21.7%, 23.1%, 20.2%, 21.9% in GCT patients preoperatively, after2 years, in control group 1 and control group 2, respectively. Levels were significantly higher in spring and summer, but no association was found with other parameters. We found a significant transient decrease of 25OHD levels with a nadir at 6-12 months after orchiectomy and a recovery thereafter.Contrasting with previous studies we found no permanent reduction of serum 25OHD levels after orchiectomy but transient postoperative drop of 25OHD levels. There were no associations of 25OHD levels with age, and levels of testosterone or FSH. Our results may point to a particular role of the testis in vitamin D metabolism and may thus enhance the understanding of the diverse physiological roles of the testis.RéSUMé: CONTEXTE: Le testicule représente un lieu où le précurseur de la vitamine D est converti en sa forme active. Il a été suggéré que la perte d’un testicule pouvait induire une réduction des taux sériques de vitamine D. La carence en vitamine D représenterait un problème de santé important à long terme pour les patients présentant des tumeurs testiculaires à cellules germinales (TCG) puisque la plupart d’entre eux survivent. Le but de cette étude était de se tourner vers les taux sériques de 25(OH)-Vitamine D (25OHD) chez les patients présentant des TCG, avant et après orchidectomie. Au total, 177 patients avec TCG ont subi des mesures des taux sériques de 25OHD, dont 83 avec mesures préopératoires et 94 avec des mesures à six points de temps particuliers, de l’immédiat postopératoire jusqu’à plus de 24 mois. Des évaluations longitudinales des taux sériques de 25OHD ont été réalisées individuellement chez les patients avec des mesures répétées. Une seconde analyse a impliqué des cohortes de patients avec des mesures à six points de temps postopératoires. Les taux sériques des patients ont également été comparés à ceux de 2 groupes témoins, l’un composé de 84 patients atteints de maladies testiculaires non néoplasiques, et l’autre de 237 patients atteints de maladies urologiques non néoplasiques. Nous nous sommes également penchés sur les associations des taux de 25OHD avec les taux de testostérone, d’hormone folliculostimulante (FSH), l’âge, l’histologie de la TCG et la saison. Des méthodes statistiques descriptives ont été utilisées pour comparer les groupes et analyser les changements au fil du temps. RéSULTATS: Des taux sériques normaux de 25OHD ont été trouvés chez 21,7%, 23,1%, 20,2%, et 21,9% des patients avec GCT, respectivement en préopératoire et après2 ans, ainsi que chez les patients du groupe témoin 1 et du groupe témoin 2. Les taux ont été significativement plus élevés au printemps et en été, mais aucune association n’a été observée avec d’autres paramètres. Nous avons retrouvé une diminution transitoire significative des taux de 25OHD avec un nadir à 6-12 mois après orchiectomie et un rétablissement par la suite. CONCLUSION: Contrairement aux études précédentes, nous n’avons trouvé aucune réduction permanente des niveaux de sérum 25OHD après orchiectomie, mais une baisse postopératoire transitoire des taux de 25OHD. Il n’y avait pas d’associations entre les taux de 25OHD et l’âge, ni avec les taux de testostérone ou de FSH. Nos résultats peuvent mettre en avant un rôle particulier du testicule dans le métabolisme de la vitamine D et peuvent ainsi améliorer la compréhension des divers rôles physiologiques des testicules.

Background: Thromboembolic events (TEEs) may significantly complicate the clinical management of patients with testicular germ cell tumours (GCTs). We analysed a cohort of GCT patients for the occurrence of TEEs and looked to possible pathogenetic factors. Patients, Methods: TEEs occurring within 6 months after diagnosis were retrospectively analysed in 317 consecutive patients with testicular GCT (median age 37 years, 198 seminoma, 119 nonseminoma). The following factors were analysed for association with TEE: histology, age, clinical stage (CS), chemotherapy, use of a central venous access device (CVA). Data analysis involved descriptive statistical methods with multivariable analysis to identify independent risk factors. Results: Twenty-three TEEs (7.3%) were observed, 18 deep vein thromboses, 4 pulmonary embolisms, and 1 myocardial infarction. Univariable risk calculation yielded the following odds ratios (ORs) : >CS1 OR = 43.7 (95% confidence intervals [CIs] 9.9–191.6); chemotherapy OR = 7.8 (95% CI 2.3–26.6); CVA OR = 30.5 (95% CI 11.0–84.3). Multivariable analysis identified only CS > 1 (OR = 16.9; 95% CI 3.5–82.4) and CVA (OR = 9.0; 95% CI 2.9–27.5) as independent risk factors. Conclusions: Patients with CSs >CS1 are at significantly increased risk of TEEs even without chemotherapy. Particular high risk is associated with the use of CVA devices for chemotherapy. Caregivers of GCT patients must be aware of the particular risk of TEEs.

Background: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts

The objective of this study was to assess the pharmacokinetics of recombinant asparaginase (rASNase, Spectrila®) in children with acute lymphoblastic leukemia using a population pharmacokinetic approach in order to explore potential dosing recommendations. Data on serum asparaginase activities of 124 children from three clinical studies were included in the analysis, covering an age range from 3 days to 17 years. Most patients received 5000 U/m2 rASNase intravenously every 3 days. The non-linear mixed effects modelling software (NONMEM®) was utilized to identify drivers of rASNase pharmacokinetics in children. Different dose adjustments were simulated for their ability to increase rASNase trough activities in children who do not reach the threshold of 100 U/L. A two-compartment model with allometric weight scaling (0.75 on clearance [CL] and inter-compartmental clearance [Q] and 1 on central [V 1] and peripheral [V 2] volume of distribution) was the best model to describe the pharmacokinetics of rASNase. PK parameters for the median child (19.5 kg) were: CL = 0.0592 L/h, V 1 = 1.18 L, Q = 0.307 L/h, V 2 = 0.316 L. Organ functions, such as liver or kidney function and laboratory values, such as fibrinogen or antithrombin III levels, showed no influence on rASNase pharmacokinetics. In simulations, changing the administration interval from 72 to 48 h was appropriate to maintain rASNase activities above the therapeutic threshold, in patients with activities below 100 U/L 72 h after the first dose. Drug monitoring is recommended to identify patients with insufficient ASNase trough activities in serum and to modify the treatment schedule, if necessary. Shortening of the treatment interval might be preferable over increasing the rASNase dose.

BACKGROUND: Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections of malignant glioma at a dose of 20 mg/kg; yet, it is unknown whether lower doses may also provide efficacy. OBJECTIVE: To perform a double-blinded randomized study comparing 3 different doses of 5-ALA. METHODS: Twenty-one patients with suspected malignant glioma were randomly assigned to 0.2, 2, or 20 mg/kg 5-ALA. Investigators were unaware of dose. Intraoperatively, regions of interest were first defined in tumor core, margin, and adjacent white matter under white light. Under violet–blue illumination, the surgeon's impression of fluorescence was recorded per region, followed by spectrometry and biopsy. Plasma was collected after administration and analyzed for 5-ALA and protoporphyrin IX (PPIX) content. RESULTS: The positive predictive value of fluorescence was 100%. Visual and spectrometric fluorescence assessment showed 20 mg/kg to elicit the strongest fluorescence in tumor core and margins, which correlated with cell density. Spectrometric and visual fluorescence correlated significantly. A 10-fold increase in 5-ALA dose (2-20 mg/kg) resulted in a 4-fold increase of fluorescence contrast between marginal tumor and adjacent brain. tmax for 5-ALA was 0.94 h for 20 mg/kg (0.2 kg: 0.50 h, 2 mg/kg: 0.61 h). Integrated PPIX plasma levels were 255.8 and 779.9 mcg*h/l (2 vs 20 mg/kg). Peak plasma concentrations were observed at 1.89 ± 0.71 and 7.83 ± 0.68 h (2 vs 20 mg/kg; average ± Standard Error of Mean [SEM]). CONCLUSION: The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence.

Introduction. Although serum tumor markers beta human chorionic gonadotropin (bHCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) are well-established tools for the management of testicular germ cell tumours (GCTs), there are only few data from contemporary cohorts of primary GCT patients regarding these biomarkers. Our aim was to evaluate marker elevations in testicular GCTs and to document their associations with various clinical characteristics.Patients and Methods. A total of 422 consecutive patients with GCTs were retrospectively analysed regarding serum levels of bHCG, AFP, and LDH during the course of treatment. Additionally, the following characteristics were recorded: histology, age, laterality, clinical stage (CS), pT-stage, and tumour size. Marker elevations were first tabulated in dichotomized way (elevated: yes/no) in various subgroups and second as continuous measured serum values. Descriptive statistical methods were employed to look for differences among subgroups and for associations of elevations with clinical parameters.Results. In all GCT patients, the frequencies of elevated levels of bHCG, AFP, LDH, and bHCG or AFP were 37.9%, 25.6%, 32.9%, and 47.6%; in pure seminomas 28%, 2.8%, 29.1%, and 30.3%; and in nonseminoma 53.0%, 60.1%, 38.7%, and 73.8%. Significant associations were noted with pT-stages >pT1, clinical stages >CS1, tumour size, and younger age. Frequencies of marker elevations dropped significantly after treatment, but LDH levels remained elevated in 30.5%-34.1%. Relapsing patients (n=27) had elevated levels of bHCG, AFP, and LDH in 25.9%, 22.2%, and 29.6%, respectively, thirteen of whom with a changed marker pattern.Conclusions. The classical GCT-biomarkers correlate with treatment success. Clinical utility is limited due to proportions of < 50% of patients with elevated levels and the low specificity of LDH. The elevation rates are significantly associated with histology, clinical and pT-stages, tumour size, and younger age. Individual marker patterns may change upon relapse. Clinically, ideal biomarkers are yet to be found.

Introduction: International guidelines are ambivalent regarding the recommendations for the management of clinical stage 1 (CS1) seminoma. Patients and Methods: During 2008-2013, 1,050 patients with seminoma CS1 were prospectively registered with regard to assessing management modality (radiotherapy, carboplatin, surveillance). Associations with tumor size, rete testis invasion, age, year of diagnosis, type of institution, and geographic location were assessed. Results: Of the total number of patients, 49.3% received carboplatin 1 course, 8.5% carboplatin 2 courses, 35.9% surveillance, and 6.3% radiotherapy. In 2013, surveillance increased significantly to 57.9%. Treatment decisions were significantly associated with rete testis invasion and tumor size. Carboplatin was applied significantly more in office clinics than elsewhere. There is some regional variation regarding treatment preferences. Conclusions: The rising acceptance of surveillance mirrors international trends. The associations with prognostic factors demonstrate care givers to be compliant with contemporary guidelines. The association with the type of institution suggests non-oncological factors to be also relevant in decision making.

Background: The efficacy and safety of recombinant Escherichia coli–asparaginase (rASNase) was compared to native E.coli asparaginase (Asparaginase medac). Methods: One hundred and ninety-nine children with newly diagnosed acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5,000 U/m² during induction (eight doses) and 10,000 U/m² during the postinduction phase (only high-risk patients; standard- and medium-risk patients received pegaspargase). Results: Median trough serum asparaginase activity levels were comparable between both groups; they ranged from 143 to 182 U/l during induction and were above the target value of 100 U/l. Complete asparagine depletion in serum was achieved in 97.9% of patients, with no significant differences between both groups. On day 33 (end of induction), only two (2%) evaluable patients in each group had measurable asparagine serum levels, and complete asparagine depletion in the cerebrospinal fluid was achieved in 98.8% and 93.6% of the patients with rASNase and Asparaginase medac, respectively. During induction, 2.1% and 5% of patients developed an allergic reaction to rASNase or Asparaginase medac, respectively. Approximately 41% of the patients in both groups had a clinical allergy or enzyme inactivation to the first dose of any asparaginase preparation in postinduction. A comparable proportion of patients in both groups developed anti-asparaginase antibodies (57%) during repeated administration of asparaginase. Minimal residual disease levels at the end of induction, 5-year event-free survival, and 5-year cumulative incidence of relapse did not differ between both groups. Conclusion: The efficacy, safety, and immunogenicity of both asparaginase preparations are comparable. This trial was registered at www.clinicaltrials.gov as #NCT00784017; EudraCT number 2006-003180-31.

Introduction: Clinical characteristics of testicular germ cell tumours (GCTs) apparently change over time, and some vary geographically. The aim of this study is to document the clinical profile of contemporary GCT patients. Patients and Methods: Four hundred twenty-two Caucasian GCT-patients treated in one German centre during 2000–2017, were analysed in terms of patient-age, laterality, histology, tumour-size, clinical stages (CS), pathological (pT)-stages and serum biomarker expression. The results were analysed descriptively and compared with the literature. Results: Median age was 36 years and 60.2% had seminoma. Βeta-human chorionic gonadotropin was expressed in 37.9% and alpha Fetoprotein in 25.6%. CS1 presenting stage was 66.6% of all GCT patients, 79.1% in seminoma, and 47.6% in nonseminoma. Tumour size was significantly associated with pT-stages and CS. Patients >50 years had significantly more seminoma (77.6%) than younger ones (57.9%). Comparison with literature data revealed a shifting towards higher age, lower CS, higher proportion of seminoma and striking differences of characteristics among geographic regions. Conclusions: A typical contemporary clinical profile of testicular GCTs is presented in this study. Median age, relative incidence of seminoma and proportion of CS1 appear to be increasing over time. Striking differences among ethnic groups regarding the characteristics of GCT require further investigation.

Bei Patienten mit einem Keimzelltumor (KZT) des Hodens gilt die kontralaterale Biopsie als Instrument zur Fruherkennung von Zweittumoren im Gegenhoden. Trotz wissenschaftlich hoher Evidenz besteht international kein Konsensus uber die Empfehlung zur Biopsie. Wir befragten Urologische Kliniken in Deutschland, um die Akzeptanz dieses Verfahrens zu evaluieren. Schriftlich wurden 326 Kliniken/Abteilungen fur Urologie in Deutschland befragt, ob sie die kontralaterale Biopsie beim KZT grundsatzlich/meistens/nur in Risikofallen oder niemals durchfuhren. Zusatzlich wurde der Kliniktyp sowie die Grose der Klinik (DRG-Falle/Jahr), die Anzahl von KZT pro Jahr sowie die Postleitzahl der Klink registriert. Die Auswertung erfolgte deskriptiv statistisch. Die Rucklaufquote betrug 86,5 %. Insgesamt 52,1 % aller Kliniken fuhren die Biopsie grundsatzlich durch, 17 % meistens, 27,3 % nur in Risikofallen und 3,5 % niemals. Die Biopsieakzeptanz ist in Universitatskliniken signifikant geringer als in urologischen Hauptabteilungen (50 % vs. 72,6 %), auch bei multivariater Betrachtung anderer Klinikmerkmale. Andere Charakteristika waren mit der Biopsierate nicht assoziiert. Norddeutsche Kliniken biopsieren deutlich haufiger als suddeutsche Kliniken. Die kontralaterale Biopsie bei KZT-Patienten ist in Deutschland gut etabliert und weithin akzeptiert. International bleibt die aktive Fruherkennung von kontralateralen Zweittumoren dagegen kontrovers. Nur in Danemark erfolgt grundsatzlich eine Biopsie, in Schweden, Osterreich und der Schweiz erfolgt eine selektive Anwendung. Bemerkenswert und ungeklart bleibt die tendenziell geringere Akzeptanz in deutschen Universitatskliniken sowie das auffallende Nord-Sud-Gefalle.

5-Aminolevulinic acid (5-ALA) elicits synthesis and accumulation of fluorescing porphyrins, predominantly protoporphyrin IX (PPIX), in malignant glioma tissue and is being used for their intraoperative identification.1-13 This fluorescence can be made visible macroscopically with the aid of standard surgical microscopes equipped with optical filters1,4,6,9,14-16 and is highly predictive of malignant glioma tissue.1,9,11,13,17,18 The lack of visible fluorescence in adjacent tissue, however, is not highly predictive of normal tissue, because biopsies taken from these areas have frequently been infiltrated by tumor cells, corresponding to a low negative predictive value.1,6,9,18 Nonvisual methods such as high-resolution spectrometry11,13 allow PPIX to be detected with greater sensitivity in these regions. Regarding visible fluorescence, 2 types have been described,1,3,9,17 “solid,” “red,” or “strong” and “weak,” “vague,” or “salmon” fluorescence (Figure ​(Figure1A,1A, B). Solidly proliferating, central, viable tumor with vascular proliferation has been associated with intense red fluorescence, and surrounding infiltrating tumor with moderate to high cell density has been associated with pink fluorescence.9,11,17 This information may help guide surgery macroscopically because the resection of strongly fluorescing tissue, which signifies gross tumor, may have a significant influence on short-term prognosis, whereas resections of weakly fluorescing tissue, which signifies infiltrating tissue, may be close to or involved with the functional brain.9 FIGURE 1 Intraoperative fluorescence image with spectrometric measurement sites. A, cavity with area of strong (red), weak (pink; separated by white line) and no fluorescence. B, corresponding white light image with biopsy/measurement sites. Nonfluorescent “near” ... To corroborate the value and reliability of macroscopic, ie, visible, fluorescence qualities for guiding surgery, we have performed a systematic collection of biopsies with differing visible fluorescence qualities, analyzed by in situ spectrometry and neuropathology. Also, we have used neuronavigation to correlate residual fluorescence with the occurrence and the volume of contrast-enhancing tumor on early postoperative magnetic resonance imaging (MRI). For bias reduction, we have included 4 different centers with blinded neuropathological and neuroradiological assessments.

The pharmacokinetics, pharmacodynamics, efficacy and safety of a new recombinant E. coli-asparaginase preparation were evaluated in infants (

Background The treatment of testicular intraepithelial neoplasia (TIN), the progenitor of testicular germ cell tumours (GCTs), is based on little data. Patients and methods Two hundred and twenty-eight GCT patients with contralateral TIN were retrospectively enrolled. Ten had surveillance, 122 radiotherapy to testis with 18–20 Gy, 30 cisplatin-based chemotherapy (two cycles), 51 chemotherapy (three cycles), and 15 carboplatin. The study end point was a malignant event (ME), defined as detection of TIN upon control biopsy or occurrence of a second GCT. The Secondary end point was hypogonadism during follow-up. Results Numbers, proportions of ME, and median event-free survival (EFS) times were: radiotherapy N = 3, 2.5%, 11.08 years; chemotherapy (two cycles) N = 15, 50%, 3.0 years; chemotherapy (three cycles) N = 12, 23.5%, 9.83 years; carboplatin N = 10, 66%, 0.9 years; surveillance N = 5, 50%, 7.08 years. EFS is significantly different among the groups. Hypogonadism rates were in radiotherapy patients 30.8%, chemotherapy (two cycles) 13%, chemotherapy (three cycles) 17.8%, carboplatin 40%, surveillance 40%. Conclusions Local radiotherapy is highly efficacious in curing TIN. Chemotherapy is significantly less effective and the cure rates are dose-dependent. Though hypogonadism occurs in one-third of patients, radiotherapy with 20 Gy remains the standard management of TIN.

Clinical T1 and T2 prostatic carcinoma is a heterogeneous tumor with respect to pathologic stage and outcome. In the authors' experience, 60% of patients have a pT2 prostatic carcinoma, and 2% to 4% have tumors less than 0.5 cm3 in volume. The latter group cannot be predicted by the use of preoperative parameters with a sufficient sensitivity and specificity. Quantitative analysis of six systematic biopsies, that is, reporting the number of biopsies with any Gleason grade 4 or 5 cancer or the number of biopsies with more than 50% Gleason grade 4 and 5 cancer, together with preoperative PSA levels can be used to predict the different pathologic stages and risk groups of patients with T1 or T2 prostatic carcinoma. CART analysis that using these preoperative parameters can predict the lymph node stage and the capsular penetration on each side of the prostate with a sufficient positive and negative predictive value and a sufficient specificity to avoid routine lymphadenectomy in approximately 80% of the patients classified as a low-risk group for having lymph nodes positive for disease. CART analysis also allows a solid identification of patients in whom the unilateral or bilateral nerve may be spared during surgery. These algorithms may be improved further by determining the HK-2 level in the blood or by including other molecular biologic markers in the analysis of the biopsies. Clinical T1 or T2 prostatic carcinoma is a heterogeneous but fairly predictable tumor.

Purpose Clinical stage 1 (CS1) testicular seminoma involves an almost 100 % disease-specific survival in controlled clinical trials. We aimed to find out whether these results can be matched in patients managed on the routine care level. Patients, methods In total, 725 patients with seminoma CS1 were prospectively enrolled from 130 institutions. Adjuvant management as decided by local physicians involved surveillance (n = 256), radiotherapy (41), 1× Carboplatin (362), and 2× Carboplatin (66). We registered type of management, age, duration of follow-up (F/U), relapse, rete testis invasion (RTI), and tumor size. Actuarial relapse-free survival curves were calculated for treatment modalities and stratified for tumor sizes and RTI. A Cox regression model was calculated to explore for factors influencing relapses. Results Disease-specific survival was 100 %. Crude relapse rates were 8.2, 2.4, 5.0, and 1.5 % for surveillance, radiotherapy, 1× Carboplatin, and 2× Carboplatin after a median F/U of 30 months. RTI and tumor size were not associated with progression in surveillance patients. One course Carboplatin caused relapses in 6.8 % in tumor sizes >4 cm and 9.3 % (actuarial 13 %) in sizes >5 cm. The Cox model revealed the association of tumor size with recurrence in the entire seminoma population (Hazard ratio 1.17; 95 % confidence intervals 1.03–1.33). Conclusions The overall outcome of CS1 seminoma managed on the routine care level mirrors that of controlled trials. Unexpectedly, the risk factors in surveillance patients were not confirmed, but tumor size proved to be a risk indicator in the entire group of seminoma. Importantly, one course Carboplatin involved low efficacy to control the disease in large tumors. Electronic supplementary material The online version of this article (doi:10.1007/s00432-016-2162-z) contains supplementary material, which is available to authorized users.

The primary objective of this augmental, prospective, uncontrolled phase II multicentre trial was to assess adverse events (AE) associated with malignant glioma resection using 5-aminolevulinic (5-ALA). During accrual, the standard of adjuvant therapy changed to concomitant radiochemotherapy with adjuvant temozolomide (RT/TMZ). Thus, this study also provided a platform for investigating the influence of RT/TMZ on survival in patients with fluorescence-guided resections. Malignant glioma patients, aged 18-75 years and with a Karnofsky performance score (KPS) ≥70%, were eligible. Data were collected on adverse events, KPS, survival and adjuvant therapies. In 243 patients evaluable for safety, 6-week AE incidence was 51.9% (nervous system disorders: 30.0%). Three patients experienced four possibly drug-related AEs. Grade III/IV incidence was 18.9% (nervous system disorders: 10.7%). About 48 h after surgery, AE incidence was 26.3% (9.9% grade III/IV), which was related to overall survival. A total of 219 patients (glioblastoma 206; anaplastic astrocytoma: 13) qualified for efficacy analysis. Median overall survival was 14.1 months (95% CI: 12.0-16.6), but 16.3 (13-19.2) months in 122 glioblastoma patients receiving RT/TMZ compared to 11.9 (9.6-14.1) months in the remaining 84 patients (P = 0.0194). Older patients (≥60 years) had less adjuvant therapies than younger patients. Median survival of older glioblastoma patients with RT/TMZ was also significantly prolonged (16.3; 12.0-17.2 months vs. 11.2; 7.4-14.1, hazard ratio = 0.55; 0.32-0.92). Risks of surgery were similar to past experiences with 5-ALA. Ancillary analyses demonstrated surgical glioblastoma patients, including the elderly, to have derived benefit from RT/TMZ. Thus, older patients should not generally be excluded from accepted therapies (fluorescence-guided resection plus RT/TMZ).

Myelodysplastic syndromes (MDSs) often occur in older adults with significant comorbidities. Therefore, a reduced-toxicity conditioning regimen may be more suitable than standard conditioning regimens before allogeneic blood stem cell transplantation. Here, we retrospectively compare the outcome of a treosulfan-based conditioning regimen with standard myeloablative TBI-based conditioning regimens in patients (pts) with MDS. A total of 48 pts with MDS were included in the study, of which 29 (60%) pts received TBI-based and 19 (40%) pts received a treosulfan-based conditioning regimen. A significantly lower relapse incidence (5% vs 34% at 3 years, P=0.019) resulting in a better, but not statistically significant relapse-free survival (RFS) (57% vs 31%, P=0.086) was observed after treosulfan-based conditioning. In pts with increased risk for significant side effects due to comorbidities (haematopoietic stem cell transplantation specific comorbidity index), the estimated 3-year RFS was significantly better in the treosulfan group: 54% (95% confidence interval (CI), 17-90%) compared with pts in the TBI group: 11% (95% CI, 0-44%; log-rank test P=0.0455). Treosulfan-based conditioning therapy is a feasible and effective regimen for pts with MDS, especially in pts with preexisting comorbidities.

Objectives: To determine preference, satisfaction, usability and local tolerability by patients, physicians and study nurses of two subcutaneously administered methotrexate (MTX) formulations of different concentrations.

Objectives Searching for testicular intraepithelial neoplasia (TIN; carcinoma in situ) in the contralateral testis of patients with germ cell tumour (GCT) may early disclose contralateral GCT. A single biopsy of the testis is thought to accurately detect TIN. Reports on false-negative biopsies have challenged this view. We investigated whether systematic two-site biopsies are more sensitive than single biopsies. We also studied the prevalence of contralateral TIN in a large patient sample. Methods A total of 2318 patients with testicular GCT underwent contralateral double biopsy. All of the biopsy pairs were examined histologically for spermatogenesis and for presence of TIN. Statistical analysis involved first, overall prevalence of contralateral TIN; second, associations of clinical factors with TIN; third, frequency of discordant findings regarding TIN among biopsy pairs; and finally, associations of discordance with clinical factors. Results A total of 119 patients (5.13%; 95% confidence interval [CI], 4.27–6.11) had contralateral TIN. TIN is associated with poor spermatogenesis (relative risk [RR] 15.74; 95%CI, 10.38–23.86) and with testicular atrophy (RR 3.78). According to TIN, 31.1% of biopsy pairs were discordant. Discordance was significantly less frequent in atrophic testes and in patients with poor spermatogenesis. Conclusions We confirmed the prevalence of contralateral TIN to be about 5%. TIN is significantly associated with poor spermatogenesis and with testicular atrophy. The diagnostic extra yield imparted by double biopsies is 18%. Discordant results regarding TIN are predominantly encountered in normal-sized testicles. The new standard in diagnosing TIN is two-site biopsy.

5-Aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas-a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity.322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670.Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery.Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.

Objective: Testicular biopsy has recently gained a role in early detection of testicular cancer. However, its use is still limited mainly because of the fear of untoward consequences. There is a paucity of data regarding unfavourable effects of testicular biopsy. Therefore, we systematically looked to the consequences of the procedure by using clinical observational methods and by modern imaging techniques, respectively. Patients, methods: 1874 patients with testicular cancer enrolled in a nation-wide contralateral biopsy study were prospectively analyzed in regard to surgical complications. Serial scrotal imaging was performed by scrotal sonography (7.5Mhz) in 55 patients and by magnetic resonance tomography (1.5 Tesla machine, surface coil, contrast media) in 60 patients, respectively. Imaging examinations were done preoperatively and again at 1 week, 6 months, 12 months, and 18 months respectively. Imaging results were tabulated according to an abnormality score and analyzed by descriptive statistics. Results: 52 patients (2.78%; 95% confidence intervals 2.05–3.60) experienced surgical complications. Forty minor complications were managed conservatively. Twelve patients (0.64%) required repeat surgery; 1 testicle was ultimately lost following a sequence of unfortunate events. No pre-existing clinical parameter was associated with complications. One week after surgery, abnormalities were detected in 33% by sonography and in 45% by MRI, respectively. Importantly, the abnormalities resolved in 96% of the cases, as found in both of the imaging modalities in the serial scans. Conclusions: Testicular biopsy is associated with a low burden of clinically significant complications. However, scrotal imaging discloses intratesticular abnormalities in a high proportion of cases one week after the biopsy. These changes represent focal haematoma, oedema or circumscript injury to vascular supply. Most of these lesions resolve with time and are thus not significant, clinically. Evidently, testicular biopsy is a safe procedure provided the vascular anatomy of the testis is respected upon surgery.

BACKGROUND AND OBJECTIVE Allogeneic transplantation can not be offered to many patients due to potential side-effects of conventional conditioning. Dose-reduced conditioning approaches improve tolerability, however, treatment efficacy may be reduced as well. We have, therefore, developed a dose intense but toxicity reduced conditioning regimen based on treosulfan and fludarabine and report first results. PATIENTS AND METHODS 65 patients with a median age of 50 years were transplanted from related (n = 21) or unrelated donors (n = 44) after conditioning with treosulfan (3 x 10, 3 x 12 or 3 x 14 g/m(2) i. v.) and fludarabine (5 x 30 mg/m(2) i. v.). 21 patients were in complete remission (CR) and 44 patients had not reached a CR at the time of transplantation. 59 of 65 patients were considered unfit for a conventional conditioning regimen. RESULTS The actuarial overall survival after 3 years is 59.2 %, the event-free survival 40.1 %. Patients with a related donor or transplantation in CR had a better overall (85.4 resp. 74.2 %) and event-free survival (52.2 % resp. 61.9 %). The cumulative incidence of relapse at 3 years was 26.2 %. Non-relapse mortality at day 100 is 17.4 % (cumulative incidence). In stepwise Cox regression analyses for overall survival, event-free survival and non-relapse mortality the covariables transplantation in CR vs. not in CR and the donor status were shown to be influential. CONCLUSIONS These results with a conditioning therapy of treosulfan and fludarabine indicate that patients despite higher age, concomitant disease or after intensive pretreatment can be successfully transplanted without increased treatment-related mortality.

Treosulphan has recently demonstrated antileukaemic activity and potent haematopoietic stem cell toxicity. Dose-escalated treosulphan (3 x 12 or 3 x 14 g/m2) combined with cyclophosphamide (Cy) was chosen for a new preparative regimen before allogeneic haematopoietic stem cell transplantation in 18 patients (median age 44, range 19-64 years) with haematological malignancies, considered ineligible for other myeloablative preparative regimens. Pharmacokinetic studies demonstrated rapid treosulphan plasma clearance and a dose-dependent increase of its maximum plasma concentrations and area under the concentration-time curves. Rapid and sustained white blood cell and platelet recovery and full donor chimerism was attained in all evaluable patients. Nonhaematological regimen-related CTC grades 3-4 adverse events were transient and predominantly consisted of cardiac (28%), gastrointestinal (39%), and hepatic (39%) toxicities. The 1-year nonrelapse mortality was 22%. Principal causes of transplant-related lethal events were infections in three of four affected patients. Only one patient died from regimen-related cardiac toxicity. The 1-year relapse estimate is 22%, overall and progression-free survival estimates are 67 and 56%, respectively. In conclusion, this new treosulphan and Cy combination is an effective, comparatively well-tolerated myeloablative preparative regimen even in patients with an increased risk for regimen-related toxic complications.

Fluorescence diagnosis induced by 5-aminolevulinic acid enables more thorough transurethral resection of superficial bladder carcinoma compared with conventional white light. We performed a prospective, single institution, randomized trial to investigate whether the residual tumor rate and long-term tumor recurrence can be decreased by fluorescence diagnosis.A total of 301 patients underwent transurethral resection of bladder tumors with white light or fluorescence diagnosis. Transurethral resection was repeated 5 to 6 weeks later to evaluate the residual tumor rate. To determine recurrence-free survival patient followup was performed every 3 months by white light cystoscopy and urine cytology. Recurrence-free survival was analyzed via Kaplan-Meier methods and multivariable Cox regression analysis.A total of 191 patients with superficial bladder carcinoma were available for efficacy analysis. The residual tumor rate was 25.2% in the white light arm versus 4.5% in the fluorescence diagnosis arm (p0.0001). Median followup in the white light arm in 103 cases was 21.2 months (range 4 to 40) compared with 20.5 (range 3 to 40) in the 88 in the fluorescence diagnosis arm. Recurrence-free survival in the fluorescence diagnosis group was 89.6% after 12 and 24 months compared with 73.8% and 65.9%, respectively, in the white light group (p = 0.004). This superiority proved to be independent of risk group. The adjusted hazard ratio of fluorescence diagnosis versus white light transurethral resection was 0.33 (95% confidence interval 0.16 to 0.67).Fluorescence diagnosis is significantly superior to conventional white light transurethral resection with respect to the residual tumor rate and recurrence-free survival. The differences in recurrence-free survival imply that fluorescence diagnosis is a clinically relevant procedure for decreasing the number of tumor recurrences.

Purpose: We prospectively validate an algorithm to predict pelvic lymph node metastasis in patients with clinically localized prostatic carcinoma.Material and Methods: A total of 293 patients with prostatic cancer were identified before pelvic lymph node dissection according to an algorithm developed with the classification and regression tree analysis as high—greater than 3 sextant biopsies containing any Gleason grade 4 or 5 cancer, intermediate—at least 1 biopsy dominated by Gleason grade 4 or 5 cancer but not high risk and low risk—all other patients. Observed and predicted frequencies of pelvic lymph node metastasis were compared.Results: The observed frequencies of lymph node metastasis were remarkably similar to the predicted frequencies, including 2.8% versus 2.2% in 85.7% of patients in the low risk group, 16.7% versus 19.4% in 10.2% intermediate and 41.7% versus 45.5% in 4.1% high, respectively. If patients in the low risk group were considered to have node negative disease the specificity and n...

Many reports on glioblastoma multiforme discuss the prognostic impact of anatomical features such as cysts, necrotic changes, extent of edema or subependymal spread of tumor cells. In the present study, we examined different growth patterns and their possible relations to patient survival.To analyze whether anatomical characteristics are related to prognosis, we reviewed the prospectively collected pre- and postoperative MRIs of 83 patients in the 5-ALA study, provided by the 5-ALA Glioma Study Group. Following a standardized analytic work flow, the tumor volume and site, presence of necrosis or cysts, and perifocal edema were assessed preoperatively. In the same way, postoperative MRI and the MRI at first recurrence were analyzed. In addition, survival time of the patients was documented.Median survival time of all 83 patients was 15.1 months (range 1.5 to 70.1, mean 18). The site or volume of glioblastoma, as well as the presence of intratumoral necrosis or cysts, did not exert a significant effect on survival time; 96.4 % of recurrences occurred within the former resection margin. Tumors with initial contact with the subependymal zone had multifocal or ventricular recurrences significantly more often. In patients with residual tumor on early postoperative MRI, the follow-up images displayed enlargement of the remnants in 91.9 % of these cases.A merely anatomical analysis of the glioblastoma growth pattern cannot reliably provide prognostic information. The occurrence of most recurrences next to the resection margin and the high percentage of growing residual tumors underline the importance of complete resections.

Summary The precursor of testicular germ cell tumours (GCTs), called testicular intra-epithelial neoplasia (TIN/CIS), is safely diagnosed immunohistologically. Testicular biopsy provides a valuable tool for early detection of GCTs in risk groups. Although this knowledge is undisputed, testicular biopsies are utilized poorly. The patterns of care regarding the use of biopsies remain unknown. Uncertainty exists about the prevalence and specific treatment of TIN/CIS. We asked clinical urologists in Germany whether or not they employed contralateral biopsies in GCT patients. We evaluated the prevalence of contralateral TIN/CIS in a retrospective analysis of 780 consecutive GCT patients. All had contralateral double biopsies. Discordance of TIN/CIS findings among biopsy pairs as well as age, histology of the primary tumour and clinical stage was noted. Evaluation of data comprised descriptive statistical methods. To evaluate treatment options for TIN/CIS, we performed a literature search. 52.1% of German urologists always perform the biopsy, 17% do it mostly, 27.3% in select cases, 3.5% never. Curiously, there was a geographic north-south gradient regarding biopsy use. Contralateral TIN/CIS was found in 5%. The median ages of patients with TIN/CIS and those without were 31.8 and 34.9 years respectively (p = 0.02). The discordance rate among biopsy pairs was of 33%. Two-site biopsies provide a 17% gain in diagnostic sensitivity. Local radiotherapy with 20 Gy is the safest treatment of TIN/CIS failing in 2%. Chemotherapy has significantly lower efficacy. Contralateral testicular biopsies in GCT patients are well accepted among German urologists. The prevalence of contralateral TIN/CIS found in this series is in accordance with previous reports. Double biopsies should be the diagnostic standard because of their diagnostic superiority. Local radiotherapy with 20 Gy is the safest way of eradicating TIN/CIS. Failures occur in only 2%, usually many years after irradiation. Cisplatin-based chemotherapy is dose dependent and less effective.

Objective: To assess usability, bioavailability, and safety of subcutaneous self-administration of 0.3 mL of methotrexate 50 mg/mL solution via a prefilled autoinjector pen (methotrexate pen) in patients with rheumatoid arthritis. Methods: The study enrolled methotrexate-naïve and methotrexate-experienced patients aged ≥16 years. Visit 1 (Day 1) included methotrexate pen usage training with documentation, patient self-injection, and a patient-training questionnaire completed by the healthcare professional. Visit 2 (Days 8–10) included evaluation of patient self-injection through four scenarios: holding needle in place for 5 s, confirming methotrexate delivery, skin pinch, and pen disposal. At Visit 2, patient opinion and training retention (since Visit 1) were also assessed. Pharmacokinetic parameters were assessed in 25 patients, who were stratified by body weight and randomized to receive injections in the abdomen or the upper thigh. Results: At Visit 1, 12 of 106 patients had questions about the pen, and 4 required self-injection assistance. At Visit 2, the mean performance rating for all scenarios was ≥9.8 (scale: 1 (very difficult)−10 (very easy)). Successful completion rates were 96.2%–100%; 91.3%–100% of patients required no assistance. Impressions of the pen were favorable; 98.1% of patients passed the written examination. All methotrexate pens effectively delivered 0.3 mL methotrexate and were intact after use. Body weight >100 kg significantly decreased total and peak methotrexate exposure when administered abdominally. No adverse effects resulted in drug discontinuation. Conclusion: The methotrexate pen was used with a high degree of effectiveness, satisfaction, and safety, indicating that this delivery system may be a viable option for patients requiring subcutaneous methotrexate.

Total-body-irradiation (TBI) based preparative regimens are considered as standard conditioning therapy for allogeneic stem cell transplantation (AHSC) in patients with acute lymphoblastic leukemia (ALL). Within a multi-center prospective phase II study we have investigated the toxicity and efficacy of a non-TBI-based regimen consisting of treosulfan, etoposide, and cyclophosphamide in patients with ALL. Inclusion criteria were complete remission, non-eligibility for TBI or patient’s wish to avoid TBI. Between July 2007 and August 2010, 50 patients with a median age of 46.5 years were enrolled at ten German centers. 74% of the patients were in 1. CR and 26% 2. or higher CR.The conditioning regimen consisted of treosulfan (12 g/m²) given intravenously on three consecutive days (-7, -6, and -5) plus etoposide (30 mg/kg BW) infused on day -4, and cyclophosphamide (60 mg/kg BW) intra­venously on day -3 and -2. GvHD prophylaxis consisted of ATG-Fresenius (Fresenius Biotech, Gräfelfing, Germany), 20 mg/kg on day -3, -2, and -1 for unrelated donors, and optional for matched related donors. All patients received cyclosporine A and short course methotrexate (days 1, 3 and 6). Donors were HLA-identical sibling (n=8), matched (n=42) or mismatched (n=10) unrelated. Primary graft-failure was observed in three patients. The toxicity was moderate including VOD in four patients. Acute graft-versus-host disease (GvHD) grade II - IV and grade III/IV was noted in 53 % and 14 %, respectively. Chronic GvHD at one year was seen in 41 %, which was extensive in 14 %. After a median follow-up of 24 months, the cumulative incidence of non-relapse mortality (NRM) at one year was 8 %, and of relapse 36 % and 51 % at one and two years, respectively. Patients in first complete remission showed a 12-months relapse-rate of 23 % compared to 69 % in patients beyond first complete remission. After 24 months, the respective rates were 34 % compared to 92 %. The estimated 2-year disease-free and overall survival was 36 % and 48 %, respectively. Patients in first complete remission experienced a median DFS of 25.7 months versus 8.9 months in patients beyond first complete remission. The 12- and 24-months DFS-rates were 69 % and 50 %, respectively, compared to 23 % and 0 %, respectively. Overall, we conclude that a conditioning regimen containing treosulfan, etoposide, and cyclophosphamide resulted in a low NRM , but a high risk of relapse in 2. or higher complete remission. This regimen might represents an alternative therapy for patients with ALL in 1.complete remission who need allogeneic stem cell transplantation but are not eligible for total-body irradiation. (registered under NCT00682305) Disclosures Kröger: Medac: Research Funding; Fresenius: Research Funding; Pierre Fabre: Research Funding. Off Label Use: Treosulfan is not approved for stem cell transplantation. Kobbe:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other.

Nerve sparing radical prostatectomy for prostate cancer should be restricted to patients who harbor tumors without capsular penetration. To our knowledge the selection criteria for nerve sparing radical prostatectomy are not clearly defined. We investigated a panel of preoperative tumor characteristics with respect to their ability to predict organ confined tumor growth for each lobe of the prostate to indicate unilateral or bilateral nerve sparing radical prostatectomy.Nine preoperative tumor characteristics in 278 patients with clinically localized prostate cancer were included in retrospective univariate and multivariate tree structured regression analysis. The association of clinical stage, serum prostate specific antigen (PSA), PSA density, and results of transrectal ultrasound and systematic sextant biopsy, including a quantitative assessment of cancer in the biopsies with organ confined tumor growth, was statistically evaluated. Except for serum PSA and PSA density preoperative characteristics were considered separately for each prostate lobe. Multivariate analysis results were validated prospectively in 353 patients.On univariate analysis the number of positive biopsies was the most useful single parameter with a positive predictive value of 83% in 274 lobes and a negative predictive value of 55%, followed by mm. of tumor in the biopsy. Of all characteristics included in multivariate analysis only the number of biopsies with high grade cancer, the number of positive biopsies and serum PSA were independent for predicting organ confined cancer. When PSA was less than 10 ng./ml. and not more than 1 biopsy with high grade cancer was identified in a lobe, organ confined tumor growth was present in 86.1% of cases. On prospective validation the same criteria led to an 88.5% incidence of organ confined prostate cancer. Pooling the 2 most favorable groups led to 391 prostate lobes (70.8% of those investigated) with a positive predictive value of 82.1% (95% confidence interval 77.9% to 85.8%). Using the multivariate approach more prostate lobes were assigned to a favorable risk group than on univariate analysis. Clinical stage and simple Gleason grade did not contribute independent information for predicting organ confined disease.Quantifying cancer and high grade cancer by systematic biopsy and serum PSA concentration are useful preoperative characteristics for predicting organ confined prostate cancer. Side specific analysis of these parameters is a flexible and reliable tool for selecting patients for nerve sparing radical prostatectomy.

Purpose/Aims: The prenatal estrogen excess hypothesis postulates abnormally high estrogen levels during pregnancy which predispose the developing gonad to testicular germ cell cance

To analyze the effects of radiochemotherapy on the pro-oxidative/antioxidative balance in plasma, we measured the total radical antioxidant parameter of plasma (TRAP) and single plasma antioxidants (uric acid, sulfhydryl groups, α-tocopherol, ubiquinone-10/total coenzyme-Q10 ratio, ascorbate, and bilirubin) every 12 h during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation (BMT). Nontransferrin-bound iron (NTBI) was monitored as a potential pro-oxidant. Plasma levels of polyunsaturated fatty acids (PUFA) were measured as substrates, and thiobarbituric acid–reactive substances (TBARS) were measured as products of lipid peroxidation. Allantoin was analyzed as the product of uric acid oxidation. Patients receiving busulfan, VP-16, and cyclophosphamide (BU/VP/CY) (n = 8) were compared with those receiving total body irradiation in addition to VP-16 and cyclophosphamide (TBI/VP/CY) (n = 8). TRAP values were within the normal range before therapy and decreased after BU/VP/CY by 37% (p < .02) and after TBI/VP/CY by 39% (p < .02). During TBI and after VP-16, a temporary increase in TRAP values occurred, which was not related to changes in individual antioxidants. In vitro experiments confirmed that VP-16 had an antioxidative effect. The concentration of uric acid declined in both groups and correlated with TRAP (BU/VP/CY: r = .80, p < .001; TBI/VP/CY: r = .84, p < .001). Levels of NTBI, which is normally not found in plasma, increased rapidly during conditioning therapy (p < .02 in both groups) and correlated inversely with TRAP (weighted intraindividual Spearman rank correlation coefficient for both groups: NTBI and TRAP: r = −.59, p < .001) and PUFA (in the radiochemotherapy group: r = −.67, p < .001). Whereas PUFA declined (p < .02 in both groups), TBARS increased (p < .05 in both groups). Furthermore, an increase of allantoin and ubiquinone-10/total coenzyme-Q10 ratio in the BU/VP/CY group was found (allantoin: p < .02; ubiquinone-10/total coenzyme-Q10 ratio: p < .05). Antioxidants only partially recovered to baseline values until day 14 after BMT. Our findings indicate oxidative stress after high-dose radiochemotherapy and suggest a contribution of NTBI therein.

In a retrospective series of 86 patients with myasthenia gravis, the only factors predictive of improvement in muscular strength after transsternal thymectomy were preoperative severity of myasthenia (90% versus 54%, p =0.0014) and HLA-B8 (79% versus 50%, p =0.0060) in bivariable and multivariable analyses. Both factors were not interrelated ( p =0.824). The statistical effect of HLA-B8 was independent from preoperative severity of disease. Typing for HLA-B8 may thus be a valuable adjunct in predicting the benefit of thymectomy in myasthenia. The observation that an MHC class I allele is associated with clinical improvement after thymectomy suggests that the clinical course of myasthenia may be influenced by class I restricted T-cells.

An algorithm including the results of systematic sextant biopsies was statistically developed and evaluated to predict the probability of pelvic lymph node metastases in patients with clinically localized carcinoma of the prostate.Clinical stage, serum prostate specific antigen concentration, Gleason score, number of positive biopsies, number of biopsies containing any Gleason grade 4 or 5 cancer and number of biopsies predominated by Gleason grade 4 or 5 cancer were recorded in 345 patients undergoing pelvic lymph node dissection and correlated with the incidence of lymph node metastases. Multivariate logistic regression, and classification and regression trees analyses were performed.In univariate analysis all variables had a statistically significant influence on lymph node status. Logistic regression showed that the amount and distribution of undifferentiated Gleason grade 4 and 5 cancer in the biopsies were the best predictors of lymphatic spread followed by serum prostate specific antigen. Classification and regression trees analysis classified 79.9% of patients who had 3 or fewer biopsies with Gleason grade 4 or 5 cancer and no biopsies predominated by undifferentiated cancer as a low risk group. In this group positive lymph nodes occurred in only 2.2% (95% confidence interval 0.8 to 4.7%).Including the results of systematic sextant biopsies substantially enhances the predictive accuracy of algorithms that define the probability of lymph node metastases in prostatic cancer. Patients thus defined as having no lymphatic spread could potentially be spared pelvic lymph node dissection before definitive local treatment.

PURPOSE: The present prospective, randomized clinical trial compares the outcome of surgical hemorrhoidectomy according to Parks and Milligan-Morgan in terms of hospital stay, duration of incapacity to work, symptom relief, length of morbidity, and patient convenience. METHODS: Thirty-four consecutive patients with third or fourth degree internal hemorrhoids were randomly allocated to the two groups. Before surgery, all patients were interviewed using a standard questionnaire, followed by rectal examination. All patients underwent a follow-up interview and examinations 1, 2, 4, 8, and 12 weeks after the operation. RESULTS: No serious postoperative complications were seen. Length of hospital stay (3.2 days for Parks hemorrhoidectomyvs. 4.6 days for Milligan-Morgan hemorrhoidectomy; 95 percent confidence interval, 0.2 and 2.6, respectively;P=0.02) and mean duration of incapacity to work (12.3 days for Parks hemorrhoidectomyvs. 20.2 days for Milligan-Morgan hemorrhoidectomy; 95 percent confidence interval, 5.7 and 10.2, respectively;P

OBJECTIVE: To evaluate the effectiveness of lymphadenectomy in the treatment of non-small cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: The extent of lymphadenectomy in the treatment of NSCLC is still a matter of controversy. Although some centers perform mediastinal lymph node sampling (LS) with resection of only suspicious lymph nodes, others recommend a radical, systematic mediastinal lymphadenectomy (LA) to improve survival and to achieve a better staging. METHODS: In a controlled, prospective, randomized clinical trial, the effects of LA on recurrence rates and survival were analyzed, comparing LS and LA in 169 patients with operable NSCLC. RESULTS: After a median follow-up of 47 months, LA did not improve survival in the overall group of patients (hazard ratio: 0.78; 95% confidence interval: 0.47-1.24). Although recurrences rates tended to be reduced among patients who underwent LA, these decreases were not statistically significant (hazard ratio: 0.82; 95% confidence interval: 0.54-1.27). However, analysis of subgroups of patients according to histopathologic lymph node staging revealed that LA appears to prolong relapse-free survival (p = 0.037) with a borderline effect on overall survival (p = 0.058) in patients with limited lymph node involvement (pN1 disease or pN2 disease with involvement of only one lymph node level); in patients with pN0 disease, no survival benefit was observed. CONCLUSIONS: Radical systematic mediastinal lymphadenectomy does not influence disease-free or overall survival in patients with NSCLC and without overt lymph node involvement. However, a small subgroup of patients with limited mediastinal lymph node metastases might benefit from a systematic lymphadenectomy.

Major histocompatibility complex molecules (HLA), the co-stimulatory molecule B7 and the intercellular adhesion molecule 1 (ICAM-1) are key molecules involved in T cell-mediated immune surveillance. We aimed at assessing the expression pattern of these immunoregulatory molecules on primary esophageal carcinomas and evaluating their prognostic significance. Representative samples of primary tumors were obtained from 53 patients who had undergone radical en bloc esophagectomy without residual tumor. Cryostat sections of these tumors were stained with monoclonal antibodies (MAbs) directed against either HLA class I, HLA class II, B7 or ICAM-1. The median follow-up was 19 months (range, 6-43). We found that HLA class I expression was deficient on 27 tumors, while a significant neo-expression of HLA class II, B7 and ICAM-1 (> or =25% positive tumor cells) was observed on 17, 29 and 25, tumors, respectively. Kaplan-Meier analyses revealed a significant beneficial influence on relapse-free survival for patients with tumors expressing HLA class I, HLA class II and B7. Cox's regression analyses demonstrated that co-expression of HLA class I and ICAM-1 was a significant and independent predictor of a reduced risk of developing tumor recurrence, whereas expression of ICAM-1 on HLA class I negative tumors was correlated with an increased risk of tumor relapse.

BACKGROUND Undescended testes and antecedent testicular tumor are recognized risk factors for testicular germ cell cancer. It has been suggested that a family history of testicular cancer constitutes another major risk indicator. This postulation is mainly based on clinical observations and on very few systematic investigations. In the current study, the authors analyzed the proportion of familial testicular cancer in their study population and estimated the relative risk created by a family history of the disease. METHODS The proportion of familial testicular cancer was analyzed in a prospective multicentric study involving 1692 patients. The median ages of patients with and without a family history of the disease were compared. In a different patient population consisting of 518 patients and 531 age-matched controls, the frequency of family history was investigated and the relative risk calculated. In addition, a literature survey was performed to look for previous systematic reports on familial testicular cancer. RESULTS In the prospective study, 18 patients (1.1%; 95% confidence interval, 0.63-1.68%) had a first-degree relative afflicted with testicular cancer. Age at presentation was not significantly different between patients with a family history and those without. In the retrospective series, the proportion of those with a family history was 1.7% (95% confidence interval [CI], 0.80-3.27%). There was a 3.1-fold increased relative risk (95% CI, 0.77-17.95) for first-degree relatives of patients with testicular cancer. Ten previous reports on familial testicular cancer were identified in the literature. Combining the results of those previous reports and the current study led to a weighted mean prevalence of familial testicular cancer of 1.35% (95% CI, 1.12-1.58%). CONCLUSIONS The current study underscores that susceptibility to testicular germ cell cancer is influenced by genetic factors. A family history of testicular cancer is encountered in about 1.35% of patients. The relative risk for first-degree relatives of patients with the disease is increased by a factor of 3-10. Cancer 1997; 80:1954-60. © 1997 American Cancer Society.

The relationship between interleukin-6 (IL-6) and the soluble interleukin-6 receptor (sIL-6R) was analyzed in 1481 serum samples of 82 patients after bone marrow or peripheral blood cell transplantation. The cytokine and its soluble receptor were measured on a daily basis starting at day -3 before and ending at day 21 after transplantation. IL-6 serum levels increased after transplantation, were at a maximum at day 6 and returned to the baseline level thereafter. The levels of sIL-6R showed an inverse course with a minimum at day 6. Statistical analysis revealed a strong inverse correlation between IL-6 and sIL-6R with a weighted Spearman rank correlation coefficient of -0.53 (P < 0.001). IL-6 may play a role in the decrease of sIL-6R either by the direct inhibitory effect on the expression of the IL-6R gene or by formation of IL-6/sIL-6R complexes followed by their internalization in target cells.