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We describe three cases of ultrasonographically diagnosed thrombosis of the internal jugular vein encountered in an oncological department. Vague symptoms often delay the diagnosis, but it should be considered when patients present with subacute unilateral oedema of the neck, root of neck, or periclavicular region. At present, treatment is heparin initially and coumarins for a minimum of three months.

Serum lactate dehydrogenase isoenzyme I catalytic concentration (S-LD-1) was measured in patients with testicular seminoma clinical stage I followed with surveillance after orchiectomy. The serum samples were obtained before orchiectomy in 110 patients (group A) and soon after orchiectomy in 55 patients (group B). In group A, 60 patients (55%) had elevated S-LD-1 and 10 patients (9%) had elevated serum human chorionic gonadotropin concentrations (S-hCG). In group B, median S-LD-1 was lower than that of group A and decreased with increasing time after orchiectomv (p = 0.001, Jonckheere-Terpstra test, one-sided). After a median follow-up of 5.1 years, 23 patients (21%) in group A had relapses. The patients with elevated S-LD-1 and those with normal S-LD-1 had a similar relapse-free survival (p = 0.79, log-rank test). Thus patients with seminoma stage I had elevated S-LD-1 more often than elevated S-hCG but an elevation in S-LD-1 did not predict a relapse during follow-up with surveillance. Further studies are required to elucidate the value of S-LD-1 in monitoring the surveillance of patients with seminoma stage I.

PURPOSE: To determine the effect of radiotherapy in doses 14 to 20 Gy on eradication of carcinoma-in-situ (CIS) testis and on the Leydig cell function. PATIENTS AND METHODS: Forty-eight patients presented with unilateral testicular germ cell cancer and CIS of the contralateral testis. The CIS-bearing testis was treated with daily irradiation doses of 2 Gy, 5 days a week, to a cumulative dose of 20 Gy (21 patients), 18 Gy (three patients), 16 Gy (10 patients), and 14 Gy (14 patients). RESULTS: All patients treated at dose levels 20 Gy to 16 Gy achieved histologically verified complete remission without signs of recurrence of CIS after an observation period of more than 5 years. One of 14 patients treated at dose level 14 Gy had a relapse of CIS 20 months after irradiation. Leydig cell function was examined before and regularly after radiotherapy in 44 of 48 patients. The levels of testosterone were lower after radiotherapy than before. Testosterone showed a stable decrease for more than 5 years after treatment (3.6% per year) without dose dependency. The levels of luteinizing hormone and follicle-stimulating hormone were increased after radiotherapy. The need of androgen substitution therapy was similar at all dose levels. CONCLUSION: Testicular irradiation is a safe treatment at dose level 20 Gy (10 × 2 Gy). Decrease of dose to 14 Gy (7 × 2 Gy) might lead to risk of relapse of CIS. Impairment of hormone production without clinically significant dose dependency is seen in the dose range 14 to 20 Gy.

The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) regimen has been the standard treatment in patients with locally advanced and metastatic urothelial cancer for the past 15 years. The minimal or moderate survival benefit-depending on prognostic features-and the severe toxicity associated with the MVAC regimen have made the search for new drugs and drug combinations of utmost importance to increase efficacy and/or decrease toxicity. In this respect, the taxanes and gemcitabine are promising new drugs. Paclitaxel and docetaxel as single agents have yielded overall response rates of 7% to 56%, depending on whether the patients have received prior chemotherapy for metastatic disease. The combination of paclitaxel and cisplatin has been explored in three studies with a total of 104 evaluable patients, a pooled overall response (OR) rate of 61%, and a complete response (CR) rate of 20%. There are two studies of docetaxel and cisplatin with a total of 91 evaluable patients, an OR rate of 54%, and a CR rate of 16%. The OR rate for paclitaxel and carboplatin in six studies was 43%, with a CR rate of 13%; however, the reported median survival was only 8.5 to 9.5 months. The OR rate for single-agent gemcitabine based on five studies was 26%, with a CR rate of 9%, which was apparently independent of whether the patients had received prior chemotherapy. The OR rate for gemcitabine and cisplatin in four phase II studies ranged from 41% to 57%, with a CR rate of 15% to 22% and a median survival of 12.5 to 14.3 months. Based on the encouraging results for the combination of gemcitabine and cisplatin (GC), a randomized phase III trial comparing GC and MVAC was begun in late 1996. This study of 405 randomized patients showed that the two regimens were associated with similar response rates, time to progression, and overall survival, whereas GC was associated with less toxicity than MVAC. On the basis of this superior risk–benefit ratio, the GC regimen should be favored as a new standard treatment in patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine and paclitaxel, with or without cisplatin, and the combination of ifosfamide, paclitaxel, and cisplatin. The triple combination of gemcitabine, paclitaxel, and cisplatin has yielded an OR rate of 78%, a CR rate of 28%, and a median survival of 24 months. An international phase III trial comparing this triple combination with GC in patients with locally advanced and metastatic urothelial cancer has now been initiated. Semin Oncol 29 (suppl 3):3-14. Copyright 2002, Elsevier Science (USA). All rights reserved.

Background: Bladder cancer is characterized by genomic instability. In this study, we investigated whether genomewide screening using single-nucleotide polymorphism (SNP) arrays could detect allelic imbalance (loss or gain of at least one allele) in bladder cancers. Methods: For microarray analysis, DNA was isolated from microdissected bladder tumors and leukocytes from 11 patients. The stage T1 tumor (connective tissue invasive) and the subsequent stage T2–4 tumor (muscle invasive) were available from eight of these patients, and only the first muscle-invasive stage T2–4 tumor was available from three of the 11 patients. The microarray contained 1494 biallelic polymorphic sequences. For microsatellite analyses, DNA was isolated from tumors and leukocytes of nine patients with primary T2–4 tumors and 13 patients with Ta (noninvasive) tumors. All statistical tests were two-sided. Results: We assigned a genotype to 1204 loci, 343 of which were heterozygous. Allelic imbalance was detected in known areas of imbalance on chromosomes 6, 8, 9, 11, and 17, and a new area of imbalance was detected on the p arm of chromosome 6. Microsatellite analysis of nine other T2–4 tumors and 13 Ta tumors showed that allelic imbalance was more frequent in T2–4 tumors than in Ta tumors (P

Background: While it is well documented that immune responses, e.g. proliferative responses, can be influenced by psychosocial factors, e.g. stress, less is known about the biological mechanisms mediating such influences. The aim of the present investigation was to study the effect of an experimental stressor on mRNA levels in peripheral blood leukocytes of thymidylate synthase (TS), a gene necessary for cell division, while investigating possible individual differences in stress reactivity. Methods: Fifteen healthy subjects were investigated under three experimental conditions: (1) exposure to a computerized mental stressor; (2) relaxation, and (3) control. Measurements included TS mRNA levels, total leukocyte number, leukocyte subtypes, and serum cortisol before (baseline), immediately after, and 1 h after each experimental condition. Results: While no significant differences were found between experimental conditions at baseline in cortisol (p = 0.9) or TS mRNA levels (p = 0.1), significantly higher TS mRNA expression was found immediately after stress compared to pretreatment levels (p < 0.02). Changes in cortisol levels indicated an effect of the experimental stressor, with higher cortisol levels seen immediately after stress as compared to both relaxation (p < 0.01) and control (p < 0.01). Subjects who scored above the median on the Tellegen Absorption Scale showed significantly (p < 0.05) greater increases in cortisol and percentage of lymphocytes and significantly greater decreases in percentage of neutrophil cells after stress. Conclusion: The results suggest that TS mRNA levels in peripheral leukocytes may be sensitive to mental stress and confirm previous findings indicating that subjects scoring high on the personality trait of absorption exhibit greater physiological stress reactivity.

Purpose. The cell cycle is known to be deregulated in cancer. We therefore analyzed the expression of the cell cycle related proteins p21, p27, p16, Rb, and L-myc by immunohistochemical staining of bladder tumors. Methods. The tissue material consisted of bladder tumors from three groups of patients; group 1, 23 patients with recurrent stage Ta (non-invasive) tumors; group 2, 22 patients presenting at their first admission with T2–4 (muscle invasive) tumors; group 3, 24 patients who experienced disease progression from Ta or T1 (invasive in connective tissue) to a higher stage. By immunohistochemical staining the protein expression was compared to allelic deletions of the corresponding genes. The allelic deletions were detected by PCR-based microsatellite analyses. Results. We detected a significant reduction in the expression levels of the cell cycle related proteins p21waf1 (P=0.002), p27kip1 (P=0.03), Rb (P=0.00002), and L-myc (P=0.00000007) in muscle invasive tumors compared to noninvasive tumors. Tumors presenting as muscle invasive at first diagnosis had significantly lower levels of p16/CDKN2A (P=0.01) when compared to muscle invasive tumors that followed Ta or T1 precursor lesions. We found no general correlation between allelic deletion of a gene and its immunohistochemical protein expression, indicating that the remaining allele may be capable of encoding a normal or even increased protein level. Conclusions. Our results support the hypothesis that bladder tumors with invasion at first diagnosis differ from those in which invasion follow superficial tumors. This difference is reflected as a different level in cell cycle related protein expression. The data also indicate that allelic deletions of cell cycle related genes do not correlate with an altered level of protein expression.

This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of the bladder. In the first trial, local treatment consisted of cystectomy (DAVECA 8901) and in the other trial the treatment was radiotherapy (DAVECA 8902); 153 eligible patients were randomized. The majority of the patients (89%) completed the protocol. The overall time to progression for all 153 patients was 12.9 months. Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy. The actuarial 5-year overall survival rate for all 153 patients was 29%, and 29% for both treatment groups. Multivariate analyses showed that T-stage, tumour size and serum creatinine were independent prognostic factors for survival. The cystectomy trial included 33 patients. Median survival was 78.9 months, 82.5 months with chemotherapy and 45.8 months without chemotherapy (p = 0.76). The radiotherapy trial included 120 patients. The median survival was 17.6 months. Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy. The 5-year survival rate was 19% in the group receiving chemotherapy and 24% in the groups not receiving chemotherapy (p = 0.98). Late toxicity grade 3 or 4 of the bladder was recorded in 25% of the patients (actuarial rate). Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 randomized patients with invasive bladder cancer.

In a previous study we found allelic imbalances of Rb and L-myc associated with disease stage and disease course in bladder cancer. The primary aim of the present study was to determine whether the changes found in tumors were reflected in urine sediments. Secondly we wanted to test if Rb and L-myc were frequently lost in urine sediments from patients with carcinoma in situ and no bladder tumor at present. Based on this we examined allelic deletions of the Rb and L-myc genes in tumor and urine from 55 patients with bladder tumors or carcinoma in situ. Deletions were examined on extracted DNA from tumors and urine sediments by the use of microsatellite markers located as close to the genes as possible. Fifty-five patients and 10 controls were included. We found no strict correlation between allelic deletions in bladder tumors and urine sediments from the same patient. Allelic deletions in urine sediments were at least as common in patients with carcinoma in situ and no bladder tumor (32%) as in patients with bladder tumors (20%). It was possible to identify allelic deletions in urine sediment from 1 patient with cystitis and no history of malignant bladder disease (6%). In conclusion we found no strict correlation between allelic deletions in bladder tumors and urine sediments. Allelic deletions in urine sediments seem to be at least as common in patients with carcinoma in situ as in patients with bladder tumors.

4554 Background: CIS is present in the contralateral testicle in 5-6% of untreated patients with unilateral germ cell cancer (GCC). A Danish screening program for contralateral CIS was initiated in order to prevent mGCC. Methods: In total, 4,180 GCC patients diagnosed from 1984 through 2007 were offered a contralateral single-site biopsy in relation to orchiectomy (intention to screen, ITS). A non-screened group included 450 patients. Recommended treatment for CIS was radiotherapy (RT) in doses of 14 to 20 Gy, also in chemotherapy treated (CT) patients. CIS-negative (CISneg) patients who developed mGCC had the biopsy revised according to today’s standard including immunohistochemical staining. Data was merged with national administrative registries, and information on second GCC and vital status was obtained for all patients up to December 2012. Results: Median observation time was 14.1 years (range 0.1-28.9). Contralateral CIS was found in 193 patients (4.6%). Seven CIS-positive (CISpos) patients develop...

This study was designed to establish prognostic factors for survival of patients with locally advanced or metastatic urothelial cancer. We have furthermore investigated changes in patient characteristics and treatment strategies during the last 20 years.Between 1992 and 1997, a total of 156 patients with newly diagnosed recurrent locally advanced disease (nonresectable, radioresistant) and/or metastatic transitional cell carcinoma of the urothelial tract were included in a protocol evaluating clinical and laboratory prognostic factors at baseline. The relationship between these characteristics and survival was analyzed using univariate and multivariate methods. The results were compared to the survival results of similar patients treated previously from 1976 to 1991.Median survival after diagnosis of recurrent locally advanced or metastatic disease was 5.8 months. Multivariate analysis showed that good performance status (PS), normal alkaline phosphatase (AP), absence of liver metastases and chemotherapy were independent prognostic factors for long survival. An increase in survival was found when comparison was made with 240 patients treated in the period from 1976 to 1991, but the period of treatment had no independent importance in multivariate analysis.PS, AP and liver metastases are the major important prognostic factors in metastatic urothelial cancer. Stage migration and increased use of chemotherapy may have contributed to improved median survival during the last 20 years.

The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) regimen has been considered standard therapy for advanced bladder cancer. However, the toxicity of this regimen motivated the development of safer and/or more effective therapy. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) is a promising new agent with activity in advanced disease. Early phase studies yielded response rates of 23% to 29% with single-agent treatment and 41% to 57% with the combination of gemcitabine/cisplatin (GC). In a randomized phase III trial involving 405 randomized patients with locally advanced or metastatic bladder cancer, data comparing gemcitabine at 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin at 70 mg/m(2) on day 2 every 28 days with standard MVAC demonstrated that the two regimens were associated with comparable response rates, time to disease progression, and overall survival. The GC regimen was associated with superior safety and tolerability, including reduced frequencies of grade 3/4 mucositis (1% v 22%), neutropenic fever (2% v 14%), and neutropenic sepsis (1% v 12%). These findings suggested that on the basis of superior risk to benefit ratio, the GC regimen should be favored as standard treatment in advanced bladder cancer. Other promising combinations include gemcitabine/cisplatin/paclitaxel, and a phase III trial comparing this triple-agent combination with the GC regimen in advanced bladder cancer patients has been initiated. Semin Oncol 28 (suppl 7):11-14.

Purpose: To identify pretreatment variables predicting overall and complete response to cisplatin-based chemotherapy for metastatic urothelial cancer, and to study the relation between response and the duration of survival. Patients and methods: A total of 119 evaluable patients with recurrent locally advanced or metastatic urothelial cancer received cisplatin-based combination chemotherapy in four consecutive phase II studies from 1987 to 1997. The relationship of pretreatment variables and response was evaluated with logistic regression, and prognostic factors for survival were analyzed with Cox's multivariate model. Results: Response was achieved in 49% of the patients with a complete response rate of 15%. Good performance status and absence of bone metastases were independently predictive of overall response. Good performance status and normal hemoglobin were independently predictive of complete response. Median survival was 8.9 months. Performance status, alkaline phosphatase, s-creatinine, liver and bone metastases were independent prognostic factors for survival. Median survival was 12.4 months in responding patients and 6.3 in non-responding patients. Response to chemotherapy was included in the multivariate model and was the strongest prognostic factor for survival. Conclusion: The presence of bone metastases, low hemoglobin or poor performance status predicts decreased chance of response to chemotherapy. Response to chemotherapy is an independent prognostic factor for prolonged survival in patients with metastatic urothelial cancer.

Gemcitabine is a promising new drug in patients with locally advanced and/or metastatic transitional cell carcinoma of the urothelium. The drug has been tested as a single-agent in one phase I study and four phase II studies. Gemcitabine was administered on days 1, 8 and 15 every 28 days with a dose in the phase II studies ranging from 1000 to 1250 mg/m(2). Response rates for single-agent gemcitabine in as well previously untreated as cisplatin-based pretreated patients ranged from 23 to 29% with CR rates between 4 and 13%. Toxicities were mild to modest and generally without grade 4 toxicities. The combination of gemcitabine and cisplatin has been tested in three phase II studies. Gemcitabine was administered in a dose of 1000 mg/m(2) on days 1, 8 and 15 every 28 days whereas the cisplatin dose and schedule varied. In one study, cisplatin was given in a dose of 35 mg/m(2) on days 1, 8, and 15 together with gemcitabine; in the two other studies in a dose of 70-75 mg/m(2) on day 1 or 2 in each treatment course. The response rates ranged from 42 to 66% with CR rates of 18, 21 and 28%. Median survival was reported in two of the studies, 12.5 and 13.2 months, respectively. Toxicities were generally manageable although the weekly schedule of cisplatin resulted in a high degree of grade 3-4 neutropenia and thrombocytopenia. Thus, the schedule has been optimized by use of monthly cisplatin in a dose of 70 to 75 mg/m(2). The two-drug combination of gemcitabine and cisplatin has also been compared with MVAC in a randomized phase III trial. Gemcitabine was administered in a dose of 1000 mg/m(2) on days 1, 8 and 15 and cisplatin in a dose of 70 mg/m(2) on day 2 every 28 days. The study was initiated late in 1996 and the planned recruitment of 400 patients was reached at the end of October 1998. The results are now eagerly awaited. Preliminary results for gemcitabine tested in two- and three-drug combinations with new agents such as paclitaxel have indicated response rates of up to 79% and these combinations should be further explored.

Udgivelsesdato: 2000-Jan-5 Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU). TS mRNA and protein levels in colorectal tumours are among the most important determinants for tumour response to 5-FU. TS mRNA levels in blood leukocytes may give information on pharmacokinetic and pharmacodynamic actions of 5-FU on TS as it has previously been shown that inhibition of TS levels by 5-FU in bone marrow leukocytes resembles the degree of TS inhibition in colorectal tumours. The aim of this study was to develop a quantitative high-throughput RT-PCR assay for TS mRNA expression in blood leukocytes (CURT-PCR). Furthermore the TS mRNA levels in blood of patients with colorectal cancer and healthy controls was compared. TS mRNA levels in 17 patients with colorectal cancer did not differ from 20 matched controls whereas a group of 14 younger controls had significantly lower TS mRNA expression than patients and matched controls. In order to investigate the sensitivity of the assay towards cellular reactions such as proliferative stimuli, isolated blood leukocytes were stimulated with phytohemagglutinin both in mitogenic and non-mitogenic concentrations and an induction of TS mRNA expression was measured in both cases. TS activity and cellular proliferation also increased but only at mitogenic concentrations, suggesting that TS mRNA expression is an early leukocyte activation marker. This new CURT-PCR assay may allow improved studies of functional kinetics of drugs with impact upon TS. Further studies are required to establish the possible clinical benefit of TS mRNA measurements in blood leukocytes.

In the present review, we have evaluated the outcome of radiotherapy in patients with bladder cancer. The exact value of radical radiotherapy is difficult to establish because changes in treatment techniques and selection of patients have biased the results. The 5-year survival rates are reported to be 35-71% in T1 tumors, 27-59% in T2 tumors, 10-38% in T3 tumors and 0-16% in T4 tumors. Several other factors, like performance status and hemoglobin level, are important for the outcome. Morbidity of radical radiotherapy depends on several treatment and patient related factors, but 50-75% experience acute intestinal or urological symptoms and 10-20% may develop severe late toxicity, depending on the kind of registration. The importance of field size or overall treatment time cannot be established from available data. Hyperfractionation with dose escalation has proven effective in one study. Preoperative radiotherapy with cystectomy has not proven better than cystectomy alone or better than radiotherapy alone. The addition of systemic chemotherapy has increased disease-free survival, but has not significantly reduced the rate of distant metastases or improved overall survival. Presently, the standard radiation regimen is a conventional dose and fractionation schedule to a total dose of 60-66 Gy with a three- or four-field technique covering the bladder and tumor. The efficacy of additional irradiation of regional lymph nodes is questionable. New treatment possibilities with advanced techniques of radiotherapy, hyperfractionation and dose escalation and/or the addition of systemic chemotherapy may improve outcome. These options should be further explored in clinical trials.

Background and purpose : The optimal treatment of elderly patients with bladder cancer is not established. This study aimed to evaluate prognostic variables for survival and morbidity, which may be important for treatment strategy. Material and methods : The medical records of 94 patients aged ≥ 75 years receiving curatively intended radiotherapy for bladder cancer were reviewed retrospectively. Results : Median age was 78 years (range 75–93 years). Fifty patients had T1-2 tumors, and 42 patients had T3-4 tumors. The total planned dose was 57.6–62.6 Gy in 24–30 fractions in 6 weeks. In 76 patients, a 2 week rest period was planned after 16 fractions (split course). Half of the patients were hospitalized during or after the treatment because of gastrointestinal or urogenital side effects. Median survival was 13.9 months (range 0.6–150.0 + months), 29% survived for 2 years and 7% survived for 5 years. Patients aged > 78 years survived for a shorter period than patients aged 75–78 years (13.4 versus 16.1 months). Univariate survival analysis revealed that low stage (T1-2), good performance status (PS ≤ 1), split course treatment, no treatment interruption due to side effects, and no hospitalization during treatment were associated with long survival. In multivariate analyses, T-stage, split course treatment, and performance status were independent prognostic factors. Conclusion : The results confirm that curative intended radiotherapy is feasible in elderly patients, but patients with stage T3-4 and PS > 1 have a short survival. These patients should be offered palliative treatment.

Do elderly patients with advanced urothelial carcinoma benefit from platinum-based chemotherapy?

Background Chronic inflammation has been recognized to foster tumour development. Whether chemotherapy can be used to neutralize chronic inflammation is unclear. Methods We evaluated baseline and nadir neutrophils in 111 patients (pts.) with non-small cell lung cancer (NSCLC) and 118 pts. with ovarian cancer (OC) treated with chemotherapy administered with dose-individualization to achieve nadir neutropenia of 1.5. We used predefined baseline neutrophil cut-offs 4.5 × 109/L (NSCLC) and 3.9 × 109/L (OC). Results Absence of chemotherapy-induced nadir neutropenia (CTCAE grade 0, neutrophils ≥ LLN) was seen in 23% of OC and 25% of NSCLC pts. Absence of nadir neutropenia was associated with decreased overall survival (OS) compared with presence (>grade 0) of neutropenia (9 vs. 14 months, P = 0.004 for NSCLC and 23 vs. 56 months; P = 0.01 for OC). Obtaining grade 3/4 neutropenia did not improve survival compared with grade 1/2 neutropenia. In multivariate analyses, baseline neutrophils ≥4.5 × 109/L (HR: 2.0; 95% CI: 1.11-3.44;P = 0.02) and absence of nadir neutropenia (HR: 1.6; 95% CI: 1.02-2.65;P = 0.04) for NSCLC and absence of nadir neutropenia (HR: 1.7; 95% CI: 1.04;2.93;P = 0.04) for OC were independently associated with short OS. Three prognostic neutrophil index (NI) groups were defined. Favourable NI: low baseline neutrophils and presence of nadir neutropenia (>grade 0), Intermediate NI: elevated baseline neutrophils and presence of nadir neutropenia (>grade 0), and Poor NI: elevated baseline neutrophils and absence of nadir neutropenia (grade 0). For NSCLC patients, the median OS was 18.0, 13.4, and 8.8 months for favourable, intermediate and poor NI, respectively (fav vs. poor P = 0.002; fav vs. intermed P = 0.04; and intermed vs. poor P = 0.03). For OC patients, median OS was 69, 52 and 23 months for favourable, intermediate and poor NI, respectively (fav vs. poor P = 0.03; fav vs. intermed P = 0.3; and intermed vs. poor P = 0.02). Interestingly, survival rates in the intermediate NI groups indicated that individualised dose of chemotherapy to induce neutropenia may partly overcome the negative impact of elevated baseline neutrophils. Conclusions A neutrophil index comprising elevated baseline neutrophils and absence of neutropenia identified a high risk group of NSCLC and ovarian cancer patients with only modest effect of chemotherapy. New treatment options for this subset of patients are required.

4502 Background: The standard treatment for stage I seminoma remains a topic for discussion. Survival rates are excellent irrespective of treatment modality (radiotherapy, carboplatin or surveillance). However, late effects might differ between treatment options. Only smaller surveillance studies with limited follow-up have previously been published. We present data from a large nationwide cohort study on surveillance in stage I seminoma patients. Methods: A nationwide and population based clinical database covering germ cell cancer patients diagnosed 1984-2007 was constructed. The database included 4,683 cases. All stage I seminoma patients followed by surveillance were identified. Possible prognostic factors for relapse were collected from patient files and pathology reports. By merging our data with the national patient registry we were able to collect data on late relapses, vital status and cause of death on all patients up to December 2012. Results: 1,822 patients with stage I seminoma were followed on a surveillance program. The median follow-up time was 15.4 years. Ten year cancer specific survival (CSS) was 99.6%. A total of 355 (19.5%) patients had a relapse after a median time of 13.7 months (range 1.2-173.7 months). Within 2-5 years after orchiectomy, 72 patients (4.0 %) had a relapse and 26 patients (1.4 %) had a relapse more than 5 years after orchiectomy. Invasion of blood or lymphatic vessels, tumor size > 4 cm and serum human chorionic gonadotropin > 200 IU/L were all predictive factors for relapse in both univariate and multivariate analyses (p

Introduction and objectives: More than 90% of bladder tumors are urothelial neoplasias, characterised as heterogeneous cell populations consisting of tumor cells, macrophages and stromal cells. At time of diagnosis, most neoplasias are non-invasive (stage Ta) or with invasion of lamina propria (stage T1). Despite advances in surgical techniques and intra-vesical therapy, patients with stage Ta and T1 have high recurrence and progression rates. Pathologic stage and grade, have limited ability to predict the invasive and metastatic potential, probably due to tumors of similar stage and grade having a significantly different biology. Biomarkers discriminating the microenvironment in non-invasive from invasive neoplasia are needed in order to improve curability. For this reason we have investigated one of the key players in proteolytic activity of invasive neoplasias, the plasminogen activation system. Components of this system: urokinase plasminogen activator (uPA), its cellular receptor (uPAR) and inhibitor (PAI-1), have prognostic, diagnostic and/or predictive value in several human cancers, but are poorly investigated in urothelial cancer. Materials and methods: Retrospectively collected, formalin fixed and paraffin embedded tissue samples (Haukeland University Hospital, Bergen) from 107 patients who underwent cystectomy for urothelial neoplasias in the period 1988-2005 were investigated. The material consists of 10 Ta, 24 T1, 73 T2-4 tumors, including 39 low-grade (LG) and 68 high-grade (HG) tumors. uPAR expression was investigated by immunohistochemistry using a polyclonal antibody against uPAR. uPAR expression was evaluated as either negative or positive. All cases were re-diagnosed by the same pathologist. Cancer cells were identified by staining for cytokeratin (CK-pan and CK7 combined), macrophages by CD68 and tumour associated myofibroblasts by α-smooth muscle actin (α-SMA). Results: 7/10 (70%) of the non-invasive neoplasias (stage Ta) showed no uPAR-immunoreactivity. The uPAR positive cells were only found in the surrounding stroma and not in cancer cells. In the neoplasias showing stromal- (stage T1) or muscular invasion (stage T2-T4), uPAR-positivity was found in 14/24 (58%) and 63/73 (86%) respectively. uPAR-positivity was found in 58/68 (85%) of HG tumors and in 17/39 (44%) LG tumors (p There was a significant trend between uPAR-positivity and T-stage for cancer cells, macrophages and myofibroblasts (p0.57). Conclusions: This study demonstrated that uPAR-positivity in the complex microenvironment of human urothelial neoplasia of the bladder significantly increases with T-stage and grade. Myofibroblasts and macrophage expression of uPAR may be an early marker for invasive potential in urothelial neoplasia of the bladder. This may help in the identification of T1 neoplasias with high invasive potential. The expression of uPAR, as well as PAI-1 and uPA, will be investigated in a larger material and correlated with survival/clinical data. Our aim is to establish predictive and prognostic tools for use in clinical setting based on semi-quantitative immunohistochemical methodology. Citation Format: Line Hammer Dohn, Martin Illemann, Gunilla Høyer-Hansen, Hans von der Maase, Ib Jarle Christensen, Jorunn Litlekalsoey, Jens G. Hoestmark, Helle Pappot, Ole Didrik Laerum. uPAR expression in the microenvironment of human urothelial neoplasia of the bladder is associated with invasive behavior and increases significantly with T-stage and grade. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B14.

Background. Cisplatin is one of the single drugs that has shown the best documented effect in treating patients with locally recurrent or metastatic urothelial cancer. To the authors' knowledge, the effect of the combination of different platinum analogues in treating transitional cell carcinoma has not been evaluated previously neither experimentally nor in clinical studies. Methods. A Phase II trial of carboplatin (200 mg/m 2 ), cisplatin (100 mg/m 2 ), and methotrexate (250 mg/m 2 ) with folinic acid rescue every 3 weeks was performed on 55 previously untreated patients with metastatic or locally recurrent urothelial cell carcinoma. Results. A response (complete response and partial response) was achieved in 21 of 51 evaluable patients (41% ; 95% confidence limits, 28-56%). Twelve patients had no change, whereas 18 had progressive disease. Eight patients (16%) achieved a complete response, and most of these survived more than 2 years. No patient with poor performance (performance status score ≥ 2) or bone metastases achieved a complete response. The median survival for all patients was 8.4 months. Multivariate survival analyses showed that performance status and alkaline phosphatase levels were significant prognostic factors for survival. Conclusion. Combination therapy with cisplatin, carboplatin, and methotrexate is feasible but offers no advantage over other combinations with cisplatin and methotrexate in treating metastatic urothelial cell cancer. It is important to select patients for treatment carefully, and further studies of prognostic factors in these patients are warranted.

Background. Prognostic factors for patients with disseminated transitional cell carcinoma of the urothelium (TCC) has been examined only in patients selected for studies with chemotherapy. This study was performed to determine important prognostic factors in patients with disseminated TCC and evaluate the impact of chemotherapy. Methods. The prognostic factors for survival were analyzed in 240 patients with disseminated TCC admitted from 1976 to 1992. Information on prior medical history, baseline variables, and treatment were related to survival after dissemination. Both univariate and multivariate analyses were performed to identify factors of independent importance. Results. Univariate analyses indicated that performance status; hemoglobin; leukocyte count; platelet count; concentrations of serum creatinine, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase; hydronephrosis; bone metastases; disease extension; and chemotherapy were related significantly to survival. Multivariate analysis demonstrated that a good performance status, a normal alkaline phosphatase concentration, and a normal serum creatinine concentration were independent prognosticators for long survival. When chemotherapy was included in the analysis, it was found to be the most important independent prognostic factor in conjunction with alkaline phosphatase and performance status. Conclusion. This study has established the importance of performance status and alkaline phosphatase as the most important prognostic factors of survival in patients with disseminated TCC regardless of treatment. Chemotherapy was found to be an independent prognostic variable that indicates a possible prolongation of survival in patients receiving chemotherapy.

From 1985 to 1988, 261 unselected patients entered a nationwide Danish study of surveillance only for testicular seminoma stage I. The median follow-up time after orchidectomy was 48 months, range 6-67 months. 49 patients relapsed (19%). Sites of relapse were paraaortic lymph nodes in 41 patients, pelvic lymph nodes in 5, inguinal lymph nodes in 2 and lung metastases in 1 patient. The median time to relapse was 14 months, range 2-37 months. The 4-year relapse-free survival was 80%. 37 of the relapsing patients (76%) had radiotherapy as relapse treatment. Of these patients, 4 (11%) had a second relapse and received chemotherapy. 1 died of disseminated seminoma. Of the relapsing patients, 12 (24%) had chemotherapy as relapse treatment because of bulky (11 patients) or disseminated disease (1 patient). None of these patients have had a second relapse. However, 2 patients died of infection due to chemotherapy-induced neutropenia. Thus, there have been three seminoma-related deaths (1.1%). The testicular tumour size had an independent prognostic significance. The 4-year relapse-free survivals were 94, 82 and 64% for tumours3, 3 to6 andor = 6 cm, respectively. Patients with tumoursor = 6 cm will now be given prophylactic radiation treatment, whereas we will continue to use surveillance only after orchidectomy for patients with tumours6 cm.

34 patients with metastatic or recurrent transitional cell carcinoma (TCC) of the urothelium were treated with cisplatin 100 mg/m2 plus methotrexate 250 mg/m2 with folinic acid rescue every 3 weeks. A response rate of 55% was achieved with two complete and 15 partial responses in 31 evaluable patients. The overall median survival was 7 months, 9 months for responding and 4 months for non-responding patients. Toxicity was generally moderate. However, 1 patient with previous infectious problems died of neutropenic sepsis. Overall, 83% of the scheduled doses of cisplatin and 96% of the scheduled doses of methotrexate were given. In conclusion, this schedule of the combination of cisplatin and methotrexate did not improve response rate or survival compared with previous studies of this two-drug combination.

1.Renal haemodynamics, lithium and sodium clearance were measured in 14 patients treated with recombinant interleukin-2 for metastatic renal cell carcinoma. 2.Patients were studied before and after 72 h of continuous intravenous infusion of recombinant interleukin-2 (18×106 i.u.·24 h-1·m-2) and 48 h post therapy. Cardiac output was measured by impedance cardiography. Effective renal plasma flow and glomerular filtration rate were determined by the renal clearances of 131I-hippuran and 99mTc-diethylenetriaminepenta-acetic acid (DTPA) respectively. Renal clearance of lithium (CLi) was used as an index of proximal tubular outflow. 3.Treatment caused a transient decrease in mean arterial blood pressure and systemic vascular resistance, but cardiac output remained unchanged. Renal blood flow decreased and renal vascular resistance increased during and after treatment. Sodium clearance decreased from 1.10 (0.63/1.19) ml/min to 0.17 (0.18/0.32) ml/min (P = 0.003). Glomerular filtration rate remained unchanged, whereas the median CLi decreased from 26 (17/32) ml/min to 17 (10/21) ml/min (P = 0.008). Calculated absolute proximal reabsorption rate of water increased from 63 (40/69) ml/min to 71 (47/82) ml/min (P = 0.04). The urinary excretion rate of thromboxane B2 and the ratio between excretion rates of thromboxane B2 and 6-keto-prostaglandin-F1α increased by 98% (P = 0.022) and 175% (P = 0.022) respectively. 4.The study suggests a specific recombinant interleukin-2-induced renal vasoconstrictor effect. Changes in renal prostaglandin synthesis may contribute to the decrease in renal blood flow. The lithium clearance data suggest that an increased proximal tubular reabsorption rate may contribute to the decreased sodium clearance during recombinant interleukin-2 treatment.

A randomized multicenter trial was started to evaluate the effect of irradiation combined with 5-fluorouracil and methotrexate on survival after surgery for rectal and rectosigmoidal carcinoma, Dukes' stages B and C. The trial was terminated prematurely after entrance of 34 patients due to frequent and serious complications. Three patients died as a direct consequence of the adjuvant treatment.

The interactions of seven cancer chemotherapeutic drugs and radiation in normal skin were studied using the mouse foot skin scoring system. Single drug doses were administered 15 min before graded single doses of irradiation or at different intervals before and after a fixed radiation dose. Adriamycin (ADM), bleomycin (BLM), methotrexate (MTX), mitomycin-C (MM-C), and cis-platinum (cis-DDP) all significantly enhanced the radiation-induced skin reactions. The dose-effect factors (DEF) for these drugs ranged from 1.07 to 1.11. Cyclophosphamide (CTX) had a radioprotective effect (DEF 0.90), whereas 5-fluorouracil (5-FU) had no effect (DEF 1.00). The effect of ADM was present at administration from 6 h before to 2 min after irradiation, and the effect of BLM from 24 h before to 4 h after irradiation. The radioprotective effect of CTX and the enhanced effect of MM-C were only present on administration 15 min before and 2 min after irradiation. MTX and cis-DDP enhanced the skin reactions only when given before irradiation.

The interactions of radiation and seven cancer chemotherapeutic drugs have been investigated in four normal tissues (intestinal crypts, skin, haemopoietic tissue and lung) and in a solid C3H mouse mammary carcinoma in vivo. All experiments were carried out with male C3D2F1 mice. The investigated drugs were adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin C (MM-C) and cis-diamminedichloroplatinum(II) (cis-DDP). Single drug doses were given at different intervals before, simultaneously with and after single doses of radiation. The normal tissue reactions following drug-radiation combinations were found to be highly complex. The interactions varied both quantitatively and qualitatively from drug to drug and from tissue to tissue. The drugs enhanced the radiation response in most cases. However, signs of radioprotection was observed for CTX in skin and for MTX in haemopoietic tissue. The interval and the sequence of the two treatment modalities were of utmost importance for the normal tissue reactions. In general, the most serious interactions occurred when drugs were administered simultaneously with or a few hours before radiation. The radiation-modifying effect of the drugs deviated from this pattern in the haemopoietic tissue as the radiation response was most enhanced on drug administration 1-3 days after radiation. Enhancement of the radiation response was generally less pronounced in the tumour model than in the normal tissues. The combined drug-radiation effect was apparently less time-dependent in the tumour than in the normal tissues.

Testicular biopsies were done in 15 consecutive patients who were believed to have extragonadal germ-cell tumours. 8 patients (53%) had carcinoma-in-situ (CIS) in the gonads, although none had clinical signs of tumour. In addition, 3 of these patients had small areas of invasive tumour growth. Germ-cell tumours can only be diagnosed as being extragonadal in origin if testicular biopsy appearances are normal.

The effect of radiation alone or in combination with cyclophosphamide (CTX), methotrexate (MTX) and 5-fluorouracil (5-FU) on the jejunal crypt cells in C3D2F1/Bom mice was studied using the microcolony survival assay. In determination of survival curves, two sections per mouse and six mice per datum point were used in order to obtain a constant coefficient of variance of D0 (approximately 5 per cent). When CTX (250 mg/kg), MTX (150mg/kg), and 5-FU (150 mg/kg) were injected intraperitoneally 15 min before irradiation, the regeneration time for the surviving crypts increased. Thus, following radiation alone the regeneration time was 90 hours and when combined with the drugs, 96, 102, and 120 hours, respectively. At these hours the crypts were of an equivalent size. Scoring the crypt number at the regeneration times was found to be necessary, since the use of a constant assay time underestimated the crypt survival following the drug-radiation combinations. Neither was a constant assay time followed by a correction for different crypt sizes found sufficient to replace the use of different regeneration times. All three drugs significantly enhanced the radiation effect without changing the D0. The DEF values for CTX, MTX, and 5-FU were 1 . 05, 1 . 08 and 1 . 13, respectively.

The interactions of radiation and 5-fluorouracil (5-FU), cyclophosphamide (CTX), or methotrexate (MTX) in mouse jejunal crypt cells were studied using the microcolony survival assay. 5-FU given from 48 hr before to 24 hr after irradiation resulted in an almost constant, increased cell kill except at injection 6 hr after irradiation, which resulted in a more pronounced effect. CTX enhanced the radiation effect only when given simultaneously with or up to 3 hr after irradiation. The effect of MTX, extremely dependent on the sequence and interval between drug administration and irradiation, was most prominent when administered 1 hr before irradiation. At this drug-radiation interval, the D0 surprisingly increased by a factor of 2.4, whereas MTX 15 min before irradiation displaced the survival curve to the left without changing the D0. The influence of MTX on the radiation response disappeared when the drug was given either 96 hr before or 3 hr after irradiation.