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The bispecific monoclonal antibody (bsAb) BIS-1 combines a monoclonal-antibody(mAb)-defined specificity for the CD3 complex, as present on all T lymphocytes, with a mAb-defined specificity for the pancarcinoma/epithelium associated glycoprotein EGP-2. In vitro studies indicate that BIS-1 can direct T lymphocytes to kill EGP-2-positive tumour target cells. T cell pre-activation is necessary for this activity and can be obtained either via incubation of isolated peripheral blood mononuclear cells with CD3 mAb, followed by short culturing in recombinant interleukin-2-containing medium, or via costimulation with CD5- and CD28-based bsAb. Clinical application of BIS-1 was started in a pilot study in which carcinoma patients suffering from malignant ascites or intrapleural effusion were treated. In this study, ex vivo activated autologous lymphocytes were applied locally, i.e. intraperitoneally or intrapleurally, in the presence of BIS-1. Local inflammation and antitumour activity were observed, whereas no or only minor systemic toxicity was seen in these patients. Intravenous administration of BIS-1 F(ab')2 in combination with subcutaneously given recombinant interleukin-2 (i.v. bsAb/rIL-2 treatment) induced transient but considerable toxicity including peripheral vasoconstriction, dyspnoea and fever with a maximal tolerated dose of 5-8 micrograms/kg. High plasma concentrations of the inflammatory cytokines tumor necrosis factor alpha and interferon gamma were observed at this dose. Whereas bsAb-dictated antitumour activity could be demonstrated to be present in blood samples of these patients in an in vitro assay, no clear clinical responses were observed. In a rat model it was found that i.v. bsAb/rIL-2 treatment of EGP-2-positive tumours was effective when a low systemic tumour burden was present, suggesting that systemic bsAb/rIL-2 treatment might be effective in situations of minimal residual disease.

In patients with disseminated nonseminomatous testicular germ cell tumors (NSTGCT), a retroperitoneal residual tumor mass (RRTM) and/or a pulmonary residual tumor mass (PRTM) are often present after successful treatment with cisplatin-based polychemotherapy. Results and complications of postchemotherapy resection of PRTM were studied and survival was calculated. In the period 1979 to 1996, 31 patients with a median age of 28 years (range, 17 to 44 years) underwent 32 thoracotomies for the resection of a PRTM. A solitary lesion was encountered nine times (28.1%) and multiple lesions were encountered 23 times (71.9%). The median size was 15 mm (range, 2 to 60 mm). There were only three major postoperative complications (9.6%): prolonged ventilation, pneumothorax, and pneumonia. In 16 patients (51.6%), the resected PRTM showed mature teratoma, while in four patients (12.9%) it showed viable cancer. In 11 patients only necrosis and/or fibrosis were found (35.5%). Resection of an RRTM had been performed prior to thoracotomy in 20 patients. There was dissimilarity between the histologic features of the resected RRTM and PRTM in 10 of the 20 patients (50%). During a median follow-up of 80 months (range, 2.5 to 203 months), five patients died from metastatic disease (16.1%). The 5-year survival rate was 86.8% and the 10-year survival rate was 82.2%. Owing to the dissimilarity between the histologic features of the postchemotherapy resected RRTM and PRTM in 50% of the patients, all sites of pulmonary residual disease must be resected in patients with disseminated NSTGCT, irrespective of the histologic features of previously resected retroperitoneal residual disease. This approach offers minimal morbidity and a high 10-year survival rate.

Purpose: We determined sexual functioning after chemotherapy for disseminated nonseminomatous testicular germ cell tumor, and evaluated the impact of resection of post-chemotherapy residual retroperitoneal tumor., Materials and Methods: A total of 155 consecutive patients treated with chemotherapy for disseminated nonseminomatous testicular germ cell tumor (between 1980 and 1994) was questioned about their sexual functioning. The patients were divided in 2 subgroups: patients treated with or without resection of post-chemotherapy residual retroperitoneal tumor. Volume and location (divided into left para-aortal or right paracaval/interaortacaval) of the resected tumor were related to absence of ejaculation as well as decreased semen amount. In addition, libido, arousal, erection and orgasm were related to ejaculatory dysfunction., Results: A total of 43 patients (27.7%) was treated with chemotherapy only and 112 (72.3%) had additional resection of post-chemotherapy residual retroperitoneal tumor mass. Overall, 22.4% reported loss of libido, 14.1% decreased arousal, 16% erectile dysfunction, 23.1% decreased orgasmic intensity, 17.4% decreased semen amount and 18.7% complete absence of antegrade ejaculation. With exception of absence of ejaculation, sexual dysfunctions were reported in similar frequencies in both treatment subgroups. In the resection of post-chemotherapy residual retroperitoneal tumor subgroup, 25.9% of the patients had complete absence of ejaculation. The other sexual dysfunctions were related neither to decreased semen amount nor to complete absence of ejaculation. The mean volume of resected tumor was higher (95 cm.3) in patients with absence of ejaculation than in those without (40 cm.3), and patients with right paracaval/interaortacaval tumor (20 of 58, 34.5%) reported more often absence of ejaculation than those with left para-aortal tumor (9 of 54, 16.7%)., Conclusions: In patients treated for disseminated nonseminomatous testicular germ cell tumor, post-chemotherapy sexual morbidity cannot be neglected. Except for loss of antegrade ejaculation, sexual dysfunctions are not related to resection of post-chemotherapy residual retroperitoneal mass. A high volume of tumor and a right paracaval/interaortacaval location predispose to loss of antegrade ejaculation.

Background: This retrospective study evaluates changes in sexual functioning after treatment for testicular cancer and investigates whether there is a relationship with different treatment modalities., Methods: A self-reported questionnaire was sent to 337 men who had been treated for testicular cancer at the University Hospital Groningen between 1977 and 1994. Medical information was obtained from the patient records., Results: A response was received from 287 men (85%); 264 patients were included in this study (78%). The mean patient age at follow-up was 37.7 years (range, 17-71 years). The mean follow-up period was 6.7 years (range, 0.25-18 years). Decrease in sexual functions was reported by 40% of patients (decrease in libido: 19%; arousal: 12% erection: 12.5%; orgasm: 19%; and ejaculation: 26%). Moreover, 23.5% of patients responding reported decreased sexual activity and 12.5% were dissatisfied with their sexual functioning. Patients with Stage II-IV nonseminoma who had been treated with polychemotherapy (PCT) with or without resection of residual retroperitoneal tumor mass (RRRTM) (PCT +/- RRRTM) reported a significantly sharper decrease in sexual functioning than patients who had been followed with a wait-and-see policy (W & S) (Stage I nonseminoma patients). It was noteworthy that patients treated by PCT alone reported more sharply decreased sexual functioning than patients treated by PCT + RRRTM. Patients treated by radiotherapy (Stage I-IIA seminoma) did not report findings significantly different from the W & S group., Conclusions: Testicular cancer patients are at risk for reduced sexual functioning, especially when treated by chemotherapy, with or without resection of residual tumor. Although chemotherapy may influence somatic aspects of sexual functioning, it appears that psychologic factors arising from the confrontation with testicular cancer play a strongly mediating (if not determining) role.

In the past 20 years, testicular cancer, which occurs in the young, has become a curable malignancy; 90% of the patients treated will achieve long-term survival. However, there is a significant morbidity associated with the management of the disease process. The literature was reviewed concerning the current treatment strategies and prognosis, as well as the long-term sequelae of the various diagnostic and therapeutic procedures. Surveillance has become a key element in the management of patients with a primary (stage I) testicular non-seminoma. Although approximately 25% of these patients will relapse, 100% survival can be achieved with cisplatin in combination with etoposide and bleomycin (BEP). Patients with a disseminated non-seminoma are usually treated with 4 courses of BEP; an 80% survival rate can be achieved. The long-term effects of chemotherapy include Raynaud's phenomenon, acral paraesthesia, hyperlipidaemia, nephrotoxicity, infertility and hormonal disturbances. Retroperitoneal lymph node dissection or resection of residual disease following chemotherapy are associated with a low mortality and morbidity rate, ejaculatory dysfunction excepted. However, with specific modifications in technique (e.g. nerve-sparing) antegrade ejaculation can be preserved in the majority of patients. Radiotherapy is used in stage I and II seminoma. With the conventional dose of 25-30 Gy to the retroperitoneal and ipsilateral iliac lymph nodes, temporary dysfunction of the germ and Leydig cells of the remaining testis may occur by scatter radiation. Patients with advanced seminoma are treated with cisplatin-based chemotherapy. To date, testicular cancer patients can receive appropriate curative treatment with acceptable acute toxicity, depending on the therapy given. The detrimental effects of late toxicities require careful study and follow-up. However, little attention is paid currently to quality of life aspects, in particular the impact of the disease and its treatment on general well-being, including sexual function.

Residual mature teratoma (RMT) is often left behind when metastases of primary nonseminomatous germ cell tumors (NSs) are treated with chemotherapy. RMT is composed of fully differentiated somatic tissue. A growing teratoma (GTE) lesion may occur after (incomplete) resection of RMT. To shed light on tumor progression or the mechanism(s) of therapy related differentiation we investigated the chromosomal pattern of the primary NSs and RMTs in twelve patients, of the primary NS, RMT, and GTE lesion in one patient, and of the RMT and GTE lesion in two patients. Although several chromosomal differences are observed between the RMT and NSs and between the GTE and RMTs in the same patient, we obtained no evidence that specific chromosomal alteration(s) play a role in metastasis or differentiation.

Background: The introduction of cisplatin-based chemotherapy has remarkably increased the survival of testicular cancer patients. With this success, the concern for a contralateral testicular tumor has increased. The aim of this study was to investigate whether the risk for contralateral testicular tumor development was influenced by cisplatin-based chemotherapy., Methods: The incidence of a contralateral testicular tumor among 365 consecutive patients with a nonseminoma testicular tumor, diagnosed in the period 1980 and 1995, was established and related to previous therapy., Results: Eleven of 365 men (3%) developed a contralateral testicular tumor. After a total of 2403 person-years at risk, 4 of 225 chemotherapy-treated patients (1.8%) developed a contralateral testicular tumor, and 7 of 140 patients (5%) treated with orchidectomy alone developed a contralateral tumor. In comparison to this surveillance subgroup, patients previously treated with chemotherapy have a relative risk of 0.30 to develop a second testicular tumor., Conclusions: In Dutch men with a nonseminoma testicular tumor, the incidence of a contralateral testicular tumor is 3%, which is 60-fold the expected incidence rate of testicular cancer. A three times lower incidence rate of a contralateral testicular tumor was found in the chemotherapy subgroup compared with those on surveillance. This supports the hypothesis that cisplatin-based chemotherapy may eradicate carcinoma in situ or early testicular cancer.

Background: TRA-1-60 is a new tumor marker for embryonal carcinoma-positive nonseminomatous testicular germ cell tumors (NSTGCT). Upper normal reference value (RV) and serum half-life (t1/2) were determined. The value was determined in the follow-up of 154 patients with stage I NSTGCT., Methods: TRA-1-60 was measured in normal controls (n = 100) to determine RV and in patients without recurrence for t1/2. In all patients, TRA-1-60 was determined at the time of orchidectomy. In 42 patients with recurrence, values were also evaluated 1 month before and at the time of computed tomography-confirmed recurrence. Predictive values and survival probability were examined and compared with values for alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG)., Results: RV was 230 U/ml and t1/2 9.5 days. Elevated TRA-1-60 at the time of orchidectomy was not associated with recurrence. One month before recurrence, 21 of 42 patients had elevated TRA-1-60 levels (50%); 10 were negative for both AFP and hCG. At the time of recurrence, 24 patients had elevated TRA-1-60 levels (57.1%): 9 were negative for AFP/hCG. Patients with TRA-1-60 levels of > 500 U/ml had a poorer recurrence-free survival probability (p = 0.015)., Conclusions: TRA-1-60 is useful in the follow-up of stage 1 NSTGCT. The combination of AFP, hCG, and TRA-1-60 may improve the early detection of recurrence.

Purpose: To establish the prevalence of sexual dysfunctions after different treatment modalities for nonseminomatous testicular germ cell tumor (NSTGCT) and to investigate whether treatment-induced angiopathy and neuropathy is related to sexual dysfunction., Patients and Methods: A questionnaire assessing sexual dysfunction was sent to 255 NSTGCT survivors. Polychemotherapy (PCT) regimens (cisplatin, vinblastine, and bleomycin [PVB], vinblastine substituted by etoposide [BEP], or cisplatin substituted by carboplatin [CEB], etoposide combined with cisplatin [EP], or with ifosfamide and cisplatin [VIP] were compared regarding treatment-induced angiopathy and neuropathy. Sexual dysfunctions were related to Raynaud's phenomenon and acral paresthesia., Results: Among the 215 responders, 56 (26%) had been treated by orchidectomy and surveillance, 42 (19.6%) by PCT, and 117 (54.4%) by PCT and resection of residual retroperitoneal tumor mass (RRRTM). Overall, loss of libido was reported by 19.1%, decreased arousal by 11.2%, erectile dysfunction by 12.1%, decreased intensity of orgasm by 20%, and ejaculatory problems by 28%. Patients treated with PVB suffered more often from Raynaud's phenomenon compared with those treated with other regimens (40.4% v 29%; P < .05) and from paresthesia (31.6% v 14.7%; P < .05). Patients with Raynaud's phenomenon had more often erectile dysfunction (28.8%) compared with those without (8.4%) (P < .05)., Conclusion: Compared with orchidectomy alone, PCT, with or without RRRTM, induced more often posttreatment sexual dysfunction. Compared with other chemotherapeutic regimens, signs of angiopathy and neuropathy were most prevalent in those treated with PVB. Erectile dysfunction was related to the chemotherapy-induced Raynaud's phenomenon but not to acral paresthesia.

Purpose: This prospective randomized trial was designed to compare the efficacy of etoposide plus cisplatin (EP) versus bleomycin, etoposide, and cisplatin (BEP) chemotherapy in patients with good-prognosis metastatic nonseminomatous testicular cancer., Patients and Methods: Four hundred nineteen patients with good-prognosis nonseminomatous testicular cancer were randomized to receive four cycles of cisplatin 20 mg/m2 on days 1 to 5 plus etoposide 120 mg/m2 on days 1, 3, and 5 with or without bleomycin 30 mg weekly., Results: Of 395 eligible patients, 169 of 195 patients allocated to EP (87%) and 189 of 200 patients allocated to BEP (95%) achieved a complete response with chemotherapy alone or after postchemotherapy surgery. These results are significantly different (P = .0075). After a median follow-up duration of 7.3 years, eight patients (4%) on each treatment arm relapsed. In view of the low number of unfavorable treatment outcomes (11%), no significant differences were detected in time to progression (P = .136) and survival (P = .262). Both the acute and late pulmonary toxicity and neurotoxicity were significantly greater in patients who received BEP, whereas Raynaud's phenomenon occurred exclusively in patients who received BEP (P < .001). Two patients treated with BEP died of bleomycin pulmonary toxicity., Conclusion: BEP is the most effective combination regimen in the treatment of disseminated nonseminomatous germ cell cancer. In this particular BEP regimen with etoposide at a dose of 360 mg/m2 per cycle, even in good-prognosis patients, bleomycin cannot be deleted without compromising treatment efficacy, but its use is associated with more toxicity (particularly pulmonary) and efforts to reduce this merit further exploration.

Purpose: This prospective randomized multicenter trial was designed to evaluate the efficacy of carboplatin plus etoposide and bleomycin (CEB) versus cisplatin plus etoposide and bleomycin (BEP) in first-line chemotherapy of patients with good-risk nonseminomatous germ cell tumors., Patients and Methods: Between September 1989 and May 1993, a total of 598 patients with good-risk nonseminomatous germ cell tumors were randomized to receive four cycles of either BEP or CEB. In each cycle, the etoposide dose was 120 mg/m2 on days 1, 2, and 3, and the bleomycin dose was 30 U on day 2. BEP patients received cisplatin at 20 mg/m2/d on days 1 to 5 or 50 mg/m2 on days 1 and 2. For CEB patients, the carboplatin dose was calculated from the glomerular filtration rate to achieve a serum concentration x time of 5 mg/mL x minutes. Chemotherapy was recycled at 21-day intervals to a total of four cycles., Results: Of patients assessable for response, 253 of 268 (94.4%) of those allocated to receive BEP achieved a complete response, compared with 227 of 260 (87.3%) allocated to receive CEB (P = .009). There were 30 treatment failures in the 300 patients allocated to BEP and 79 in the 298 allocated to CEB (log-rank chi 2 = 26.9; P < .001), which led to failure-free rates at 1 year of 91% (95% confidence interval [CI], 88% to 94%) and 77% (95% CI, 72% to 82%), respectively. There were 10 deaths in patients allocated to BEP and 27 in patients allocated to CEB (log-rank chi 2 = 8.77; P = .003), which led to 3-year survival rates of 97% (95% CI, 95% to 99%) and 90% (95% CI, 86% to 94%), respectively., Conclusion: With these drug doses and schedules, combination chemotherapy based on carboplatin was inferior to that based on cisplatin. This BEP regimen that contains moderate doses of etoposide and bleomycin is effective in the treatment of patients with good-prognosis metastatic nonseminoma.

Objective: To determine the effects of intramuscular injections with testosterone (Sustanon) on sex-hormone levels, sexual functioning and general well-being in patients treated with orchidectomy for bilateral testicular cancer., Patients and Methods: The study comprised seven men (median age 38 years, range 25-46) who had undergone orchidectomy for bilateral testicular cancer. Patients received intramuscular injections with testosterone every 3 weeks and blood samples for hormone analysis were collected from each patient at three times: one day after testosterone injection (t1), halfway between subsequent injections (t2) and just before injection (t3). Plasma hormone levels were then related to sexual function, as assessed by self-reported data on sexuality and general well-being, measurements of nocturnal penile tumescence and rigidity (NPTR) and erectile function elicited by visual erotic stimulation (VES), determined at t1, t2 and t3., Results: During the 3-week interval between injections, there was a sixfold decrease in plasma testosterone level (mean testosterone 35.8, SD 7.8, and 6.0, SD 2.5 nmol/L, at t1 and t3, respectively). At t1, five of the men had a plasma testosterone level above the upper normal limit (> 35 nmol/L) and at t2 and t3, testosterone levels were below the reference range (< 10 nmol/L) in three and six men, respectively. Oestradiol (E2) levels showed the same pattern: at t1 the mean (SD) E2 level was 0.17 (0.07) nmol/L and at t3 0.07 (0.01) nmol/L. In contrast to follicle-stimulating hormone, luteinizing hormone (LH) mirrored the decline in plasma testosterone after injection, with the lowest levels at t1 and the highest at t3. Other hormone levels remained unchanged. Three patients reported loss of libido, decreased arousal, erectile dysfunction, fatigue and mood depression. However, neither the arousal nor the erectile problems could be verified by VES. There was no relationship between plasma testosterone levels, the reported sexual dysfunctions and the results of NPTR and VES measurements. Although unrelated to a specific testosterone level, three patients reported increased irritability, excessive sweating, hot flushes and heat intolerance at the end of the injection interval. These adverse effects of declining plasma testosterone were related to loss of libido and other sexual problems., Conclusion: In most patients castrated for bilateral testicular cancer and receiving intramuscular injections with testosterone, plasma testosterone levels were outside the normal range. After injection, there was a rapid decline of plasma testosterone to levels below the lower normal limit. With the exception of oestradiol, sex-hormone levels were not correlated to testosterone levels. Sexual functioning was not affected by the fluctuations of plasma testosterone level. However, at the end of the injection interval, adverse psychological and physical effects had a significant impact on libido and arousal.

In this update, the recent developments in the treatment of patients with advanced seminoma are reviewed. Also, the approach for patients with residual disease after chemotherapy is described. It is concluded that the combination of etoposide and cisplatin seems to be the standard treatment for patients with advanced seminoma, showing a durable response in about 90% of the patients. Although the combination of etoposide and carboplatin is less effective, newer carboplatin-based combinations seem to have a comparable efficacy. Residual disease after chemotherapy can be safely observed if the diameter is less than 3 cm; however, residuals larger than 3 cm frequently show a vital tumor and surgical evaluation should therefore be considered.

Objective: To evaluate the resection of the retroperitoneal residual tumour mass (RRTM) for histological examination after chemotherapy in patients with disseminated non-seminomatous testicular germ cell tumours (NSTGCTs), with particular attention to surgical morbidity., Patients and Methods: From 1979 to 1995, 112 patients (mean age 28 years, range 16-53) with NSTGCT had residual disease after chemotherapy for which surgical evaluation was indicated; the histology of the residual tumour and the surgical complications were assessed. Possible associations between the occurrence of surgical complications and the age of the patient, size of the residual tumour, operative duration, previous laparotomy and pathological findings were evaluated., Results: The median size of the residual tumour was 4 cm (range 0-18); histological examination revealed viable tumour in 9%, mature teratoma in 44% and necrosis/fibrosis in 44% of the patients. In three patients (2.8%) no residual tumour mass was found at laparotomy. There were 26 complications in 20 patients (18%); urinary tract infection was the most common, occurring in nine patients (8%). One patient died during the induction of anaesthesia. There were no significant relationships between the occurrence of complications and age, size of the residual tumour, operative duration, previous laparotomy or pathological findings., Conclusion: The resection of RRTM after polychemotherapy treatment for disseminated NSTGCT is a safe surgical procedure, with low treatment morbidity consisting mainly of urinary tract infection. Knowledge of the potential complications may help to prevent morbidity. However, the surgical evaluation of the ultimate effect of polychemotherapy remains the gold standard.

Background: After chemotherapy for a metastatic nonseminomatous germ cell tumor, pulmonary masses may be seen on a computed tomography scan. These residual masses may contain one of three histologic elements: necrosis, mature teratoma, or cancer. Because surgical resection of masses containing only necrosis is unnecessary, the authors aimed to predict the histology of these residual masses., Methods: Six study groups contributed patient data on a total of 215 patients undergoing thoracotomy after cisplatin-based induction chemotherapy for metastatic testicular nonseminomatous germ cell tumors. Logistic regression analysis was used to estimate the probability of necrosis, mature teratoma, and cancer in relation to predictors known before thoracotomy., Results: The pulmonary mass histology was necrosis in 116 patients (54%), mature teratoma in 70 (33%), and cancer in 29 (13%). Necrosis was found at thoracotomy in 89% of those patients with necrosis at retroperitoneal lymph node dissection (RPLND). Other predictors included the primary tumor histology, prechemotherapy tumor marker levels, change in mass size during chemotherapy, and the presence of a single, unilateral mass. Multivariate combination of predictors yielded reliable models (goodness-of-fit tests, P > 0.20), which discriminated necrosis well from other histologies, especially if RPLND histology was available (area under the receiver operating characteristic curve, 0.86)., Conclusions: This analysis indicated subgroups of patients with a high probability of necrosis and a low risk of cancer for whom close follow-up of the residual pulmonary mass might be considered. In most patients, a RPLND should be performed before a thoracotomy is considered, because the probability of necrosis is generally higher at thoracotomy than at RPLND and the histology at RPLND is a strong predictor of the histology at thoracotomy.

Cardiac function was evaluated in 86 breast cancer patients after standard chemotherapy, followed by ablative chemotherapy and chest irradiation. One patient died of subacute heart failure 3 months after ablative chemotherapy. At a minimum of 1 year's follow-up (range 1-11 years) left vertricular ejection fraction (LVEF) was marginally abnormal in 4 of 27 disease-free survivors. One exceptional patient who received two transplantations is alive, with serious heart failure occurring after the second ablative chemotherapy. Including this patient, the percentage of patients free of clinical and subclinical cardiac dysfunction at 7 years is 78% (95% CI 61-95%). After ablative chemotherapy, cardiotoxicity was rarely life-threatening. The impact of subclinical cardiotoxicity in the long term is not clear and needs continued evaluation.

Our aim was to study the extent of pulmonary toxicity after high-dose chemotherapy and radiotherapy in breast cancer patients. In a retrospective study the pulmonary symptoms and chest X-rays were analyzed before, during and after treatment in 17 patients, treated with loco-regional radiotherapy to the breast/chest wall and the regional lymph nodes after the completion of high-dose chemotherapy and autologous bone marrow transplantation for locally advanced breast cancer. Lung function was evaluated between 15 and 46 months after completion of the irradiation. Nine patients (53%) had pulmonary symptoms during and/or within two months from irradiation. Radiographic changes were seen in twelve patients (71%) and a decreased diffusion capacity occurred in nine patients (53%). The spirometric values (VC and FEV1) were abnormal in two patients (12%). There is a high incidence of radiation pneumonitis, although no consistent correlation between the various parameters (pulmonary symptoms, chest X-rays and lung function tests) could be found.

Purpose: Venous access ports (VAPs) can be used to administer polychemotherapy to patients with malignancies. The purpose of this study was to evaluate perioperative and late complications related to VAP implantations and to analyze factors that may predict the development of complications., Patients and Methods: During the period 1983 to 1994, 135 VAPs were implanted in 132 patients with disseminated testicular tumors. In a retrospective study, the perioperative and late complications were recorded in this homogeneous patient group. Multivariate analysis was performed to detect factors that may predict the development of complications., Results: The median age of the patients was 28 years (range, 16 to 55). Perioperative complications were recorded in five patients (3.7%): pneumothorax in two (1.5%), blood loss in two (1.5%), and mediastinal bleeding in one (0.7%). The ports remained in situ for a total of 55,247 days (median, 413; range, 7 to 1,607). In 31 patients (23%), 42 late complications developed (31%): system obstruction in 13 (9.6%), thrombosis in 11 (8.1%), infection in six (4.4%), catheter defect in six (4.4%), extravasation in four (3.0%), and local skin necrosis in two (1.5%). Late complications were significantly more common in patients who had received chemotherapy before VAP implantation (P < .001). Univariate analysis showed that there were significantly more complications after VAP implantation under local anesthesia than under general anesthesia (P < .05)., Conclusion: Polychemotherapy could be administered in an adequate manner using a VAP. Complications occurred in 26.7% of a homogeneous group of patients who received a VAP implantation for polychemotherapy for disseminated testicular cancer. Chemotherapy treatment before VAP implantation was the only independent risk factor for late complications.

Residual retroperitoneal masses may remain after chemotherapy for metastatic non-seminomatous testicular cancer, which harbour residual tumour or totally benign tissue (necrosis/fibrosis). These residual masses may be effectively removed by a surgical resection. We evaluated current selection criteria and tried to develop alternative criteria in a data set of 544 patients, who had retroperitoneal lymph node dissection of residual masses. Six resection policies were identified from the literature. Two alternative policies were developed with logistic regression analysis. Evaluation of the policies focused on the true-positive rate (resection in case of tumour), and the false-positive rate (resection in case of necrosis). It appeared that most current policies use the size of the residual mass (> or = 10 mm or > or = 20 mm) as the predominant selection criterion. This resulted in high true-positive rates (most > 90%), but false-positive rates between 37% and 87%. The alternative policies included five well-known predictors of necrosis in addition to residual mass size (primary tumour histology, prechemotherapy levels of the three tumour markers alphafetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH) and mass shrinkage during chemotherapy). This strategy resulted in improved true- and false-positive rates, even when categories of the predictors were simplified for practical application. We conclude that a simple statistical model, based on a limited number of patient characteristics, provides better guidelines for patient selection than those currently used in clinical practice.

To minimize interleukin-2-related toxicity while retaining its efficacy, a treatment schedule utilizing subcutaneous IL-2 was evaluated in a phase II setting. Eighty unselected, consecutive patients with metastatic or recurrent renal cell carcinoma (RCC), mean age 58 years (range, 21 to 76), received IL-2 on an outpatient basis, 5 days per week for 4 or 6 consecutive weeks. During the first 5-day cycle, a dose of 18 million IU IL-2 was administered once a day; during subsequent cycles the dose in the first two days was reduced to 9 million IU. Two 6-week or three 4-week courses were given maximally. Patients who had completed at least one full course were considered evaluable. To circumvent flu-like symptoms, all patients received a maximum oral dose of 3 g acetaminophen daily. Seventy-seven patients were assessable for response. Three (4%) complete responses (CR) and 6 (8%) partial responses (PR) were observed, and 44 (57%) patients had stable disease (SD). Response durations were 64, 29, 29+ months for the CR and 2, 6, 8, 11, 32, 47 months for the PR. The median length of survival of all patients was 12 months, whereas the median survival of responders and non-responders was 35+ and 10+ months, respectively (P < 0.001). Side effects included fever, chills, nausea, vomiting, and transient inflammation and induration at the injection sites. These complications were acceptable, even in the patients with concomitant disease, and completely disappeared after cessation of IL-2. Subcutaneous IL-2 mediates antitumor responses, has limited side effects and is also suitable for elderly RCC patients with concomitant disease.

A European Conference on Continuing Medical Education (CME) in Oncology was designed and organised in Dublin (Ireland), on 12th and 13th October 1995 by the European School of Oncology in collaboration with University College Dublin and with the financial support of the European Commission (Europe Against Cancer Programme). Two experts were invited from each Member State and all attended the Conference with the sole exception of the representatives of Luxembourg, who did not attend due to unexpected important commitments. Observers were invited to contribute to the discussion as representatives of organisations that were involved either directly or indirectly in CME. The Conference took the format of a plenary session coupled with the identification of five discussion groups formed to debate key areas in CME at a European level in oncology (Table 1). As a result of these discussions and subsequent consultations, an agreement was reached on the following statements: (a) Continuing Medical Education (CME) is an ethical duty and an individual responsibility for each doctor. Although CME should remain voluntary at the present time, it is nevertheless a professional obligation since almost 50% of medical knowledge becomes obsolete after ten years. It should be organised with clear guidelines for medical personnel working in hospitals, in primary health care and in private practice. (b) The CME system within the European Union (EU) should remain self-directed without the necessity for interval examinations: it should be interdisciplinary and must be driven and controlled by the profession itself. (c) A common concept and system within a CME framework may have a considerable impact on EU integration. It should certainly be developed, maintained and monitored at national level but on the basis of a common European model to ensure scientific and cultural interchange among Member States. (d) It was agree that a credit system is needed to help doctors keep track of their CME activities: the system should be based on the accumulation of credit points (one credit equalling one hour of continuing medical education) and monitored at a national level. Credit transfer among Member States is vital to facilitate exchange between Member States. (e) Oncology provides a very useful model of CME within which guidelines can be proposed and tested. Harmonisation of CME systems among the different European cancer organisations and scientific societies within this model system may represent a useful basis that other specialities can follow.

Testicular germ cell tumors (TGCT) of adolescents and adults are, for clinical and pathological reasons, divided in seminomas (SE) and nonseminomatous germ cell tumors (NS). Whether and to what degree these two entities are pathogenetically related is still controversial and a matter of debate. TGCT may contain both SE and NS components. Cytogenetic studies of the SE and NS components of these mixed TGCT might shed light on the pathogenetic relationship between both components. Separate cytogenetic analysis was performed on both components of three cases of mixed TGCT with both SE and NS components. The karyotypes of both components were compared with each other. In one case, the SE and NS component share eight different structural chromosomal abnormalities, indicating that the SE and NS component are pathogenetically closely related and have a common neoplastic pathway for a considerable length. Both components of the other two cases have, respectively, i(12p) and no structural chromosomal abnormalities in common. Our results, together with data from the literature, indicate that in mixed TGCT with SE and NS components, both components may have either a monoclonal or a polyclonal origin.

The additive effect of peripheral blood stem cells (PBSCs) to autologous bone marrow transplantation (ABMT) on haematopoietic reconstitution, after ablative chemotherapy in patients with locally advanced breast cancer, was evaluated. Patients were treated with induction chemotherapy, followed by ablative chemotherapy consisting of mitoxantrone and thiotepa. Group I (n = 14) received ABMT and granulocyte macrophage-colony stimulating factor (GM-CSF), group II (n = 11) received ABMT, PBSCs and granulocyte-colony stimulating factor (G- CSF). PBSCs were harvested after a low-dose cyclophosphamide (750 mg/m2), followed by G-CSF. Stem cell harvest was routinely started 12 days after cyclophosphamide. Compared to group I, group II showed a significant reduction in the median number of days for leukocytes < 0.5 x 10(9)/L 4.5 days, leukocytes < 1.0 x 10(9) / l 5.5 days, platelets < 20 x 10(9)/ l 9 days and platelets < 40 x 10(9) / l 12.5 days. The median number of transfusions of platelets fell from 11.5 to 7 and of red blood cells from 8.5 to 6. The median hospitalisation duration declined from 40.5 to 30 days, fever above 38 degrees C with 7.5 days, fever above 38.5 degrees C with 4 days and antibiotic treatment with 8.5 days in group I versus group II. Improvement of haematological recovery, duration of fever and hospitalisation was observed by the addition of PBSCs, obtained after a relatively low-dose cyclophosphamide and G-CSF and stem cell pheresis on fixed days, to autologous bone marrow and growth factor in the period after ablative chemotherapy.

Purpose: To evaluate the safety, tolerability, and efficacy of varying doses of recombinant human interleukin-6 (rhIL-6) after chemotherapy., Patients and Methods: In this phase I/II study, 19 breast (stage III to IV) or non-small-cell lung cancer (NSCLC) patients received mitoxantrone (10 mg/m2) and thiotepa (40 mg/m2) every 3 weeks, followed by rhIL-6 subcutaneously (days 5 to 15) at six dose levels: 0.5, 1.0, 2.5, 5.0, 10.0, and 20.0 micrograms/kg/d body weight/d (micrograms/kg/d). rhIL-6 was increased to the next level in the individual patient in case of incomplete bone marrow recovery (leukocyte count < 3 x 10(9)/L and/or platelet count < 100 x 10(9)/L at day 22) and/or platelet nadir less than 25 x 10(9)/L in two consecutive cycles., Results: Flu-like symptoms were observed in most of the patients. Nausea and vomiting were reported in seven of 48 and 19 of 48 cycles, respectively. Dose-limiting toxicity at 20.0 micrograms/kg/d of rhIL-6 consisted of World Health Organization (WHO) grade 3 to 4 flu-like symptoms, nausea, and vomiting. Platelet recovery was faster in cycle 1 at 10.0 and 20.0 micrograms/kg/d of rhIL-6 than at lower dose levels (P < .05); thrombocytopenia grade 4 was observed at most levels. However, only two patients needed platelet transfusions (1.0 and 2.5 micrograms/kg/d rhIL-6). rhIL-6 effects on leukocytes were not dose-related, with a trend for the neutrophil nadir to increase with rhIL-6 up to 10 micrograms/kg/d. rhIL-6 dose escalation did not affect hematologic parameters and chemotherapy cycle duration. Hemoglobin (P < .001) and cholesterol (P < .05) levels decreased, while acute-phase proteins increased., Conclusion: rhIL-6 following chemotherapy is tolerable up to 10 micrograms/kg/d; flu-like symptoms and nausea were dose-limiting at 20 micrograms/kg/d. Platelet nadir did not differ for the various rhIL-6 doses. However, a faster platelet recovery was observed at 10.0 and 20.0 micrograms/kg/d of rhIL-6.

Immunobiologic parameters measured during a phase I trial of intravenously (i.v.) administered bispecific monoclonal antibodies (BsmAb) in renal cell carcinoma (RCC) patients are described. The BsmAb used, BIS-1, is reactive with a pancarcinoma-associated 38 kDa transmembrane glycoprotein, EGP-2, as well with the CD3 complex. Patients received during a 2 h i.v. infusion F(ab')2 fragments of BIS-1 at doses of 1, 3, or 5 micrograms/kg body weight during concomitantly applied subcutaneous (s.c.) IL-2 treatment. Acute but transient BIS-1 F(ab')2-related toxicity was observed at the 3 and 5 micrograms/kg dose level, and the maximum tolerated dose (MTD) was set at 5 micrograms/kg. A dose-dependent binding of BIS-1 F(ab')2 to circulating T lymphocytes was found. The in vivo occupancy of CD3 molecules on T lymphocytes was highest at teh end of the infusion period and then rapidly decreased, as shown by flow cytometry. A much slower decrease of BIS-1 F(ab')2 binding was observed in vitro, suggesting migration of BIS-1 F(ab')2-loaded T lymphocytes from the circulation. A strong but transitory leukopenia was observed, in which LFA-1 alpha bright, CD3/CD8 double positive T cells left the circulation preferentially. This phenomenon was most likely induced by elevated TNF-alpha and IFN-gamma plasma levels, which were at a maximum shortly after the end of the infusion. Isolated peripheral blood mononuclear cells obtained from patients directly after treatment with BIS-1 F(ab')2 at the 3 and 5 micrograms/kg dose level showed increased EGP-2-directed antitumor activity.

Malignant transformation may be caused by gene deregulation resulting from specific chromosomal rearrangements, by amplification, by mutations in proto-oncogenes, by loss of tumor suppressor genes, or a combination of these. We investigated the role of numerical and structural chromosomal abnormalities in 102 cytogenetically abnormal cases of primary testicular germ cell tumors of adolescents and adults (TGCT) [32 seminomas (SE) and 70 nonseminomatous germ cell tumors (NS)]. We confirmed that an isochromosome for 12p, i(12p), is the only consistent structural chromosomal abnormality in TGCT, present in about 70% of our cases. Both the frequency and the number of copies of i(12p) are higher in NS than in SE. This may suggest that i(12p) is involved in tumor progression. Besides i(12p), several clonal structural chromosomal abnormalities were found, but none appeared to be specific. SE and NS had chromosome numbers in the triploid range, with significantly higher numbers in SE than in NS (average modal chromosome numbers of 73.4 in SE and 65.0 in NS). Both in SE and NS, some chromosomes were significantly underrepresented (e.g., 11, 13, 18, and Y) and others overrepresented (e.g., 7, 8, 12, 21, and X). In SE, a significantly higher copy number of chromosomes 7, 15, 19, and 22 was found and a significantly lower number of chromosome 17, compared with NS. These chromosomes may play an important role in the differentiation of TGCT.

Disappointing results after surgery alone for locally advanced adenocarcinoma of the cardia and the distal oesophagus (stage IIIB/IV) prompted us to combine surgery with neo-adjuvant chemotherapy. With a remission rate of about 70% the combination of etoposide, adriamycin and cisplatin (EAP) has been considered to be the superior treatment, but it has inherent severe toxicity. The authors conducted a phase II study of combined treatment with Carboplatin, 4-Epiadriamycin and Teniposide (CET) to ameliorate this toxicity and to evaluate the effectivity of this regimen in patients with these unresectable tumours. A regimen of 4 cycles of Carboplatin 300mg/m2, 4-Epiadriamycin 80mg/m2 and Teniposide 100mg/m2 was administered intravenously. Treatment cycles were repeated every 3 weeks in patients with initially unresectable adenocarcinoma of the gastro-oesophageal junction proven at laparotomy and/or CT scanning. Nineteen patients were studied and 17 underwent a second laparotomy in an attempt to resect the tumour radically. Eleven patients (65%) of the re-explored group achieved tumour reduction, enabling resection with curative intent. Recurrences, however occurred in 9 patients after a median of 9.5 (4-42) months. One patient died postoperatively as a result of pulmonary embolism. Only one patient remained free of disease after 42+ months. Leucopenia and thrombocytopenia of WHO grade 23 occurred in 58% and 37% of the patients, respectively. This regimen appears to be effective in patients with locally advanced adenocarcinoma of the cardia and the distal oesophagus. Although it can be used in an outpatient setting, the overall toxicity is relatively high and the results are comparable with other less toxic regimens.

We report the immunomodulatory effects of an intravenous treatment with F(ab')2 fragments of the bispecific monoclonal antibody BIS-1 during subcutaneous recombinant interleukin 2 (rIL-2) therapy of renal cell cancer (RCC) patients. BIS-1 is directed against both the CD3 antigen on T cells and the EGP-2 molecule on carcinoma cells and some normal epithelia. The amount of BIS-1 F(ab')2 bound to peripheral blood lymphocytes (PBLs) increased dose-dependently. This occupation degree was highest at the end of the 2 h infusion and rapidly decreased subsequently. During the first hour of BIS-1 F(ab')2 infusion the number of PBLs decreased slowly. This was followed by an increase in serum tumour necrosis factor alpha (TNF-alpha) concentrations and a rapid decrease in the numbers of peripheral blood lymphocytes, monocytes and eosinophils. In our view, the most likely explanation for the observed decrease in occupation degree of BIS-1 F(ab')2 and the rise in TNF-alpha levels is based on the assumption that BIS-1-carrying T cells leave the circulation. The CD3 antigens on these extravasated T cells become cross-linked by EGP-2 antigens, inducing TNF-alpha secretion. This results in an enhanced decrease in the numbers of PBLs, monocytes and eosinophils. These preliminary results suggest that BIS-1 F(ab')2 treatment during IL-2 therapy may induce local T-cell activation.

Twenty-nine patients with metastatic or T4 breast cancer who were in pathologically proven complete remission after induction chemotherapy, received intensification chemotherapy with autologous bone marrow support. Twelve patients had T4 breast cancer, 17 had metastatic disease. The median age was 42 years (27-52). Intensification consisted of cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. in 24 patients, or thiotepa 800 mg/m2 i.v. and mitoxantrone 50-75 mg/m2 i.v. in 5 patients. The median observation is 7 years. Median survival is 36 months. Ten year relapse-free survival is 20%. For patients with metastatic disease median survival is 34 months, time to relapse 18 months; two patients (12%) have survived disease-free for more than 6 years. The patients with T4 cancer have a median survival of 80 months and a median time to relapse of 53 months; four patients (33%) have survived more than 5 years disease-free.

In phase I studies, lobaplatin showed activity in ovarian cancer patients pretreated with platinum. A phase II trial with lobaplatin was performed in patients with refractory or relapsed ovarian cancer to define activity and pharmacokinetics. Twenty-two patients were treated with lobaplatin administered as an intravenous bolus every 4 weeks. Dependent on creatinine clearance (CRCL) patients received 30 or 50 mg m-2 lobaplatin as the starting dose. Twenty-two patients received 78 courses (median 3, range 1-6). In eight patients total platinum (TPt) in plasma and urine, free platinum (FPt) in plasma ultrafiltrate (both measured by atomic absorption spectrometry) and lobaplatin in plasma ultrafiltrate measured (by high-performance liquid chromatography) were measured. Toxicity was confined to mild nausea and vomiting, mild leucocytopenia (WHO grade 3 in 18% of the courses), and renal function-related thrombocytopenia (WHO grade 3/4 in 53% of the courses). A correlation was found between CRCL and reduction in platelet count (r = -0.77; P < 0.01). No renal toxicity was encountered. Five of 21 evaluable patients (24%) achieved a response (four complete remissions and one partial remission). Remissions occurred mainly in patients who relapsed more than 6 months after primary treatment. The median survival from start of lobaplatin treatment was 8 months. The mean areas under the curve (AUCs) were 4.2 +/- 0.5, 3.0 +/- 0.6, and 3.2 +/- 1.1 h mgl-1 for TPt, FPt and lobaplatin respectively. The free platinum fraction (FPt/TPt) was initially very high, indicating low protein binding. FPt was essentially present as intact lobaplatin. Four hours after infusion 54 +/- 5% and 24 h after infusion 74 +/- 3% of the lobaplatin dose was excreted in the urine. In conclusion, lobaplatin is a platinum compound with anti-tumour activity in patients with relapsed ovarian cancer, especially in those who have platinum-sensitive tumours. The main toxicity of lobaplatin is thrombocytopenia and its dose should be corrected according to renal function.

We have investigated whether an alternating induction chemotherapy regimen of PVB/BEP is superior to BEP in patients with poor-prognosis testicular non-seminoma. A total of 234 eligible patients were randomised to receive an alternating schedule of PVB/BEP for a total of four cycles or four cycles of BEP. Poor prognosis was defined as any of the following: lymph node metastases larger than 5 cm, lung metastases more than four in number or larger than 2 cm, haematogenic spread outside the lungs, such as in liver and bone, human chorionic gonadotrophin > 10,000 IU l-1 or alphafetoprotein > 1000 IU l-1. The complete response (CR) rates to PVB/BEP and BEP were similar, 76% and 72% respectively (P = 0.58). In addition, there was no significant difference in relapse rate, disease-free and overall survival at an average follow-up of 6 years. The 5-year progression-free and survival rates in both treatment groups were approximately 80%. The PVB/BEP regime was more toxic with regard to bone marrow function; the frequencies of leucocytes below 1000 microliters-1, leucocytopenic fever and platelets below 25,000 microliters-1, throughout four cycles were 28% vs 5% (P < 0.001), 16% vs 5% (P = 0.006), and 10% vs 1% (P = 0.001) respectively. Neuropathy also occurred more often in the PVB/BEP arm: 47% vs 25% (P = 0.001). This study shows that an alternating regimen of PVB/BEP is not superior to BEP and that it is more myelo- and neurotoxic.

Purpose: A wait-and-see policy for patients with stage I nonseminomatous testicular germ cell tumors (NSTGCT) was evaluated in a prospective study. The frequency and time of recurrence, detection of recurrence, and presence of unfavorable prognostic factors were investigated., Patients and Methods: During the period 1982 to 1992, 154 patients with stage I NSTGCT (median age, 29 years) underwent orchidectomy and were monitored at follow-up evaluation with physical examinations, alfafetoprotein (AFP) and beta-human choriogonadotropin (hCG) levels, chest x-rays (CXR), and computed tomographic (CT) scans of the abdomen and chest. Multivariate logistic regression analyses were performed to identify prognostic factors., Results: During a median follow-up period of 7 years (range, 2 to 12), recurrence was found in 42 patients (27.3%). All cases of recurrence were detected within 2 years, 90% in the first year after orchidectomy. In 29 patients (69.0%), recurrence was detected in the abdominal lymph nodes. Nine patients (21.4%) had metastases in the retroperitoneum and mediastinum and/or lungs, and four patients (9.6%) had metastases only in the mediastinum or lungs. The majority of recurrences (97.6%) were detected by tumor markers and CT scans. Recurrence was related to the presence of vascular invasion, embryonal carcinoma (E), elevated preoperative hCG level, and absence of mature teratoma (M). Only vascular invasion was an independent risk factor. After polychemotherapy treatment for recurrence, the survival rate for the total group was 98.7%., Conclusion: The wait-and-see policy is a reliable method for follow-up monitoring of patients with stage I NSTGCT. Even in patients with unfavorable prognostic factors, it is justified to await the possible appearance of metastases. For the future, it is recommended that CXR be omitted from the schedule, and it might be feasible to discontinue follow-up evaluations after 5 years.

Purpose: To develop a statistical model that predicts the histology (necrosis, mature teratoma, or cancer) after chemotherapy for metastatic nonseminomatous germ cell tumor (NSGCT)., Patients and Methods: An international data set was collected comprising individual patient data from six study groups. Logistic regression analysis was used to estimate the probability of necrosis and the ratio of cancer and mature teratoma., Results: Of 556 patients, 250 (45%) had necrosis at resection, 236 (42%) had mature teratoma, and 70 (13%) had cancer. Predictors of necrosis were the absence of teratoma elements in the primary tumor, prechemotherapy normal alfa-fetoprotein (AFP), normal human chorionic gonadotropin (HCG), and elevated lactate dehydrogenase (LDH) levels, a small prechemotherapy or postchemotherapy mass, and a large shrinkage of the mass during chemotherapy. Multivariate combination of predictors yielded reliable models (goodness-of-fit tests, P > .20), which discriminated necrosis well from other histologies (area under the receiver operating characteristic (ROC) curve, .84), but which discriminated cancer only reasonably from mature teratoma (area, .66). Internal and external validation confirmed these findings., Conclusion: The validated models estimate with high accuracy the histology at resection, especially necrosis, based on well-known and readily available predictors. The predicted probabilities may help to choose between immediate resection of a residual mass or follow-up, taking into account the expected benefits and risks of resection, feasibility of frequent follow-up, the financial costs, and the patient's individual preferences.

Background: A Phase II study of combination treatment with 5-fluorouracil (5-FU), leucovorin (LV), and interferon alpha-2a (IFN) in patients with previously untreated metastatic colorectal cancer was previously reported by the authors. Therapy was on an outpatient basis and consisted of LV 60 mg orally every 8 hours days 1-3, IFN 18 x 10(6) IU subcutaneously days 1-3, and bolus 5-FU 750 mg/m2 intravenously days 2-3. Treatment was repeated every 14 days, until a maximum of 8 courses was administered. A response rate of 54% [95% confidence interval (CI), 34-72%] was observed. However, remission duration after cessation of therapy was short, with a median duration of 5 months (range, 2 to 13+ months)., Methods: Subsequent to the above study, patients on this induction treatment who achieved remission received maintenance therapy: the above described 3-day regimen every 6 weeks until progression, for a maximum of 2 years., Results: Fifty-three patients were enrolled in the induction regimen and 18 out of 29 patients who achieved remission received maintenance treatment. In 50 assessable patients 3 complete recoveries and 26 partial recoveries were observed for a response rate of 58% (CI, 43-72%). Median remission duration of patients receiving maintenance therapy was 9.4 months (CI, 8.4-10.3 months) compared with 4.7 months (CI, 3.2-6.2 months) for patients without maintenance therapy. Median overall survival of all patients was 16.6 months. Toxicity of maintenance therapy was confined to WHO grade 2., Conclusions: The high response rate of this 5-FU/LV/IFN regimen holds true in a larger group of patients. The group that received maintenance treatment had a remission duration of just over 9 months, the maintenance regimen added little toxicity.

The administration of platinum-based chemotherapy induces serotonin release from the enterochromaffin cells, causing nausea and vomiting. This study was conducted to evaluate parameters of serotonin metabolism following platinum-based chemotherapy given in combination with the serotonin type-3 antagonist tropisetron as an antiemetic agent. In nine chemotherapy-naive patients with disseminated germ-cell tumors, parameters of serotonin metabolism in both blood and urine were evaluated during two consecutive courses of platinum-based chemotherapy. Serotonin concentrations in platelet-rich plasma and platelet-poor plasma as well as urinary 5-hydroxyindoleacetic acid (5-HIAA) and serotonin levels were measured during the full length of the courses. By means of comparison with the antiemetic agent chlorpromazine, used on day 1 of the first course only, the effect of the serotonin type-3 antagonist tropisetron, the antiemetic agent used during the rest of the courses, on these parameters was studied. Clinical effects were also recorded. No change in the parameters of serotonin metabolism could be demonstrated during either course by the serotonin type-3 antagonist tropisetron. Also in vitro, no effect of tropisetron on the active serotonin uptake by platelets was found. Serotonin levels in platelets showed no correlation with emetic response. However, the platelet serotonin content decreased significantly between the first and the second course (P < 0.01). The significant reduction in platelet serotonin content observed between the first and the second course indicates a depletion of total body serotonin. The role of a serotonin type-3 antagonist might be affected by the altered serotonin equilibrium during later courses of chemotherapy.

Two malignant extragonadal germ cell tumors are reported, histologically classified as immature teratomas, having pseudodiploid karyotypes with complex structural rearrangements but lacking isochromosome 12p or other rearrangements involving 12p. The absence of 12p material in structural rearrangements was confirmed by chromosome painting. In the two tumors the following common chromosomal breakpoints were found: 6p21, 6p22, 6q23, and 11q13. Exactly the same chromosomal regions, 6p22::6q23 and 6p21::11q13, were involved in fusions. The two tumors belong to a new entity of extragonadal immature teratomas of adults which may be located in the retroperitoneum and posterior mediastinum and are prone to blood borne metastasis.

The efficacy and toxicity of intraperitoneal (i.p.) cisplatin plus systemic etoposide were studied in 36 patients with small (< 2 cm) residual i.p. ovarian cancer after achieving a partial response to platinum-based, first-line chemotherapy. Treatment comprised 90 mg/m2 i.p. cisplatin with intravenous (i.v.) sodium thiosulphate (day 1) and 600-800 mg/m2 i.v. etoposide (days 1 and 2), every 4 weeks for four to six cycles. 7 patients achieved a pathological complete response (pCR), one a pathological partial response and 16 were clinically stable without evidence of disease. After a median follow-up of 13 months, the median progression-free survival (PFS) was 11 months (95% confidence interval 7-16 months). The actuarial PFS at 24 months is 22% (95% confidence interval 8-36%). Three of six relapses after achieving a pCR (50%) were sited i.p., and 9 of 14 other patients with disease progression (64%) had an i.p. relapse, indicating insufficient local efficacy. There was no renal toxicity, but grade 3-4 leucopenia occurred in 63% and grade 3-4 thrombocytopenia in 8% of cycles, while nausea, vomiting and complete alopecia were common. Although side-effects were acceptable, the efficacy of treatment with i.p. cisplatin plus i.v. etoposide is limited.

Unlabelled: The aim of the study was to define an effective regimen as induction treatment in chemotherapy naive patients with advanced breast cancer as preparation for ablative chemotherapy., Patients and Methods: Patients with locally advanced or metastatic breast cancer (AJCC stage IIIB or IV) received 5-fluorouracil, methotrexate with leucovorin rescue and prednisone, alternating with doxorubicin and vincristine for six cycles. Results One hundred and eleven patients were eligible. All patients were evaluable for toxicity and seventy were evaluable for response. Thirty patients achieved a complete remission (43%) and 24 a partial remission (34%). Hematological toxicity was acceptable, as in 7% of 602 treatment cycles patients were admitted for neutropenic fever. Patients with liver metastases had a higher incidence of leucopenic fever, 32% compared to 15% for all patients, and a 25% incidence of cerebellar neuropathy compared to 9% for all patients. Mucositis more severe than WHO grade I occurred in 8% of cycles. Nausea and vomiting were not severe and cardiac or renal toxicity did not occur. Thromboembolic events occurred in 7% of the patients., Conclusions: This induction regimen carries a 43% complete and 77% overall remission rate, which is high compared to other conventional and even escalated regimens. The toxicity profile is acceptable except for the higher incidence of leucopenic fever and the reversible 5-FU cerebellar syndrome in patients with liver metastases.

Combinations of dacarbazine (DTIC) and other cytotoxic agents or alpha-interferon were given to 136 patients in five different regimens. The total response rate was 32% (95% confidence interval 24-40%); 13% had a complete remission. Female patients had a significantly higher chance of response than male patients: 46% vs 23%. There was also a difference in complete response rate: 25% vs 9%. The overall survival was 6 months; 8% of patients had a response of more than 6 months and 2% of more than 2 years. Although response rates vary among the various regimens described in the literature, the complete response rates are quite similar and the long-term disease-free survival of these combinations may be similar to that of dacarbazine alone.

In a phase I trial the toxicity and immunomodulatory effects of combined treatment with intravenous (i.v.) bispecific monoclonal antibody BIS-1 and subcutaneous (s.c.) interleukin 2 (IL-2) was studied in renal cell cancer patients. BIS-1 combines a specificity against CD3 on T lymphocytes with a specificity against a 40 kDa pancarcinoma-associated antigen, EGP-2. Patients received BIS-1 F(ab')2 fragments intravenously at doses of 1, 3 and 5 micrograms kg-1 body weight during a concomitantly given standard s.c. IL-2 treatment. For each dose, four patients were treated with a 2 h BIS-1 infusion in the second and fourth week of IL-2 therapy. Acute BIS-1 F(ab')2-related toxicity with symptoms of chills, peripheral vasoconstriction and temporary dyspnoea was observed in 2/4 and 5/5 patients at the 3 and 5 micrograms kg-1 dose level respectively. The maximum tolerated dose (MTD) of BIS-1 F(ab')2 was 5 micrograms kg-1. Elevated plasma levels of tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were detected at the MTD. Flow cytometric analysis showed a dose-dependent binding of BIS-1 F(ab')2 to circulating T lymphocytes. Peripheral blood mononuclear cells (PBMCs), isolated after treatment with 3 and 5 micrograms kg-1 BIS-1, showed increased specific cytolytic capacity against EGP-2+ tumour cells as tested in an ex vivo performed assay. Maximal killing capacity of the PBMCs, as assessed by adding excess BIS-1 to the assay, was shown to be decreased after BIS-1 infusion at 5 micrograms kg-1 BIS-1 F(ab')2. A BIS-1 F(ab')2 dose-dependent disappearance of circulating mononuclear cells from the peripheral blood was observed. Within the circulating CD3+ CD8+ lymphocyte population. LFA-1 alpha-bright and HLA-DR+ T-cell numbers decreased preferentially. It is concluded that i.v. BIS-1 F(ab')2, when combined with s.c. IL-2, has a MTD of 5 micrograms kg-1. The treatment endows the T lymphocytes with a specific anti-EGP-2-directed cytotoxic potential.

In the present study, we examined the distribution of integrin subunits and extracellular matrix proteins in normal testis, intratubular germ cell neoplasia (ITGCN), and primary and metastatic seminomas. Compared to normal testis in ITGCN, Sertoli cells showed increased expression of alpha 3, alpha 6, and beta 1 integrin subunits. Malignant intratubular germ cells stained for alpha 3, alpha 6, and beta 1 integrin subunits. Progression of ITGCN to invasive seminoma was associated with loss of alpha 3 integrin subunit expression by tumor cells. Consequent to this loss, it can be speculated that the strong expression on ITGCN may be related to the noninvasive character of the lesion as is also known from other noninvasive tumors. All tumors showed a strong expression of alpha 6 and beta 1 integrin subunits. The alpha 5 integrin subunit was weakly expressed in primary seminomas in all stages. No differences were observed in integrin expression between primary and metastatic tumors. The distribution of extracellular matrix proteins was heterogeneous and revealed clear architectural differences between seminomas that may reflect different stages of tumor stroma formation. To our knowledge, the results presented in this study provide the first information on the possible role of tumor-extracellular matrix interactions in the biological behavior of ITGCN and testicular seminomas.

To define the activity of an individually escalated dacarbazine (DTIC) dose combined with interferon-alpha-2a (IFN), granulocyte-colony stimulating-factor (G-CSF) and ondansetron, 20 patients (pts) with metastatic melanoma were treated with DTIC, ondansetron 8 mg iv, G-CSF 300 micrograms sc and IFN 9 MU sc. Treatment was performed every 21 days to a maximum of 6 courses. DTIC dose was escalated with 250 mg/m2 in case of acceptable toxicity to 1250, 1500 and 1750 mg/m2 in (projected/realized), 14/19, 8/11 and 0/5 pts, respectively. Dose escalation prohibiting toxicities were thrombocytopenia (10 pts), leukopenia (9 pts), and nausea/vomiting (2 pts). Four partial remissions were observed, for a response rate of 20% (95% confidence interval, 6 to 44%). Duration of responses was 1, 2, 3 and 3 months. Median overall survival was 8 months.

Patients with breast cancer and a high number of involved axillary lymph nodes have a poor prognosis, despite adjuvant chemotherapy. The 5-year disease-free survival (DFS) in this group amounts to 30-40% and the 10-year DFS is only 15-20%. Therefore, new treatment modalities are being sought for this group of patients. The aim of the present study was the evaluation of the efficacy of high-dose chemotherapy combined with autologous bone marrow support. 24 patients with a primary breast cancer with more than five involved axillary lymph nodes received, after surgery, six courses of induction chemotherapy followed by ablative chemotherapy and reinfusion of autologous bone marrow. All patients were premenopausal or less than 2 years postmenopausal. Induction chemotherapy consisted of methotrexate (MTX) 1.5 g/m2 intravenous (i.v.) and 5-fluorouracil (5-FU) 1.5 g/m2 i.v. on day 1, prednisone 40 mg/m2 orally on days 2-14, doxorubicin 50 mg/m2 i.v. and vincristine 1 mg/m2 i.v. on day 14. Courses were repeated six times every 4 weeks. 10 patients received cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. as intensive regimen, in 14 patients this comprised mitoxantrone 50 mg/m2 i.v. and thiotepa 800 mg/m2 i.v. Reinfusion of autologous marrow followed on day 7. Finally, patients received locoregional radiotherapy for extranodal disease and tamoxifen 40 mg daily orally over a period of 2 years. The median age of patients was 42 years, range 29-54. The median number of involved nodes was 10. During induction therapy, fever requiring i.v. antibiotics occurred in 4% of 144 courses, 14% of patients suffered from mucositis WHO grade 2-3, and the other patients had mucositis grade 1. During the ablative chemotherapy, 1 patient died, 6 developed septicaemia, 5 showed mucositis grade 3-4 and the other patients had mucositis grade 1 or 2. In the follow-up, 1 patient died from acute cardiac failure. Reversible radiation-induced pneumonitis occurred in 7 out of 14 irradiated patients; symptoms started directly following radiotherapy and lasted for several weeks, but disappeared in due course. During follow-up, 2 patients with six and > 10 positive nodes, respectively, have relapsed after 18 and 36 months, both in the cyclophosphamide/etoposide regimen. Median observation is 3 years, disease-free survival at 5 years is predicted to be 84%. Intensive treatment in these patients with high numbers of involved axillary lymph nodes is a toxic regimen, but may improve the chance of surviving free of disease.