Wj Sluiter

Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre

58 patients with biopsy-proven Wegeners granulomatosis (WG) were prospectively screened for clinical evidence of the disease 3-monthly, with antineutrophil cytoplasmic antibody (ANCA) measurements every month. Over 24 months, ANCA rose in 20 patients, 9 of whom were randomly assigned to receive combined 9 and 3 month courses of cyclophosphamide and prednisolone, respectively, at the time of ANCA rise; and 11 patients who were untreated except if there was a clinical relapse. 6 of 11 untreated patients relapsed within 3 months of ANCA rise. 3 of the remaining 5 patients relapsed after 3 months. There were no early or late relapses in patients randomised to treatment. Patients receiving no treatment at the time of ANCA rise took more cyclophosphamide and prednisolone than patients who were treated. Side-effects did not significantly differ between the two groups.

Cardiovascular Morbidity in Long-Term Survivors of Metastatic Testicular Cancer

PURPOSE To determine whether long-term survivors of metastatic testicular cancer have an increased risk of cardiovascular morbidity more than 10 years after chemotherapy. PATIENTS AND METHODS Eighty-seven patients treated with cisplatin-containing chemotherapy before 1987 who were in remission for at least 10 years and whose ages were </= 50 years at the time of analysis were evaluated for the occurrence of cardiovascular events. Sixty-two of 87 patients were additionally evaluated for cardiac damage and cardiovascular risk factors. Their cardiovascular risk profile was compared with that of 40 patients with comparable age and follow-up duration treated with orchidectomy only for stage I disease. RESULTS Major cardiac events were found in five (6%) of the 87 patients (age at time of event, 30 to 42 years; time after chemotherapy, 9 to 16 years): two with myocardial infarction and three with angina pectoris with proven myocardial ischemia. An increased observed-to-expected ratio of 7.1 (95% confidence interval, 1.9 to 18.3) for coronary artery disease, as compared with the general male Dutch population, was found. In addition, one patient experienced a cerebrovascular accident. Exercise ECG did not reveal cases of subclinical coronary artery disease. Echocardiography showed normal systolic left ventricular function in most patients, but diastolic left ventricular function was disturbed in 33% of the patients. Of 62 chemotherapy patients, 79% had hypercholesterolemia, 39% had hypertension, 25% still experienced Raynauds phenomenon, and 22% had microalbuminuria. Compared with patients with stage I disease, the chemotherapy patients had higher blood pressure and higher total cholesterol and triglyceride levels and were more insulin-resistant. CONCLUSION In long-term survivors of metastatic testicular cancer, we observed a significantly increased risk for occurrence of cardiac events accompanied by a persisting unfavorable cardiovascular risk profile. Accurate follow-up, focused on cardiovascular complications and aimed at intervention in these young cancer survivors, seems to be important.

Long-term Follow-up of Cardiovascular Risk Factors in Patients Given Chemotherapy for Disseminated Nonseminomatous Testicular Cancer

OBJECTIVE To assess cardiovascular risk factors over time in patients who received chemotherapy for disseminated testicular cancer and were apparently cured. DESIGN Cohort study. SETTING Referral center. PATIENTS Fifty-seven consecutive patients (median age, 28 years; range, 16 to 43 years) who received cisplatin-containing chemotherapy between 1978 and 1985. MEASUREMENTS Serum cholesterol and high-density lipoprotein (HDL) levels, body mass index (BMI), blood pressure, kidney function, and hormonal status were monitored during follow-up after chemotherapy (median follow-up, 88 months; range, 56 to 143 months). The BMI and cholesterol values obtained 4 to 6 years after chemotherapy were compared with values from a sample of healthy, age-matched Dutch men; the cholesterol level was also compared with that of 31 patients treated with orchidectomy for stage I disease. RESULTS The mean cholesterol level in patients at the start of chemotherapy was 3.96 +/- 0.98 mmol/L [153 +/- 38 mg/dL], increasing 4 to 6 years later to 6.12 +/- 1.20 mmol/L [237 +/- 46 mg/dL] (P less than 0.001); 49 of 57 patients had an elevated low-density lipoprotein (LDL) cholesterol level (greater than 3.4 mmol/L [130 mg/dL]), with a mean level of 4.47 +/- 1.05 mmol/L [173 +/- 41 mg/dL]. Compared with a sample of healthy Dutch men, the chemotherapy group had an elevated cholesterol level (P less than 0.05). At 4 to 6 years, the mean HDL cholesterol level was 0.76 +/- 0.18 mmol/L [29 +/- 7 mg/dL], which was low compared with that of the healthy Dutch men (P less than 0.05). The mean BMI for all patients was 2.8% higher than expected 4 to 6 years after chemotherapy (P less than 0.01) but was not higher than expected 7 to 10 years after chemotherapy. CONCLUSIONS In addition to other known late side effects of chemotherapy in patients with testicular cancer, hypercholesterolemia and overweight might represent risk factors for cardiovascular disease in such patients, especially in those who are younger.

Familial testicular cancer in a single-centre population

Familial occurrence of testicular cancer suggests a genetic predisposition to the disease. A genetic susceptibility may also be reflected by the occurrence of bilateral testicular neoplasms and the high rates of urogenital developmental anomalies in families prone to testicular cancer. In this study, the proportion of familial testicular cancer cases was analyzed retrospectively in a single-centre population of 693 testicular cancer patients treated between 1977 and 1997 and the relative risk (RR) for first-degree relatives of patients was estimated. In addition, the existence of bilateral testicular neoplasms and urogenital developmental anomalies in familial testicular cancer patients was evaluated. 24 of the 693 patients (3.5%) had a first-degree relative with testicular cancer. These 24 cases belonged to 17 families; in 7 of these 17 families both affected first-degree family members were part of the study population of 693 patients. Consequently, the 693 studied patients belonged to a total of 686 families. Thus, the actual proportion of familial testicular cancer was 2.5% (17 of 686 families). The familial cases consisted of 11 brother pairs, including 2 pairs of identical twins and 1 pair which also had two affected cousins, and 6 father-son pairs (in total 36 cases, 12 treated elsewhere). Estimates of the RR to first-degree relatives showed a 9- to 13-fold increased RR to brothers (P < 0.001) and a 2-fold increased RR to fathers (P = non-significant (n.s)) of testicular cancer patients. Among the 36 patients with familial testicular cancer, 2 (5.6%) had bilateral testicular cancer, 4 (11.1%) had undescended testis, 3 (8.3%) had inguinal hernia, and 1 (2.8%) showed renal hypoplasia. The present data on familial occurrence of testicular cancer may lend support to a role of genetic factors in the aetiology of testicular cancer.

Tamoxifen effects on subjective and psychosexual well-being, in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy

To evaluate the impact of tamoxifen on subjective and psychosexual well-being in breast cancer patients in relation to type of prior chemotherapy and menopausal status. Longitudinal interview study in breast cancer patients during and after adjuvant tamoxifen use. Menopausal status was defined by last menstrual period and serum oestradiol and FSH levels. Gynaecology outpatient clinic, Tertiary Referral Hospital, January 1995 to September 1999. Breast cancer patients <56 years of age, participating in a randomised trial comparing adjuvant high-dose (n=45) and standard-dose (n=53) chemotherapy, followed by radiotherapy and tamoxifen. Relative incidence and correlation of subjective and psychosexual symptoms during and after tamoxifen. During tamoxifen the most frequent complaints were hot flushes (85%), disturbed sleep (55%), vaginal dryness and/or dyspareunia (47%), decreased sexual desire (44%) and musculo-skeletal symptoms (43%). Disturbed sleep correlated with hot flushes (P<0.0005) and concentration problems (P<0.05). Decreased sexual interest correlated with vaginal dryness (P<0.0005) and/or dyspareunia (P<0.0005). In the high-dose group more patients became postmenopausal (95% vs 33%) and more patients reported symptoms than in the standard-dose group (P<0.05). After discontinuation of tamoxifen, symptoms decreased significantly. However, hot flushes, disturbed sleep and vaginal dryness persisted more often in patients who remained postmenopausal after high-dose chemotherapy (P<0.05). Overall, during tamoxifen patients reported many symptoms. More patients become postmenopausal after high-dose chemotherapy, and they remain often symptomatic after tamoxifen.

Nephrotoxicity of cis-diamminedichloride platinum (CDDP) during remission-induction and maintenance chemotherapy of testicular carcinoma

SummaryWe studied renal function in nine patients with disseminated testicular carcinoma before and after remission-induction and maintenance therapy with a drug combination containing cis-platinum. The median glomerular filtration rate (GFR) decreased during remission-induction therapy from 146 to 118 ml/min. No effect of cumulative toxicity on the median GFR was found during maintenance therapy, nor did the median GFR improve. The median effective renal plasma flow (ERPF) decreased during the total period from 705 to 514 ml/min. No significant changes in median filtration fraction (FF) and serum creatinine were observed. It is suggested that intrarenal hemodynamic effects are important in the nephrotoxicity of cis-diamminedichloride platinum (CDDP).

Dietary supplementation with lish oil modifies renal reserve filtration capacity in postoperative, cyclosporin A-treated renal transplant recipients

Abstract. The effect of a daily supplementation of 6 g fish oil (30% C20:5 omega‐3 = EPA and 20% C22:6 omega‐3 = DHA) for 1 month on renal function variables was investigated in a placebo‐controlled (6 g coconut oil), prospective, randomized, double‐blind study in acute postoperative cyclosporin A (CyA)‐treated renal transplant recipients. Seventeen patients ingested placebo capsules (EPA‐) and 14 patients fish oil (EPA +). Renal function tests were performed using the simultaneous determination of 1251‐iothalamate and 1311‐hippuran clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively. Renal reserve filtration capacity was assessed by dopamine infusion, amino acid infusion, and a combination of both stimuli. After 1 month there were no significant differences in rejection episodes, CyA dose, or CyA levels. In contrast to our earlier observations, serum creatinine, creatinine clearance, GFR, and ERPF did not differ between the EPA‐and EPA + groups. Filtration fraction (FF) differed significantly, being 0. 21 in the EPA‐group versus 0. 26 in the EPA+ group. To exclude the possible influence of a rejection episode, the nonrejecting patients were analyzed separately, creating the subgroups EPA + re‐and EPA‐re‐. These two groups were comparable in age, donor age, and GFR. The EPA + regroup had a significantly lower ERPF (164 ml/min per 1. 73 nr) than the EPA‐re‐group (262 ml/min per 1. 73 m2). FF was significantly higher in the EPA + re‐group (0. 26) than in the EPA‐re‐group (0. 21). Following dopamine, no significant differences in the percentage increase of GFR and ERPF between both groups were observed, while FF fell to the same extent in both groups. Following amino acids, the fish oil‐treated patients had a significantly better response on GFR (EPA + re‐15. 3 versus EPA‐re‐10. 6%; P < 0. 05). The near‐normal FF and the better response on amino acid infusion strongly suggest that at 1 month postoperatively, the CyA‐and fish oil‐treated patients have more balanced renal hemodynamics than the CyA‐and coconut oil‐treated patients.

Antipyrine metabolism in patients with disseminated testicular cancer and the influence of cytostatic treatment

SummaryAntipyrine plasma clearance and rates of metabolite formation were measured on four occasions in eight patients with disseminated nonseminomatous testicular cancer. Antipyrine tests were performed before, during (2X), and after treatment with a combination of cisplatin (P), vinblastin (V), and bleomycin (B). Pretreatment values were compared with a male control group (n=14) matched for age and body weight. Antipyrine plasma clearance was 20% higher in patients with testicular cancer (first experiment) than in the control group. This difference was mainly due to a 35% higher clearance for production of 3-hydroxymethylantipyrine (HMA), while clearance for production of norantipyrine (NORA) and 4-hydroxyantipyrine (OHA) was not significantly different from the control group. A reduction in CLHMA was observed after complete remission (fourth experiment), indicating that the presence of the tumor may be related to a selective increase of HMA formation. Treatment with the PVB combination resulted in a 30% increase in antipyrine plasma clearance (second and third experiments), whereas the rates of formation of the main metabolites of antipyrine were all increased to the same extent. These accelerating effects of PVB treatment persisted for at least 6 weeks after the start of the last treatment cycle.The data presented in this paper demonstrate that the presence of a testicular tumor and the use of cytostatics can have an accelerating and partially selective effect on oxidative drug-metabolizing enzyme activity in man.

Influence of Combination Chemotherapy with cis-Diamminedichloroplatinum on Renal Function: Long-Term Effects

Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined in 8 patients with disseminated testicular carcinoma before, during and 1 year after termination of a combination chemotherapy with cis-diamminedichloroplatinum (CDDP). The decrease in median GFR in comparison with the pretreatment value was 15.5% at the start of the maintenance therapy, 23% at the end of the maintenance therapy and 15.5% 1 year after termination of therapy. The comparable reduction in ERPF at those instants was 15.5, 19 and 23.5%, respectively. At all intervals the changes in GFR were significantly reduced in comparison with pretreatment values. No significant change in both GFR and ERPF was found either during or after discontinuation of maintenance treatment. The fall in ERPF was significant during the total period of treatment as well as during the total time of observation. Thus, no cumulative nephrotoxicity during therapy, nor improvement in renal function thereafter was found. Serum levels of creatinine and beta-2-microglobulin did not express the changes in renal function.

A new in vitro assay for quantitation of chemotherapy-induced mucositis

Patients receiving high-dose chemotherapy (HD-CT) are at risk of severe mucositis. Most prevention studies evaluate the degree of mucositis on clinical, and therefore subjective, measurements. The aim of this study was to develop an objective in vitro assay of chemotherapy-induced mucositis. Twelve patients with locally advanced breast carcinoma received HD-CT followed by peripheral stem cell reinfusion. Before and twice weekly after HD-CT, the mucosa was evaluated by an oral washing, a buccal smear and the World Health Organization (WHO) toxicity grading; furthermore, blood leucocyte levels were determined. For the oral washings, the percentage of viable epithelial cells was determined by trypan blue dye exclusion and leucocytes were counted by fluorescence microscopy after incubation with acridine orange. Maturity of buccal cells was assessed by staining buccal smears for morphology according to Papanicolaou (Whitacker D and Williams V, 1994). Eight healthy volunteers served as controls. The mean percentage (+/- s.e.m.) of viable oral epithelial cells was stable in controls (44 +/- 2%). In patients, they increased after HD-CT, which was significant after day 7 compared with pretreatment (P < or = 0.05). In addition, a shift from mature to immature epithelial cells in buccal smears was observed. Oral leucocyte levels were closely correlated with the blood leucocyte counts. The WHO score followed the results of these other evaluations with some delay. The viability of buccal cells obtained by oral washings increases after HD-CT. This is possibly because of desquamation of the upper oral mucosa layer, with a shift from mature to more immature cells. These data can be quantitated, and this assay may therefore be useful in studies aimed at prevention of mucositis.