A randomized phase III adjuvant study in high-risk cervical cancer: simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): a NOGGO-AGO Intergroup Study.

BACKGROUND: Simultaneous adjuvant platinum-based radiochemotherapy in high-risk cervical cancer (CC) is an established treatment strategy. Sequential paclitaxel (Taxol) and platinum followed by radiotherapy may offer further advantages regarding toxicity. PATIENTS AND METHODS: An open-labeled randomized phase III trial was conducted to compare paclitaxel (175 mg/m(2)) plus carboplatin (AUC5) followed by radiation (50.4 Gy) (experimental arm-A) versus simultaneous radiochemotherapy with cisplatin (40 mg/m(2)/week) (arm-B) in patients with stage IB-IIB CC after surgery. Primary objective was progression-free survival (PFS). RESULTS: Overall, 271 patients were randomized and 263 were eligible for evaluation; 132 in arm-A and 131 in arm-B appropriately balanced. The estimated 2-year PFS was 81.8% [95% confidence interval (CI) 74.4-89.1] in arm-B versus 87.2% (95% CI 81.2-93.3) in arm-A (P = 0.235) and the corresponding 5-year survival rates were 85.8% in arm-A and 78.9% in arm-B (P = 0.25). Hematological grade 3/4 toxicity was higher in arm-B. Alopecia (87.9% versus 4.1%; P < 0.001) and neurotoxicity (65.9% versus 15.6%; P < 0.001) were significantly higher in arm-A. Early treatment termination was significantly more frequent in arm-B than in arm-A (32.1% versus 12.9%; P = 0.001). CONCLUSIONS: Sequential chemotherapy and radiation in high-risk CC could not show any significant survival benefit; however, a different toxicity profile appeared. This sequential regime may constitute an alternative option when contraindications for immediate postoperative radiation are present.

[The lateral profile of the lumbar vertebrae following lumbosacral spondylodesis--comparison between Harrington rods and a transpedicular fixation system (Zielke's USIS method)]. / Das laterale Profil der Lendenwirbelsäule nach lumbosacraler Spondylodese--Vergleich zwischen Harringtonstäben und einem transpedikulären Fixationssystem (USIS nach Zielke).

We compared the lateral profile of the lumbar spine after lumbosacral dorsal fusion in two groups of each 32 patients with comparable age, sex distribution and indication; one group had been fused with the use of two short Harrington rods, the other with the Universal Spinal Instrumentation System (USIS) according to Zielke/Harms. The sparing of motion segments using a transpedicular system is demonstrated by the average number of 1.7 fused motion segments compared to 2.2 with the Harrington rods. The average increase of cyphosis of the fused area could be reduced with USIS from 7.3 to 3.0 degrees in spite distraction. The greatest difference could be seen in cases of spondylolisthesis (2.0 degrees compared to 8.2) and in fusions including three segments (2.0 versus 7.0). No significant difference in total lordosis of the lumbar spine could be evaluated and there was no influence of preoperative mobility on the grade of postoperative cyphosis. The early results of lumbar fusion using USIS are clinically satisfying in spite of a relative high rate of rod fracture. measures to achieve a higher stability and diminish the rate of implant failure are discussed.

[Controlled ultra-high dosage methotrexate therapy in three patients with metastatic osteosarcoma (author's transl)]. / Ultrahochdosierte Methotrexattherapie mit plasmaspiegelgesteuerter Verabreichung bei 3 Pateiten mit metastasierendem Osteosarkom.

9 HDMTX infusions with 30 to 55 g MTX and leucovorin rescue were given to 3 patients with multifocal osteosarcoma. Resistance to standard MTX infusions with up to 12 g/m2 body surface in 4 hours indicated the administration of these higher doses (27 g/m2 body surface on average) over a shorter period of time (160 min on average). MTX input was controlled by the increase in plasma MTX levels which were determined by EMIT enzyme assay within a few minutes of sampling. The plasma MTX levels were found to be up to 10 times (average 4 times) higher than those achieved by the standard infusion. All infusions proved to be relatively well tolerated in all 3 cases, although, thrice after 36 hours an increased leucovorin rescue had to be made for 12 hours, because of delayed renal methotrexate excretion; the usual leucovorin rescue (15 mg every 6 hours) was given for an average of five days. No therapeutic effects were seen either clinically, radiologically, or histologically. The resistance to HDMTX in these three patients could not be broken by HDMTX PLRD infusions.

Potential role of middle molecular compounds in the development of uremic anemia.

In preceding papers it was demonstrated that middle molecular fractions isolated from uremic patients (MM) impair hemoglobin synthesis by inhibiting the enzyme Delta-aminolevulinic acid dehydrase (D-ALA-D) and by diminishing the globin synthesis in reticulocytes from healthy subjects. Additionally, the susceptibility to oxidative damage of erythrocytes is increased in the presence of MM. Studies were undertaken to elucidate the underlying mechanisms. It was found that the MM induced D-ALA-D inhibition is reversed both by Zn and by GSH in vitro indicating that MM exert their effect on the enzyme either by affecting essential SH-groups within the enzyme molecule or by altering the enzyme configuration by interaction with the Zn atom. MM causing an increased oxidative hemolysis rate (OHR) also inhibit the catalase activity and the glucose consumption of normal and uremic erythrocytes. It is concluded that the augmented OHR in uremia is induced by accumulating hydrogen peroxide which cannot be sufficiently removed due to the MM mediated catalase inhibition and the concomitant impairment of the glucose utilisation.

Continuous peritoneal dialysis (CPD)--an alternative to hemodialysis in acute renal failure after cardiovascular operations.

In our experience hemodialysis proved to be unsatisfactory in the treatment of acute renal failure after cardiovascular surgical intervention because of its negative influence on the often critical hemodynamic situation of the patients. In 21 cases we performed a continuous peritoneal dialysis (CPD) for 1 to 29 (mean 9.2) days by using a Tenckhoff catheter (16). Treatment was started when anuria occurred or when serum nonprotein nitrogen increased. Satisfactory volume equilibration was established by this treatment. A pathological increase of serum electrolytes could be prevented; serum potassium, in particular, did not exceed 5.6 mVal/l. No dysfunctions in acid-base balance occurred. The serum levels of nonprotein nitrogen decreased: Serum carbamid was diminished from 229 +/- 14 mg% to 160 +/- 10 mg% and serum creatinine from 7.7 +/- 0.6 mg% to 6.0 +/- 0.8 mg% (p < 0.05). Disturbances of hemodynamic and respiratory functions could be avoided by CPD. Peritoneal reactions were noted in 5 cases. In our opinion continuous peritoneal dialysis seems to be a suitable alternative to hemodialysis in the treatment of acute renal failure after open heart surgery.

Simultaneous hemofiltration/hemodialysis (HF/HD): short- and long-term tolerance. Introduction of a system for automatic fluid replacement.

Data are presented concerning our experiences with simultaneous hemofiltration and hemodialysis (HF/HD) in uremic patients. Ten randomly selected patients have been treated for two and a half to three years with either conventional hemodialysis (HD, 3 x 4 hours/week, 1.4 m2 surface area Cuprophan dialyzer) or HF/HD (RP-6, 3 x 3 hours/week). No differences could be detected with regard to the blood chemistry or the blood pressure between the two groups of patients. During HF/HD the well-being of the patients was better than during HD, which can be attributed to a greater stability of the blood pressure and of the serum osmolarity and to a decrease of the intraocular pressure during treatment. An apparatus is described which is in use enabling the automatic replacement of the required substitution fluid. With regard to the performance and the tolerance, HF/HD is comparable to hemofiltration, but the treatment sessions are shorter.

Influence of the plasticiser di-2-ethylhexyl-phthalate on drug metabolising enzymes in the liver of uraemic rats.

After bilateral or subtotal nephrectomy male rats were given intraperitoneal injections of the plasticiser di-2-ethylhexylphthalate (DEHP) at differing time intervals in doses that do not affect the liver of normal rats. 200mg DEHP/100g body weight had no influence on the parameters measured. After administering 7 x 200mg/100g body weight for 14 days, liver weight and in vitro activity of the mixed function oxidation system increased significantly. In addition, the hexobarbital sleeping time decreased, indicating a stimulation of the activity of drug metabolising enzymes in vivo. Similar results were obtained after the administration of 56 x 50mg DEHP/100g body weight for 19 weeks. It is concluded that uraemic rats are more susceptible to inducing effects, but that the DEHP toxicity is of little importance.

Influence of middle molecules on the anemia of uremic patients.

To evaluate their toxicity at the cellular level, middle molecules from uremic serum were incubated with erythrocytes from healthy subjects and the activity of the enzyme Delta-aminolevulinic acid dehydrase (D-ALA-D) and peroxidative hemolysis were investigated. Uremic middle molecules caused a significant decrease of the D-ALA-D activity of normal erythrocytes which was not due to differences in the concentrations of Pb, Cd or Zn. The decreased enzyme activity could be restored by adding reduced glutathione (GSH; 5 mmol/L) together with the middle molecules to the assay system. Uremic middle molecules caused a significant increase of peroxidative hemolysis in normal erythrocytes. Uremic middle molecules contribute to the anemia of uremic patients by impeding hemoglobin synthesis and by increasing peroxidative hemolysis, possibly by affecting SH-groups. H2O2-producing compounds should be avoided in uremic patients.

Influence of essential amino acids and keto acids on protein metabolism and anemia of patients on intermittent hemodialysis.

Ten patients were treated with 10 g/day of essential amino acids orally; nine patients received 9.5 g/day of a mixture of essential amino acids (lysine, threonine, tryprophan, histidine, and tyrosine) and keto analogues of isoleucine, leucine, phenylalanine, valine, and methionine. A control group of 11 patients received no supplementation. All patients were on a liberal food intake amounting to 1 g of protein per kilogram of body weight and 31 kcal/kg of body weight daily. Before and 3 months after the beginning of the supplementation, the following parameters were measured: amino acids, albumin, transferrin, urea and creatinine concentrations in plasma, hemoglobin, and hematocrit in blood. None of these parameters was altered by either treatment. It is concluded that supplementation with essential amino acids or their keto analogues is ineffective in well-nourished dialysis patients.

Enzyme induction in the uremic liver.

Forty-five days after subtotal nephrectomy or sham-operation of male rats, microsomal enzymes were investigated in vitro. The activities (per milligram) of microsomal protein of two esterases and of two glucuronyltransferases were normal in the uremic rats. The mixed-function oxidation system had lower activities per milligram of protein than that in sham-operated controls. Due to a decrease of the microsomal protein content of the uremic liver, the activities of these enzymes were decreased when calculated for the whole liver. In contrast, the glucoronidation of phenolphthalein remained normal when related to the whole liver, due to an increased activity per mg of protein. Treatment with the plasticizer di-(2-ethylhexyl)-phthalate caused a significant increase of the liver wet weight, the microsomal protein content, and the activity per mg of protein for the demethylation of aminopyrine in subtotally nephrectomized rats but was without influence on the liver of sham-operated controls. It is concluded that uremia itself does not induce liver microsomal enzymes. The microsomal enzymes, however, remain inducible by foreign compounds even under uremic conditions.

Hemodiafiltration: a new alternative to hemofiltration and conventional hemodialysis.

A new dialysis method, termed hemodiafiltration, is proposed. The procedure consists of the combination of hemofiltration and conventional hemodialysis using high flux membranes with a transmembrane pressure (TMP) of 300--500 mmHg and a dialysate flow of 900 ml/min. Due to the combination of convective mass transfer and diffusion, the clearance values of both small and larger molecules are significantly higher than during hemofiltration or hemodialysis alone with the same membranes. The removal of excess water is better tolerated than during hemodialysis. With this new method, six patients have been successfully treated for six months (three times per week, three hours per treatment) without side effects. Thus hemodiafiltration appears to be the method of choice to shorten dialysis time.

Simultaneous hemofiltration/hemodialysis: an effective alternative to hemofiltration and conventional hemodialysis in the treatment of uremic patients.

Hemofiltration and hemodialysis were performed simultaneously with the Polyacrylnitrile membrane in a single pass dialyzate flow system. Due to the combination of convective mass transfer and diffusion, the clearances of both small and large molecules were significantly higher than during hemofiltration or hemodialysis alone. The removal of excess water was better tolerated than during hemodialysis. Six patients have been treated by this technique for 6 months 3 X 3 hr/week without side effects, and the new procedure appears to be the method of choice to shorten dialysis time.