Phenylalanine tolerance in three phenylketonuric women pregnant with fetuses of different genetic PKU status.

Pregnancy management in phenylketonuric women includes continuous dietary control starting before conception, aiming to maintain blood phenylalanine concentrations in a desirable range, irrespective of the fetal genetic PKU status. While the maternal phenylalanine hydroxylase (PAH) genotype will influence metabolic control, an effect of the fetal genetic PKU status on maternal metabolic control during pregnancy has not been described. We monitored three pregnancies of women with classical PKU by dietary protocols of daily phenylalanine intake, phenylalanine blood concentrations, and obstetric care. Patients 1 and 2 carried a heterozygous (not PKU-affected) fetus, while patient 3 was pregnant with a PKU-affected fetus (PAH p.R408W and p.R408W). The expected increase in phenylalanine tolerance during the course of pregnancy was observed in patients 1 and 2 in whom phenylalanine intake could be steadily increased from 400 to 1700 mg/day while phenylalanine blood concentrations remained in the desired range. Gain of body weight was 13.0 and 17.7 kg, respectively. In patient 3, the phenylalanine tolerance did not rise above 600 mg/day, and phenylalanine blood concentrations were above the desired range on several occasions. Caloric intake was therefore encouraged, which led to a weight gain of 20.0 kg. The course of pregnancy was otherwise normal in all three cases, and infants with normal birth weight and head circumference were born. The different phenylalanine tolerance in pregnancies with PKU-affected and non-affected fetuses suggests that PAH genotype and metabolic situation of the fetus influence maternal metabolic control. A phenylalanine tolerance remaining low in the third trimester of pregnancy may indicate fetal PKU.

Impaired plasma antioxidative defense and increased nontransferrin-bound iron during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation.

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

Nontransferrin-bound iron in serum of patients receiving bone marrow transplants.

Nontransferrin-bound iron (NTBI) and other parameters of iron status were measured in 40 patients undergoing bone marrow transplantation (BMT) prior to conditioning therapy (between day -10 and -7), at the time of BMT (day 0), and 2 weeks later (day + 14). Serum iron and transferrin saturation values were normal before conditioning therapy. At day 0 serum iron values were high and median transferrin saturation was 98% (changes in the values of both serum iron and transferrin saturation, p < .0001). Transferrin saturation values were still elevated 2 weeks posttransplant (day +14 vs. baseline values, p = .0001). Starting at low NTBI levels pretransplant (median 0.4 micromol/l, range 0-4.2 micromol/l, controls: < or = 0.4 micromol/l), all patients revealed high levels on day 0 (median 4.0 micromol/l, range 1.9-6.9 micromol/l, p < .0001) and 2 weeks posttransplant (median 2.7 micromol/l, range 0-6.2 micromol/l, p < .0001). These observations indicate that the plasma iron pool in patients undergoing BMT increases to a level at which the normal ability to sequestrate iron becomes exhausted and considerable amounts of NTBI appear in serum. This "free" form of iron can mediate the production of reactive oxygen species and may cause organ toxicity in the early posttransplantation period.

Experience with liposomal Amphotericin-B in 60 patients undergoing high-dose therapy and bone marrow or peripheral blood stem cell transplantation.

60 patients undergoing bone marrow or stem cell transplantation were treated with liposomal Amphotericin-B for documented or suspected mycosis. 34 patients had a prior course of conventional Amphotericin-B with the following adverse effects: increasing creatinine above 1.4 mg/dl (n = 17), increasing creatinine below 1.5 mg/dl (n = 9), no response (n = 6), and clinical side-effects (n = 4). Liposomal Amphotericin-B failed in 6/7 patients with culture-proven mycosis who died from infection with Aspergillus (n = 2) and Candida (n = 4), respectively. One patient with Candida lambica sepsis was cured. No patient with clinically or serologically suspected or diagnosed infection died from mycosis. Liposomal Amphotericin-B was well tolerated in 57 patients, even after side-effects of the conventional formulation. Adverse effects occurred in three cases, requiring the withdrawal of the drug in one patient. Due to toxic side-effects of the high-dose therapy and transplant-related complications, it was difficult to evaluate the influence of liposomal Amphotericin-B on laboratory parameters. Eight patients showed a decrease of creatinine levels, which had increased above normal values under preceding therapy with conventional Amphotericin-B. Liposomal Amphotericin-B is well tolerated in patients undergoing high-dose therapy and bone marrow transplantation. The efficacy of liposomal Amphotericin-B needs to be investigated in randomized studies in comparison with conventional Amphotericin-B.

Bone marrow transplantation for Philadelphia-chromosome-positive acute lymphoblastic leukemia.

The outcome of 14 bone marrow transplants (BMT) (autologous 4; allogeneic 10) for Philadelphia-chromosome (Ph1) positive acute lymphoblastic leukemia (ALL) was analyzed. Preparative regimens consisted of etoposide (VP16) (30 or 45 mg/kg BW) (n = 14), cyclophosphamide (CY)(120 mg/kg BW) (n = 14), and total body irradiation (TBI)(12 Gy) (n = 13) or busulfan (Bu)(16 mg/kg) (n = 1). All patients receiving autologous marrow were in complete remission (CR) (three patients in 1.CR, one patient in 2.CR) at the time of BMT. For allogeneic BMT (nine related, one unrelated donor), seven patients were in first CR, two patients in first refractory relapse, and one patient in second relapse. With a median follow-up of 503 days (range 93-1522 days), eight out of 14 patients are alive in remission (six out of 10 patients receiving allogeneic, and two out of four patients receiving autologous BMT). Disease-free survival for all patients is 46%. Causes of death were relapse (n = 3) and transplant-related toxicity (n = 3). All patients tested for the bcr/abl rearrangement by reverse transcriptase-polymerase chain reaction (RT-PCR) were negative 4 weeks post-BMT. Two of the three patients who subsequently relapsed were repeatedly RT-PCR positive prior to relapse (test not done in the third). Considering the negligible cure rate of Ph1-positive ALL with conventional chemotherapy regimens, our data support the concept of early (> or = 1 CR) BMT (allogeneic > autologous (purged) following triple therapy with TBI, VP16, and CY.

[Parenteral feeding during aggressive chemotherapy of various neoplasms]. / Die parenterale Ernährung bei aggressiver Chemotherapie verschiedener Neoplasien.

Cancer patients are often extremely cachectic. Therefore, they become poor risks for adequate chemotherapy. Consequently, they are either excluded from antitumor therapy or receive only reduced dosage regimens. Since the patient's response to cancer chemotherapy depends on immunocompetence which, in turn, is related to the nutritional state, adequate nutrition is the key to effective treatment. Parenteral nutrition, which in the literature is often referred to as hyperalimentation, can overcome and prevent cachexia. We treated 19 patients with advanced malignancies of various kinds using aggressive chemotherapeutic regimens and parenteral nutrition. The tolerance for chemotherapy in our patients was improved and the patients gained weight.

Suxamethonium-induced hyperkalaemia in patients with severe intra-abdominal infections.

In nine patients, undergoing repeat operations because of severe intra-abdominal infection developing after major abdominal surgery, serum potassium concentrations were monitored during induction of anaesthesia. Four patients showed an increase of serum potassium ranging from 2.5 to 3.1 mmol/litre above baseline values within 3-6 min after suxamethonium 100 mg i.v. In five patients there was no change. The four patients demonstrating an increase had suffered from pyrexia and leucocytosis for at least 2 weeks. The other five had signs of infection for no more than 9 days. It is concluded that patients with signs of severe intra-abdominal infection lasting longer than 1 week represent an additional category susceptible to suxamethonium-induced hyperkalaemia. They should receive only non-depolarizing muscle relaxants. When the use of suxamethonium is unavoidable, the injection of a non-depolarizing muscle relaxant before the administration of suxamethonium is recommended.

[Suxamethonium-induced hyperkalaemia in patients with severe intraabdominal infections (author's transl)]. / Hyperkaliämie nach Succinylcholin bei septischen Patienten der Abdominalchirurgie

A serious danger to the circulation following the administration of suxamethonium is known to occur in patients reacting with an abnormal release of potassium. So far the following groups of patients have been found to be at an increased risk: burns, multiple trauma, tetanus, neurological disorders, uraemia. As a result of our investigations patients with severe intraabdominal infections are also to be regarded as at risk. Four of ten patients with this diagnosis have shown an increase of serum-potassium of more than 2.5 mequiv/l following suxamethonium injection in spite of a prophylactic small dose of nondepolarizing relaxant. The predisposing factors are high fever of over a week's duration and a leucocytosis of more than 10,000/cu. mm. A possible hypothesis and pathogenesis of the abnormal efflux of potassium is discussed. Prophylaxis consists of using only nondepolarizing relaxants in these cases. When there is a special indication for suxamethonium the potassium increase can be lessened if the patient is given a small dose of nondepolarizing relaxant prior to the administration of suxamethonium.