The 48-hour tetrahydrobiopterin loading test in patients with phenylketonuria: evaluation of protocol and influence of baseline phenylalanine concentration.

BACKGROUND: The 24- and 48-hour tetrahydrobiopterin (BH4) loading test (BLT) performed at a minimum baseline phenylalanine concentration of 400 µmol/l is commonly used to test phenylketonuria patients for BH4 responsiveness. This study aimed to analyze differences between the 24- and 48-hour BLT and the necessity of the 400 µmol/l minimum baseline phenylalanine concentration. METHODS: Data on 186 phenylketonuria patients were collected. Patients were supplemented with phenylalanine if phenylalanine was <400 µmol/l. BH4 20mg/kg was administered at T = 0 and T = 24. Blood samples were taken at T=0, 8, 16, 24 and 48 h. Responsiveness was defined as ≥ 30% reduction in phenylalanine concentration at ≥ 1 time point. RESULTS: Eighty-six (46.2%) patients were responsive. Among responders 84% showed a ≥ 30% response at T = 48. Fifty-three percent had their maximal decrease at T = 48. Fourteen patients had ≥ 30% phenylalanine decrease not before T = 48. A ≥ 30% decrease was also seen in patients with phenylalanine concentrations <400 µmol/l. CONCLUSION: In the 48-hour BLT, T = 48 seems more informative than T = 24. Sampling at T = 32, and T = 40 may have additional value. BH4 responsiveness can also be predicted with baseline blood phenylalanine <400 µmol/l, when the BLT is positive. Therefore, if these results are confirmed by data on long-term BH4 responsiveness, we advise to first perform a BLT without phenylalanine loading and re-test at higher phenylalanine concentrations when no response is seen. Most likely, the 48-hour BLT is a good indicator for BH4 responsiveness, but comparison with long term responsiveness is necessary.

Effects of fructose restriction on liver steatosis (FRUITLESS); a double-blind randomized controlled trial.

BACKGROUND: There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. OBJECTIVES: The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. METHODS: Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (<7.5 g/meal and <10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center. RESULTS: Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: -57.0 g/d; 95% CI: -77.9, -39.5 g/d; and -38.8 µmol/d; 95% CI: -91.2, -10.7 µmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P < 0.001 and P = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: -0.7% point, 95% CI: -2.0, -0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups. CONCLUSIONS: Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group.This trial was registered at clinicaltrials.gov as NCT03067428.

A randomized comparison of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in patients with advanced breast cancer.

The efficacy and side-effects of megestrol acetate and medroxyprogesterone acetate in postmenopausal patients with advanced breast cancer were compared in a prospectively randomized study. The dosage of MA was 2 X 80 mg p.o. or MPA 2 X 500 mg p.o. daily, given as a secondary hormonal treatment, mostly after previous treatment with tamoxifen. Ninety-eight patients entered the study and 92 were evaluable for effect, 48 patients on MA and 44 on MPA. Age, main tumor site and prior treatment were not different, but there was a preponderance of ER-negative tumors in the MA group. Responses appeared to be more frequent in the MPA-treated group (25% vs. 43%), predominantly in bone lesions, 12% for MA and 45% for MPA. Median progression-free survival was comparable, 15 vs. 10 months, and overall survival was not different (20 vs. 16 months). Toxicity was frequent, occurring in 83% vs. 74% of patients: increased appetite, nausea and dizziness in more than 20%, and a preponderance of pyrosis and breathlessness on MA and hot flashes, sweating and tremors on MPA. Cushingoid symptoms were present in about a quarter of the patients treated for more than 3 months. The occurrence of thrombo-embolic episodes and cardiovascular events was evenly distributed. Patients on MPA had more often increase in body weight, systolic blood pressure and serum creatinine than those treated with MA. It is concluded that MPA may be more effective for treatment of bone metastases, at the expense of more progestational side-effects. The occurrence of Cushingoid effects is frequent but similar in both arms, while the incidence of cardiovascular or thrombo-embolic events cannot be related to the use of either compound.

Induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with locally advanced and disseminated breast cancer.

In 56 patients with disseminated or locally advanced breast cancer it was attempted to reach a state of no evidence of disease by a remission induction regime containing prednisone, 5-fluorouracil, methotrexate, doxorubicin and vincristine. If successful, patients received an intensification regimen consisting of cyclophosphamide (7 g/m2) and etoposide (1.5 g/m2) with autologous bone marrow reinfusion. The complete remission rate of the induction regimen was 52% and the partial remission rate 42%. 32 patients received the intensification regimen. Two toxic deaths occurred. The median time to disease progression in the group with disseminated disease was 15 months. After a median observation of 4 years, 11 out of 19 patients with locally advanced breast cancer were free of disease. It is concluded that this approach may lead to prolonged disease-free survival in patients with locally advanced breast cancer, but does not influence the survival in disseminated disease.

False-positive findings in mammography screening induces short-term distress - breast cancer-specific concern prevails longer.

The aim of this study was to examine psychological distress in a mammography screening process as a consequence of screening after adjusting for background, personality and prescreening distress. Subjects, aged 50 years, were invitees at their first screening. There were three groups; normal findings (n=1407), false-positive findings (n=492) and referents from outside the screening programme (n=1718, age 48-49 years). Distress was measured as illness worry, anxiety, depression, cancer beliefs and early detection behaviour. Measurements were one month before screening invitation with follow-ups at 2 and 12 months postscreening. At 2 months, there was a moderate multivariate effect of group on distress; and intrusive thinking and worry about breast cancer, in particular, were most frequent amongst the false positives. Intrusive thinking still prevailed at 12 months, in addition to a higher perceived breast cancer risk and susceptibility. Distress related to screening and false-positive findings seems to be moderate, but prevailing cancer-specific concerns call for improvements in screening programmes.

Intensive chemotherapy with autologous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes.

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.

Plasma deoxycholic acid is related to deoxycholic acid in faecal water.

Bile acids are considered as a risk factor for colorectal carcinogenesis. They were analysed in samples of faecal water and plasma of fasting heparine blood from 23 urolithiasis patients. Linear regression showed that the highest percentage of variance (52%) was explained by the model: plasma deoxycholic acid (micromol/l) = -3.11 + 0.96(+/-0.25*) 10log deoxycholic acid in faecal water (micromol/l) + 0.35(+/-0.15*) pH of faecal water -0.41(+/-0.19#) defacation frequency (number of stools/day); *P < 0.05, #P = 0.055. In future studies, analysing blood levels of unconjugated deoxycholic acid may substitute faecal measurements.

Mechanism of adrenal suppression by high-dose medroxyprogesterone acetate in breast cancer patients.

To investigate the mechanism of adrenal suppression by high-dose MPA, we performed direct and indirect stimulation tests in postmenopausal women with disseminated breast cancer who were receiving MPA and in a postmenopausal breast cancer control group. A partial adrenal insufficiency was found during Synacthen stimulation, confirmed by a slight increase of 11-desoxycortisol after metyrapone, despite a sufficient rise in ACTH levels. Peak levels of androstenedione and 17-OH progesterone after Synacthen correlated with those after metyrapone. Peak cortisol levels after Synacthen also correlated with the sum of cortisol and 11-desoxycortisol values after metyrapone, indicating the presence of a maximum adrenal response and a sufficient rise of endogenous ACTH after metyrapone. As the peak levels of cortisol and androstenedione were highly correlated with baseline values, a short Synacthen stimulation test may give a good indication as to whether adrenal suppression by MPA is adequate. The adrenal androgen androstenedione is the precursor of the main postmenopausal oestrogen, oestrone. In this way, adrenal suppression may constitute an important therapeutic effect of high-dose MPA.

Metabolism of a [18F]fluorine labeled progestin (21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone) in humans: a clue for future investigations.

Assessment of estrogen receptors and progesterone receptors (PR) with PET may allow the determination of the hormone responsiveness of tumors without the need for multiple biopsies, and the monitoring of the effect of hormonal therapy. In spite of the favourable characteristics of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone ([18F]FENP) found in preclinical studies, the compound failed to reveal the presence of PR in breast carcinomas and meningiomas. In view of the clinical significance of the PR assay in human breast cancer, it is worthwhile to explore mechanisms that are potentially involved in the inadequacy of [18F]FENP to image PR with PET. Our present study on the in vivo metabolism of [18F]FENP in humans demonstrates a rapid clearance and biotransformation of the compound. Results of incubation experiments suggest that the metabolic conversion of [18F]FENP is not restricted to the liver, but also occurs in blood cells (presumably the erythrocytes) and tumors (breast carcinomas and meningiomas). The predominant metabolite of [18F]FENP in plasma during the rapid distribution phase and in tumors is identified as 20-dihydro-[18F]FENP. The conversion of [18F]FENP to its 20 alpha- or 20 beta-hydroxy metabolite has a deleterious effect on the binding affinity for PR. Our findings do not justify a conclusion as to the extent of in vivo extrahepatic biotransformation of [18F]FENP, or its significance in the ineffectiveness of [18F]FENP as an imaging agent for PR. On the other hand, the ability of breast carcinomas and meningiomas to metabolize [18F]FENP avidly appears to preclude selective imaging of PR in these tumors during the time of a PET examination. It is imperative to evaluate the metabolic stability of a [18F]fluorine labeled progestin in an early stage of future screening procedures.

Regional perfusion for recurrent malignant melanoma of the extremities.

Seventeen patients with a local recurrence or intransit metastases of a malignant melanoma of the arm or leg were treated by normothermic regional perfusion with phenylalanine mustard. Seven of these patients had regional lymph node metastases as well. The follow-up period was with five to eight years or until the time of death. Two years after treatment, eleven of the seventeen patients were still alive. After a five year follow-up, six patients were still alive without demonstrable recurrence or metastases. Only three patients had a recurrence in an extremity; two of these three patients simultaneously showed general metastization.

Developing quality indicators for general practice care for vulnerable elders; transfer from US to The Netherlands.

BACKGROUND: Measurement of the quality of healthcare is a first step for quality improvement. To measure quality of healthcare, a set of quality indicators is needed. We describe the adaptation of a set of systematically developed US quality indicators for healthcare for vulnerable elders in The Netherlands. We also compare the US and the Dutch set to see if quality indicators can be transferred between countries, as has been done in two studies in the UK, with mixed results. METHOD: 108 US quality indicators on GP care for vulnerable elders, covering eight conditions, were assessed by a panel of nine clinical experts in The Netherlands. A modified version of the RAND/UCLA appropriateness method was used. The panel members received US literature reviews, extended with more recent and Dutch literature, summarising the evidence for each quality indicator. RESULTS: 72 indicators (67% of US set) were (nearly) identical in the Dutch and US sets. For some conditions, this percentage was much lower. For undernutrition, only half of the US indicators were included in the Dutch set. For depression, many indicators were discarded or changed in a significant way, with the result that only five of the original 17 indicators (29%) are the same in the Dutch and the US set. CONCLUSIONS: Quality indicators can be transferred between countries, but with caution, because in two of the three studies on transferring indicators between the US and Europe, 33-44% of the indicators were discarded. For some conditions in the current study, this percentage is much higher. For undernutrition, there is hardly any evidence, and differences between the indicator sets can be attributed to differences in expert opinion between the countries. For depression, it seems that different evidence is considered important in the US and in The Netherlands, of which the Dutch body of knowledge is not known in the US.

Acute and chronic job stressors among ambulance personnel: predictors of health symptoms.

OBJECTIVES: To predict symptomatology (post-traumatic distress, fatigue, and burnout) due to acute and chronic work related stressors among ambulance personnel. METHODS: Data were gathered from 123 ambulance workers in The Netherlands in a longitudinal design. At two measurements they completed standardised questionnaires to assess health symptoms, such as the Impact of Event Scale, the Maslach Burnout Inventory, and the Checklist Individual Strength. Acute stressors were assessed with specific questions, and chronic work related stressors were measured with the Questionnaire on the Experience and Assessment of Work. RESULTS: Most of the ambulance workers had been confronted with acute stressors in their work. They also reported more chronic work related stressors than a reference group. Of the participants, more than a tenth suffered from a clinical level of post-traumatic distress, a tenth reported a fatigue level that put them at high risk for sick leave and work disability and nearly a tenth of the personnel suffered from burnout. Best predictors of symptomatology at time 2 were lack of social support at work and poor communication, such as not being informed about important decisions within the organisation. CONCLUSIONS: Ambulance personnel are at risk to develop health symptoms due to work related stressors. Although, acute stressors are related to health symptoms, such as fatigue, burnout, and post-traumatic symptoms, it was not found to predict health symptoms in the long term. Main risk factors have to do with social aspects of the work environment, in particular lack of support from the supervisor as well as colleagues and poor communication. When implementing workplace interventions these social aspects need to be taken into account.

Isolated regional perfusion in the treatment of malignant melanomas of the extremities.

The authors present a survey of changed views on the treatment of patients with malignant melanoma of the extremities. In addition to conventional therapy, regional perfusion is discussed. Over the period 1964-1970, 115 perfusions were performed in 75 patients. The perfusions were confined to patients with a tumor infiltrating beyond the stratum papillare. The 4-year survival of 30 patients with a primary tumor, without demonstrable metastases at the moment of perfusion, was found to be 77%. The percentage of local recurrences was significantly lower after perfusion than after conventional surgery.

Palliative and curative electrocoagulation for rectal cancer. Experience and results.

The 18-year experience with electrocoagulation of rectal cancer in 51 patients is reported. The "boiling" technique used in this study is described. Electrocoagulation for palliative purpose was carried out in 18 patients. One patient is alive without evidence of disease after 4 years. The remaining 17 patients died within 2 years. Electrocoagulation for cure was performed in 33 patients. In two patients abdominoperineal resection was needed for residual tumor. All cases were strictly followed, and none of the patients died of cancer. Recurrent tumor was never seen, and the crude 5-year survival was 71%. The authors describe the criteria for selection any patient should meet in order to be eligible for electrocoagulation with curative purpose and advocate caution in making the choice between radical and local surgery.

Local recurrence and survival in patients with (Clark Level IV/V and over 1.5-mm thickness) stage I malignant melanoma of the extremities after regional perfusion.

During the period 1965-1974, 110 patients with stage I malignant melanoma of the extremities were treated by regional isolated perfusion with L-phenylalanine mustard and local excision. In order to study local recurrence and survival, only patients with a primary melanoma Clark Level IV or V and a tumor thickness of more than 1.5 mm were accepted in this study. The determinate survival in patients followed for 5-14 years in 78%; 17% developed positive regional lymph nodes. The local skin recurrence rate was 9% (9 patients); four of these 9 patients simultaneously had distant metastases; the other five patients are alive with NED after retreatment. This series of patients, too, shows that tumor thickness determines the prognosis, both as to local recurrence and as to survival. The mean tumor thickness in the hyperthermically perfused patients was found to clearly exceed that in the normothermically perfused, the mean values being 4.85 mm and 3.87 mm, respectively. Yet local recurrence and regional lymph node metastases proved to be less frequent after hyperthermic than after normothermic perfusion, although the difference was not statistically significant.

Some aspects of the treatment of primary malignant melanoma of the extremities by isolated regional perfusion.

This paper reviews the changing concepts in the treatment of patients with malignant melanoma localized on the arm or leg. In addition to conventional surgical treatment, isolated regional perfusion of the extremities is discussed. An evaluation is presented of clinical and histological criteria applied to determine indications for conventional surgical treatment and for perfusion. It is maintained that isolated regional perfusion of arm or leg should be performed when the primary tumor meets one of the following criteria: (1) depth of tumor invasion beyond the papillary layer (Clark levels III, IV and V); (2) vascular invasion; (3) tumor diameter exceeding 1 cm; (4) ulceration. If none of these four criteria applies, conventional surgical treatment alone has proved to give very good results.

Clinical and endocrine effects of cyproterone acetate in postmenopausal patients with advanced breast cancer.

A phase II study with cyproterone acetate (CPA) was done as the primary treatment in female breast cancer patients. Twenty-three patients, mean age 64 years, range 52-75 years, were entered and treated with CPA 400 mg daily. Twenty patients were evaluable and responses were sparse. There was one partial and one complete remission, 17 patients were stable and one patient progressed within 3 months. Side-effects were frequent: five patients complained of nausea, three had severe weight loss, one suffered from depression and seven showed disturbed liver function tests. Six patients had to stop treatment for side-effects, while two other patients were taken off treatment because they developed an acute necrotizing hepatitis. The hepatitis recovered after drug withdrawal in both patients. The serum levels of CPA, cortisol, androstenedione, DHAS, LH, FSH and prolactin were measured during CPA treatment. The levels of cortisol and androstenedione did not change, while LH, FSH and DHAS were suppressed. The DHAS showed an inverse relation to serum CPA concentrations. The prolactin levels rose uniformly. The therapeutic effect of CPA in postmenopausal patients with advanced breast cancer is disappointing, and inferior to that of other progestins. Side-effects are frequent, possibly as a result of the high dosage used in this study. The hormonal changes are different from those of other progestins, which may explain the different efficacies.