First demonstration of the effectiveness of peptide receptor radionuclide therapy (PRRT) with 111In-DTPA-octreotide in a giant PRL-secreting pituitary adenoma resistant to conventional treatment.

In prolactin-secreting giant adenomas, cabergoline treatment is the first line approach. Surgery and/or radiotherapy are indicated when the tumour is resistant to medical treatment and continues growing, causing visual field impairment. Data concerning other therapeutic approach are scanty. Although PRL-secreting tumours may express somatostatin receptors type 2, 3 and 5, somatostatin analogs treatment is generally ineffective and peptide receptor radionuclide therapy (PRRT) has never been reported. A 58 year-old woman complaining of severe neurological symptoms caused by a giant prolactinoma, relapsing after surgery and not-responding to dopamine-agonists and octreotide LAR treatment, underwent four cycles of PRRT with 111-Indium-DTPA-octreotide with remarkable tumour shrinkage and a significant improvement in clinical conditions. No side effects were reported. This is the first report on the effectiveness and safety of PRRT with radio-labelled somatostatin analogs in a patient with aggressive giant prolactinoma resistant to conventional treatment.

A survey of natural protein intake in Dutch phenylketonuria patients: insight into estimation or measurement of dietary intake.

This study investigated which methods patients and parents used to determine phenylalanine (Phe) intake and the relationship between the methods applied, age, and blood Phe concentration, as this practice had not been studied before in relation to metabolic control. A questionnaire was sent to 327 Dutch phenylketonuria patients (age 0-29 years) to investigate the method used to determine Phe intake (either by estimation, exact measurement, or a combination of both). Mean blood Phe concentration of each individual patient was related to the method reported to be used. Three different age groups (<10 years, > or =10-15 years, and > or =16 years) were distinguished. The response rate for the questionnaires was 73%. In these 188 patients, data for both Phe concentrations and questionnaires could be used. Of these, 75 used exact measurement, 75 used estimation, and 38 used both methods. The number of patients that estimated Phe intake clearly increased with age. Whatever method was used, an increase in Phe concentrations was seen with age. During childhood, exact measurement was used more frequently, and from adolescence on estimation was used more frequently. The method (exact measurement and/or estimation) did not result in statistically different Phe concentrations in any of the three age groups, although blood Phe concentration tended to be lower in adolescence using exact measurement. Data suggest that estimation and exact measurement of Phe intake are both reliable methods. Therefore, in addition to exact measurement, patients should be instructed in both methods at an early age, so that both methods can be used adequately.

[186Re]HEDP in the palliation of painful bone metastases from cancers other than prostate and breast.

AIM: Palliative therapy using [186Re]hydroxyethylidene diphosphonate (HEDP) has been widely tested in patients with bone metastases from prostate and breast cancers. Whereas, to the best of our knowledge, only few cases of bone metastases from tumors other than prostate and breast treated with [186Re]HEDP have been reported. The aim of this paper is to report our experience with 186Re-HEDP in the palliation of painful bone metastases from tumors other than prostate and breast. METHODS: In this study 41 patients (17 non-small cell lung cancer-NSCLC, 1 small cell lung cancer, 1 lung neuroendocrine tumor, 8 bladder cancer, 3 kidney cancer, 3 gastric cancer, 1 uterine carcinoma, 1 colon cancer, 1 rhinopharynx carcinoma, 1 medullary thyroid carcinoma, 1 ovarian cancer, 1 esophagus cancer, 2 carcinoma of unknown origin) are evaluated. All patients had lesions with increased [99mTc]MDP uptake and none had radiological findings of mainly osteolytic lesions. A total of 46 therapeutic cycles were performed using a [186Re]HEDP activity of 1 295 MBq for each administration. After treatment, patients were followed up for 3 months or to the time of pain recurrence (if longer than 3 months). Responses were evaluated using a validated method considering the modifications of pain index, analgesic intake and performance status. RESULTS: Treatment efficacy was complete in 49% (20/41) of patients, partial in 36% (15/41) and negative in 15% (6/41). Namely, we observed 35% (6/17) complete, 41% (7/17) partial and 24% (4/17) negative responses in patients with NSCLC and 63% (5/8) complete, 25% (2/8) partial and 12% (1/8) negative responses in patients affected by bladder cancer. The median duration of pain relief in responder patients was 10 weeks. A mild platelet toxicity occurred in 32% (13/41) of patients. CONCLUSIONS: Pain palliation with [186Re]HEDP seems highly effective and safe also in patients with bone metastases from cancers other than prostate and breast. Patients who can benefit from the treatment with [186Re]HEDP can be selected on the basis of [99mTc]MDP bone scan and radiological examination findings.

Evaluation of chromogranin A expression in patients with non-neuroendocrine tumours.

BACKGROUND: Chromogranin A (CgA) is well established as a serum marker for neuroendocrine tumours and has also been associated with some non-neuroendocrine tumours, suggesting a possible role for somatostatin analogues such as octreotide in the treatment of these tumours. OBJECTIVE: The aim of this study was to measure plasma CgA levels in patients with various non-neuroendocrine tumours in order to identify those patients who might benefit from octreotide therapy. METHODS: Plasma CgA levels were tested in 151 patients with metastatic non-neuroendocrine tumours. Patients with highly elevated levels were assessed by OctreoScan scintigraphy to determine their somatostatin receptor status, and those with positive results were offered treatment with the somatostatin analogue octreotide, 20 mg every 4 weeks, and followed up every 3 months. RESULTS: CgA levels were elevated (>18 U/L) in 34/72 patients with breast cancer, 11/21 with lung cancer, 10/28 with gastrointestinal cancer, 7/12 with gynaecological cancer, 6/9 with genitourinary cancer, 5/5 with haematological cancer, and 3/4 with head and neck cancer. Eight patients with CgA levels >150 U/L underwent scintigraphy, five of whom (two colorectal, two prostate, one non-small cell lung cancer [NSCLC]) showed positive results and received treatment with octreotide. Follow-up for a mean 12-16 months showed improvements in biochemical parameters, cenesthesis and quality of life. CONCLUSION: CgA levels were found to be elevated in approximately 50% of patients with non-neuroendocrine tumours. Further studies are required to determine the value of CgA as a marker for non-neuroendocrine tumours and the role of somatostatin analogues as a treatment for these tumour types.

Further characterisation of the in situ terminal deoxynucleotidyl transferase (TdT) assay for the flow cytometric analysis of apoptosis in drug resistant and drug sensitive leukaemic cells.

Apoptosis, originally defined by specific morphological changes, is characterised biochemically by non-random cleavage of DNA. Depending on cell type, this DNA cleavage proceeds from 300 and 50kbp fragments prior to, concomitantly with, or in the absence of 180bp integer fragmentation. Incorporation into fragmented DNA of biotin-labelled nucleotides by terminal deoxynucleotidyl transferase (TdT) has recently become a standard flow cytometric assay for the identification and quantitation of apoptosis. Nucleotide incorporation is visualized using avidin-tagged fluorescein isothiocyanate (FITC) (Gorczyca et al.: Cancer Res 53:1945-1951, 1993; Jonker et al.: Cytometry (Suppl 13):Abstr 99A, 1993). Here, we characterise this assay further in three different haemopoietic cell lines. Drug-induced DNA damage is not identified by the TdT assay unless it is coupled to the apoptotic response. This was demonstrated using cells in which activation of the oncogenic Abelson-encoded protein tyrosine kinase suppressed drug-induced apoptosis, but did not inhibit drug-induced DNA damage (by melphalan, hydroxyurea, or etoposide). Furthermore, the TdT assay identifies DNA fragments formed during apoptosis induced by etoposide and N-methylformamide in HL60 and MOLT-4 cells, including those high molecular weight DNA fragments formed in MOLT-4 cells which were not further cleaved to 180-200bp integer fragments. Our results support the use of flow cytometry and the TdT assay to reliably measure apoptotic cells in heterogeneous cell samples.

Investigation of the mechanism of higher order chromatin fragmentation observed in drug-induced apoptosis.

Apoptosis is characterized by the nonrandom cleavage of DNA. After continuous treatment of MOLT-4 human T lymphoblastoid cells with the topoisomerase II inhibitor etoposide (50 microM) and the nongenotoxic agent N-methylformamide (300 mM), apoptosis was confirmed by electron microscopy. Analysis of DNA integrity by conventional gel electrophoresis failed to detect internucleosomal DNA cleavage. Resolution of DNA by field inversion gel electrophoresis showed fragments of 50 kilobases (kb). Etoposide induced the transient appearance of an additional DNA band of > 600 kb, which was temporally coincident with DNA-protein complex formation and was rapidly reversible upon drug removal. This DNA band was not observed after N-methylformamide treatment. In situ DNA end-labeling showed the incorporation of biotinylated dUTP into 50-kb DNA fragments but not etoposide-induced DNA fragments of > 600 kb. DNA end-labelling with terminal deoxynucleotidyltransferase was therefore not dependent upon intenucleosomal DNA cleavage, and fragments of approximately 50 kb were characterized by free 3'-OH termini that were not occluded by topoisomerase II protein. Although we considered that topoisomerase II potentially played an active role in the fragmentation of higher order chromatin during apoptosis, the results showed that DNA cleavage by topoisomerase II induced reversible, protein-associated fragments of > 600 kb and not irreversible cleavage to 50-kb fragments. The reversible cleavage of DNA to fragments of > 600 kb appears to be a signal for the engagement of apoptosis and is not an initial step in the sequential unwinding of chromatin.

[Metal or plastic endoprostheses in malignant obstructive jaundice. A randomized and prospective comparison]. / Metall- oder Kunststoffendoprothesen bei malignem Verschulssikterus. Ein randomisierter und prospektiver Vergleich.

In a prospective randomized trial 58 patients (24 men, 34 women, mean age 67 +/- 13 [42-89] years) with inoperable malignant jaundice were treated with synthetic (S; n = 29) or expanding metal endoprostheses (M; n = 29). After endoscopic retrograde cholangiopancreatography patients were divided into a group with hilar (K: n = 7; M: n = 6) or distal involvement (K: n = 22, M: n = 23). In two cases with hilar involvement (28%) a synthetic endoprosthesis could not be implanted, while early prosthesis occlusion (after 2 days) was observed in one case. But in this group it was possible to implant all metal stents. In the group with distal involvement both synthetic and metal endoprostheses were successfully implanted. In the M group the proportion of patients with prosthesis failure (13.6%) was significantly higher than in the S subgroup (40.9%). The cholangitis incidence was 9% in the M group, significantly less (P less than 0.05) than in the K group (40.9%). Duration of hospital stay to treat prosthesis-related complications was significantly less in the M group (average 2.9 days) than the K group (12.9 days). It would be a great advance in palliative tumour treatment if it were possible significantly to reduce, by means of metal stents, the incidence of late cholangitis and the duration of hospital stay necessary to treat late complications. But improvement in the technique of implanting metal stents would be essential before their general use in distal lesions can be recommended.

Genetic and non-genetic control of myocardial calcium.

Some aspects of the genetic and non-genetic control of the amount and rate of calcium cycled during steady-state activation of papillary muscles from right ventricular rabbit myocardium are presented. Genetic reorganization of the intracellular structure of the myocardium is achieved by producing right ventricular pressure overload and thyrotoxic hypertrophy. The mechanical performance of the pressure overload heart is slowed while time to peak tension is increased. These changes are associated with an increase in myothermal economy. In thyrotoxic hypertrophy the rate of mechanical performance is increased while time to peak tension is decreased. These alterations are associated with a decrease in myothermal economy. Tension-independent heat is used as an index of calcium cycling. In pressure overload hearts the amount and rate of calcium cycling is decreased. In contrast in thyrotoxic hypertrophy the amount of calcium cycled is unchanged while the rate is increased. In the pressure overload hearts there is a decrease in sarcoplasmic reticular (SR) Ca++ ATPase, whereas in the thyrotoxic preparations the message is increased. The change in the rate of calcium uptake in pressure overload and thyrotoxic hearts is correlated with a change in the amount of SR Ca++ ATPase mRNA. Calcium cycling was also altered by non-genetic inotropic intervention. Isoproterenol (1 microM) increases the amount of calcium cycled during each contraction relaxation cycle and the rate at which it is removed. These alterations are associated with an increase in force and a foreshortened twitch. Incubating the papillary muscle in high calcium (11 mM) also increases the force and the amount of calcium released into the cytosol. Under these circumstances the rate of uptake is not significantly increased and, accordingly, the isometric twitch is not foreshortened. In the presence of verapamil (14 microM) the peak twitch force is decreased and the isometric myogram is foreshortened. These changes are associated with a decrease in the amount of calcium released during activation and the rate at which it is removed.