Haematopoietic toxicity of radium-223 in patients with high skeletal tumour burden.

UNLABELLED: In patients with metastasized, castration resistant prostate cancer (mCRPC) treatment with radium-223 (Xofigo) is an attractive therapeutic option. In particular, patients with high tumour load seem to profit from this treatment in regard of survival and quality of live. Aim of this study was to stratify mCRPC patients according to a quantitative imaging marker derived from routine bone scans (EXINI bone) and analyze haematopoietic toxicity of Xofigo in these patients. PATIENTS, METHODS: Toxicity and oncologic outcome were investigated in a cohort of 14 patients with high tumour load. Additionally, based on a web survey, experience of toxicity in 41 high tumour load patients in Germany in 2014 was collected. RESULTS: In patients with a bone scan index (BSI) greater than 5, significant toxicity occurred in more patients than expected from the ALSYMPCA trial. This was associated with application of fewer cycles. Similar experiences have been made in other centers in Germany. Approximately 7% of these patients will need very long time or will not recover from grade ≥ 3 toxicity. CONCLUSION: Close follow-up of haematopoietic indices and, in case of toxicity, early termination of therapy is in particular necessary in late stage disease where limited bone marrow reserve is likely.

6-18F-fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to 123I-metaiodobenzyl-guanidine scintigraphy in the detection of extraadrenal and hereditary pheochromocytomas and paragangliomas: correlation with vesicular monoamine transporter expression.

CONTEXT: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) may be better detected by (18)F-fluorodihydroxyphenylalanine-positron emission tomography (FDOPA-PET) than (123)I-metaiodobenzyl-guanidine (123-I-MIBG) scintigraphy. OBJECTIVE: The objective of the study was to correlate functional imaging results with immunohistochemical, molecular-genetic, and biochemical findings. DESIGN AND SETTING: Thirty consecutive patients with suspected PHEO/PGL presenting at a tertiary referral centre were investigated in a prospective study. PATIENTS: Twenty-five patients had confirmed PHEO/PGL. Thirteen of 25 patients had a hereditary PHEO/PGL syndrome (two multiple endocrine neoplasia II, six succinate dehydrogenase complex, subunit D, two succinate dehydrogenase complex, subunit B, one von Hippel Lindau tumor suppressor protein, two Neurofibromatosis-1), and 12 of 25 were classified as sporadic. Five patients had hormonally inactive adrenal incidentalomas. MAIN OUTCOME MEASURES: In all patients computed tomography scan and/or magnetic resonance imaging as well as both 123-I-MIBG scintigraphy and FDOPA-PET were performed. Resected tumors were examined by immunohistochemistry for expression of the vesicular monoamine transporter (VMAT)-1 and -2 and other markers. RESULTS: A total of 64 lesions were found with both functional imaging modalities. FDOPA-PET detected 62 lesions, whereas only 34 lesions were detected by 123-I-MIBG scintigraphy. This resulted in an overall sensitivity and specificity for FDOPA-PET of 98 and 100% and for MIBG of 53 and 91%, respectively. Comparable sensitivities were found for adrenal and extraadrenal abdominal lesions (94 vs. 97%), whereas in thoracic/cervical lesions, the sensitivity for 123-I-MIBG scintigraphy (15%) was inferior to that of FDOPA-PET imaging (100%). Immunohistochemistry demonstrated a lack of VMAT-1 expression in all MIBG-negative tumors. Clinical predictors for MIBG negativity were a predominant norepinephrine/normetanephrine secretion, an age less than 45 yr, and a hereditary cause. CONCLUSION: FDOPA-PET is superior to 123-I-MIBG scintigraphy in patients with extraadrenal, predominantly noradrenaline-secreting, and hereditary types of PHEO/PGL. The lack of VMAT-1 expression predicts negativity for MIBG-scintigraphy.

Demonstration of pulmonary beta2-adrenergic receptor binding in vivo with [18F]fluoroethyl-fenoterol in a guinea pig model.

PURPOSE: The new beta2 radioligand (R,R)(S,S) 5-(2-(2-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol ([18F]FE-fenoterol; [18F]FEFE), a fluoroethylated derivative of racemic fenoterol, was evaluated in vivo and ex vivo using a guinea pig model. METHODS: Dynamic PET studies over 60 min with [(18)F]FEFE were performed in nine Hartley guinea pigs in which a baseline (group 1, n=3), a predose (group 2, n=3; 2 mg/kg fenoterol 5 min prior to injection of [18F]FEFE) or a displacement study (group 3, n=3; 2 mg/kg fenoterol 5 min post injection of [18F]FEFE) was conducted. RESULTS: In all animal groups, the lungs could be visualised and semi-quantified separately by calculating uptake ratios to non-specific binding in the neck area. Premedication with non-radioactive fenoterol and displacement tests showed significant reduction of lung uptake, by 94% and 76%, respectively. CONCLUSION: These data demonstrate specific binding of the new radioligand to the pulmonary beta2-receptors in accordance with ex vivo measurements. Therefore, [18F]FEFE seems to be suitable for the in vivo visualisation and quantification of the pulmonary beta2-receptor binding in this animal model.

[Radioimmunotherapy for treatment of acute myeloid leukaemia and myelodysplastic syndrome: conceptual chances]. / Radioimmuntherapien zur Behandlung der akuten myeloischen Leukämie und des myelodysplastischen Syndroms: Konzeptionelle Chancen.

The prognosis of patients with acute myeloid leukaemia (AML) has improved considerably by introduction of aggressive consolidation chemotherapy and haematopoietic stem cell transplantation (SCT). Nevertheless, only 20-30% of patients with AML achieve long-term disease-free survival after SCT. The most common cause of treatment failure is relapse. Additionally, mortality rates are significantly increased by therapy-related causes such as toxicity of chemotherapy and complications of SCT. Including radioimmunotherapies in the treatment of AML and myelodyplastic syndrome (MDS) allows for the achievement of a pronounced antileukaemic effect for the reduction of relapse rates on the one hand. On the other hand, no increase of acute toxicity and later complications should be induced. These effects are important for the primary reduction of tumour cells as well as for the myeloablative conditioning before SCT. This paper provides a systematic and critical review of the currently used radionuclides and immunoconjugates for the treatment of AML and MDS and summarizes the literature on primary tumour cell reductive radioimmunotherapies on the one hand and conditioning radioimmunotherapies before SCT on the other hand.

[Anti-TNF antibodies in the treatment of inflammatory intestinal stenoses in Crohn's disease]. / Anti-TNF-Antikörper zur Therapie von entzündlichen Darmstenosen bei Morbus Crohn.

Stenoses are a frequent complication in patients with Crohn's disease and represent a major diagnostic and therapeutic challenge. The proper assessment of the nature of a stenosis as inflammatory or fibrotic is critical for appropriate treatment, since symptomatic fibrotic stenoses require surgical resection. Standard diagnostic procedures to assess the nature of a stenosis include endoscopy, conventional contrast radiography and magnetic resonance tomography. Recent data suggest, that the positron-emission-tomography possesses a high sensitivity and specificity to confirm inflammatory activity in the bowel. The recombinant monoclonal anti-TNF-antibody Infliximab (Remicade) has been approved for the treatment of steroid refractory and steroid dependent Crohn's disease in Germany since 9/2000 and the efficacy of Infliximab is well documented. However, few data exist about the treatment of inflammatory stenoses with Infliximab. We performed a retrospective analysis of our experience with Infliximab in patients with Crohn's disease with special reference to patients with inflammatory stenoses. Among a total of 21 patients treated with Infliximab 11 patients had an inflammatory stenosis. 9 of these patients responded well to Inflimab and became completely asymptomatic for a considerable period of time. Infliximab was tolerated well except for one patient who developed an intrabdominal abscess. The notable clinical response of patients with inflammatory stenoses to Infliximab suggests that treatment with Infliximab might be helpful to postpone or avoid surgical intervention. This finding should be further investigated in a prospective randomized study.

Noninvasive assessment of Crohn's disease activity: a comparison of 18F-fluorodeoxyglucose positron emission tomography, hydromagnetic resonance imaging, and granulocyte scintigraphy with labeled antibodies.

OBJECTIVES: Detection of disease activity in Crohn's disease (CD) is of crucial importance for diagnosis and management of the disease. Noninvasive methods for monitoring are desirable and comprise hydromagnetic resonance imaging (hydro-MRI) and leukocyte scintigraphy. In addition, a recent case report indicated the potential of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to assess CD activity. However, comparative prospective studies are lacking. METHODS: Between February, 1999 and August, 2000, 59 patients with CD were enrolled in a prospective study to assess disease activity by FDG-PET, hydro-MRI, and immunoscintigraphy with anti-nonspecific cross-reacting antigen 95 antigranulocyte antibodies. In 28 of these patients, colonoscopy could be performed. Twelve patients with irritable bowel syndrome and 20 tumor patients without gut inflammation served as controls. Results were compared by statistical analysis. RESULTS: FDG-PET detected 127 pathological findings (average maximum standardized uptake value = 4.4 +/- 1.1) in the terminal/neoterminal ileum (37), small bowel (24), and colon (66) of 54 patients with CD, whereas no pathological findings were seen in five patients with CD, the control patients with irritable bowel syndrome, and the tumor patients without gut inflammation. In contrast, examination with hydro-MRI or granulocyte antibodies detected less pathological findings in CD patients. Forty-five of the detected foci were accessible to endoscopic verification. The correlation of the foci with endoscopic findings showed a high specificity (>89%) of all three methods to detect inflamed areas in the terminal ileum and colon of patients with CD, although analyses by hydro-MRI and granulocyte antibody scan had strikingly lower sensitivities (40.9% and 66.7%) than FDG-PET analysis (85.4%). CONCLUSIONS: FDG-PET appears to be a reliable noninvasive tool for simultaneous detection of inflamed areas in the small and large bowel of patients with CD. FDG-PET can be used to detect disease activity in the terminal ileum and colon of CD patients with high sensitivity and specificity.

Therapeutic angiogenesis for ischemic heart disease.

The de-novo formation of vessels (angiogenesis) and the remodelling of preexisting collateral vessels (arteriogenesis) are processes that occur naturally in ischemic heart disease. Promoting these processes by administration of various substances or other physical stimuli (therapeutic angiogenesis) may provide a future strategy for the treatment of ischemic vascular diseases. Mechanisms of angiogenesis and arteriogenesis, as well as trials of therapeutic angiogenesis in animal models and humans are reviewed.

Angiogenesis and arteriogenesis--not yet for prescription.

Angiogenesis is the growth of new vessels from preexisting vessels by sprouting and intussusception with ischemia being the major stimulus. Circulating endothelial precursor cells have recently been found to participate in this process. The remodeling of preexisting bridging collateral arterioles, i.e., arteriogenesis, should be a much more efficient mechanism to compensate for the gradual or intermittent occlusion of a major epicardial or peripheral artery. Arteriogenesis is associated with an active growth process. It is probably not dependent on ischemia but initiated by local hemodynamic and mechanical effects on the vessel that occur with increasing blood flow. A variety of growth factors that act not only by stimulating endothelial and smooth muscle cell proliferation and migration, as well as substances that increase recruitment and activation of monocytes have been demonstrated to stimulate angiogenesis and arteriogenesis. Several clinical phase I trials suggest the feasibility and short-term safety of treatment with growth factors or their genes. The VIVA trial, the only phase II trial that has been published in this field, employed VEGF165 by intracoronary infusion followed by several intravenous infusions and did not demonstrate any increase of exercise time or angina by VEGF over placebo. The strong sustained placebo effect was surprising. Concerns about the long-term exacerbation of angiogenesis-dependent pathologic processes, like malignant tumors, atherosclerotic plaque formation and proliferative retinopathies, will require careful follow-up. Pro-angiogenic and pro-arteriogenic therapies may need further sophistication before they enter clinical practice.

Downregulation of protein kinase cdelta activity enhances endothelial cell adaptation to hypoxia.

BACKGROUND: Although protein kinase C (PKC) has been implicated in ischemic cell death, the role of individual PKC isoenzymes in the response of endothelial cells (ECs) to hypoxia is unknown. METHODS AND RESULTS: To test the effect of hypoxia on the activity of individual PKC isoenzymes, human ECs were exposed to 95% N(2) with 5% CO(2) for 24 hours. This severe hypoxia reduced PKCdelta specific activity in both human umbilical vein ECs (HUVECs) and a HUVEC-derived EC line (ECVs) significantly (80.5+/-5.7% and 55.5+/-8. 6% of normoxia controls, respectively); the activities of PKCalpha and PKCepsilon were unchanged. The protein levels of PKCalpha, PKCdelta, and PKCepsilon were unchanged by hypoxia. To determine whether PKCdelta downregulation by hypoxia was linked to EC function, ECVs in which PKCdelta was stably overexpressed (PKCdelta-ECs) were exposed to hypoxia. A significant increase in cell death was observed in PKCdelta-ECs compared with controls (5.8+/-0.6% versus 2. 3+/-0.4% at 24 hours, 13.2+/-1.2% versus 4.1+/-0.4% at 48 hours, P<0. 05) during hypoxia. Neither the DNA laddering assay nor TUNEL staining revealed an increase in apoptosis of PKCdelta-ECs exposed to hypoxia, suggesting a hypoxia-induced increase in nonapoptotic cell death of PKCdelta-ECs. Inhibition of NO synthase with N(G)-monomethyl-L-arginine (L-NMMA) affected neither the decline in PKCdelta activity nor the EC death induced by hypoxia. CONCLUSIONS: PKCdelta activity is decreased by hypoxia by a mechanism that does not involve NO synthase; this downregulation appears to enhance EC survival during hypoxia by decreasing nonapoptotic cell death.

[Hyperthyroidism in a premature infant due to transplacental passage of maternal thyrotropin receptor antibodies]. / Frühgeborenenhyperthyreose durch diaplazentar übertragene TSH-Rezeptor-Antikörper der Mutter.

The duration of the stimulating effect of transplacental transferred thyrotropin-receptor-antibodies (TRAb) is discussed by the example of a 23 years old woman suffering from Graves' disease with a severe hyperthyroidism. She became pregnant six weeks after the diagnosis was obtained and then discontinued her antithyroid medication on her own responsibility. On a check-up in the 20th week of pregnancy, a hyperthyroidism was once more found, leading to a therapy with propylthiouracil, which however, was again interrupted by the patient a few weeks later. In the 32nd week, she gave birth to a male child that already presented with distinct signs of thyrotoxicosis and developed a continuous deterioration of the condition, including a tachycardia with up to 190 beats per minute, fever, tremor and a respiratory disorder. Assay of the newborn serum revealed a severe hyperthyroidism. The TRAb level was 180 U/l (normal range < 15). A therapy with propranolol and prednisolone was initiated, leading to a significant improvement of the general condition. Nevertheless, after 12 days, there was still no notable decrease of the hormone levels. Therefore an antithyroid medication was started, which caused normal thyroid hormone levels within 9 days. However, after the therapy was stopped, a hyperthyroidism was again observed within one week, requiring another, low-dose antithyroid medication, which was administered for 26 days. After this period, the TRAb level was down to 25 U/l and no more hyperthyroidism was found. The biological half-life of the TRAb was 20 days in our case.

Increased prostaglandin E2 and leukotriene B4 synthesis in isolated colonic mucosal cells in inflammatory bowel disease. a preliminary report.

The synthesis of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in colonic mucosal cells was investigated in 7 patients and 10 controls. Biopsies obtained from the descending colon were isolated biochemically by a special technique and the suspension of isolated colonic cells was incubated during 45 min. Compared with healthy subjects, patients with an inflammatory bowel disease showed a significantly increased PGE2 production. The LTB4 synthesis was enhanced as well, but this change was not statistical. We conclude that PGE2 is the dominant eicosanoid during less severe inflammatory bowel disease. Age and gender did not influence PGE2 or LTB4 synthesis.

Primary enduring negative symptoms in schizophrenia and major depression.

Primary enduring negative symptoms (PENS) were studied in 26 patients with DSM-III-R schizophrenia and in 94 patients with unipolar major depressive episodes 5 years after the index episode. PENS were assessed with the Schedule for Deficit Syndrome (SDS). Negative symptoms were also assessed with the Scale for Assessment of Negative Symptoms (SANS) and subclassified into primary and secondary according to the SDS. The frequency of PENS did not differ significantly between schizophrenics and non-schizophrenic patients. Enduring negative symptoms (regardless of whether primary or not) were more frequently observed in schizophrenia (65% according to the SDS, and 88% according to the SANS) than in patients who had major depressive episodes (29% according to the SDS and 32% according to the SANS). By applying the SDS criteria for PENS, their frequency decreased in a manner which would probably affect the availability of patients samples for testing antinegative drugs. The results suggest that neither the negative symptomatology nor the primary enduring subtype ("deficit") is specific for schizophrenia. This finding might imply potential advantages of non-nosological, functional approaches for research into PENS.

Negative symptoms and the course of positive symptoms in deficit schizophrenia.

Differences in the patterns of negative symptoms between two subgroups of inpatients with chronic schizophrenia and a deficit syndrome were examined: one subgroup presented episodic symptoms, while the other exhibited a continuous course of positive symptoms. Patients with a continuous course of positive symptoms showed significantly higher affective blunting and anhedonia according to the SANS, a lower BPRS activation score and a lower age of onset in males than episodic cases. These results suggest that in deficit schizophrenia different courses of positive symptoms are associated with different severity degrees and different patterns of negative symptoms.

Subtypes of negative symptoms: the primary subtype in schizophrenic and non-schizophrenic patients.

1. The specificity of negative symptoms remains an open question and requires further research. 2. Subtyping negative symptoms has been showed to be a very relevant point for the identification of primary negative symptoms and for their pharmacotherapy. Negative symptoms as a whole have been demonstrated in schizophrenic and non-schizophrenic patients, but these studies did not report about the primary and secondary subtypes. 3. The present study is the first one investigating primary negative symptoms in schizophrenic and non-schizophrenic patients. 84 consecutively admitted psychiatric patients have been studied 5 years after their discharge. 4. All negative symptoms (including the primary subtype) according to Carpenter (Kirkpatrick et al. 1989) and Andreasen (Andreasen 1981) could be identified in all diagnostic groups.