Targeted radionuclide therapy with RAFT-RGD radiolabelled with (90)Y or (177)Lu in a mouse model of αvß3-expressing tumours.

PURPOSE: The αvß3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvß3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with ß(-) emitters in a nude mouse model of αvß3 integrin-expressing tumours. METHODS: Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvß3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (177)Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvß3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvß3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. RESULTS: Injection of 37 MBq of (90)Y-RAFT-RGD into mice with large αvß3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvß3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvß3-negative tumours. CONCLUSION: (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvß3-expressing tumours for internal targeted radiotherapy.

[The PSA caught out]. / Le PSA pris en défaut.

INTRODUCTION: With the widespread use of prostate specific antigen (PSA) prescription and despite the automatization of PSA assessment, clinicians should not forget the analytical interference of PSA immunoassays due to the presence of heterophilic autoantibodies in a patient. MATERIAL AND METHODS: This article details some clinical cases, mechanisms involved in the interference and how to overcome this problem. RESULTS: The reported and documented interferences led to useless explorations even erroneous diagnosis. CONCLUSION: Before any unexpected PSA value in relation to the clinical symptomatology, it is strongly recommended to verify the absence of any interference before any invasive procedure or therapy modification.

First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX plus (125)IUdR.

PURPOSE: Neoplastic meningitis is often the final outcome of disseminated cancer and is rapidly lethal. Its limited treatment relies on systemic or intrathecal chemotherapy with methotrexate (MTX) or thiotepa. When 5-iodo-2'-deoxyuridine labeled with (125)I ((125)IUdR) is incorporated into the DNA of mitotic tumor cells, the Auger electrons emitted during iodine decay are highly cytotoxic. The radiotherapeutic efficacy of (125)IUdR administered intrathecally has also been established in animals bearing spinal cord tumors, and MTX is known to potentiate the response. This approach has not been tested in the clinic. METHODS: A 44-year-old woman, with locally advanced pancreatic cancer, was treated for three years with complete systemic remission, but then relapsed with cytologically proven neoplastic meningitis. The patient was given four successive intrathecal injections of MTX (10 mg) every 12 h and, with the fourth dose, 1850 MBq (125)IUdR, followed by four additional MTX doses. The response was monitored by cytology and CA19.9 (carbohydrate antigen 19.9) levels in the cerebrospinal fluid (CSF) as well as by clinical status of the patient. RESULTS: The follow-up of cytology and CA19.9 levels in the CSF showed dramatic improvement within 26 days followed by a biological relapse on Day +36. There was no evidence of local central nervous system toxicity. Three months later, neoplastic meningitis recurred and meningeal tumor infiltration was observed on magnetic resonance imaging. Six months after MTX-(125)IUdR treatment, the patient died. CONCLUSION: (125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.

[Contribution of dynamic interpretation of CA 125 measurements to the understanding of an atypical clinical case]. / Contribution de l'interprétation dynamique du CA 125 dans la compréhension d'un cas clinique atypique.

The dynamic interpretation of the serum concentrations of markers is frequently used to calculate biological indicators of therapeutic efficiency and relapse. But analysis of marker kinetics can also help improve our understanding of the natural history of different types of cancer and their evolution under treatment. This application is illustrated by an analysis of CA 125 kinetics measured in a patient with stage III ovarian cancer treated with multiple lines of chemotherapy and who had a survival time of 9 years.

[Severe hypercalcemia of unusual cause, looking for the culprit: Case report and review of the literature]. / Hypercalcémie sévère de cause inhabituelle, à la recherche du coupable : cas clinique et revue de la littérature.

INTRODUCTION: Hypercalcemia is not a rare event and can lead to severe consequences. Its main etiologies are primary hyperparathyroidism and neoplasic conditions. The iatrogenic etiology by vitamin D intoxication is more rarely found. CASE PRESENTATION: A 76-year-old finish woman comes to the emergency room for chest pain. Her medical history is impossible to specify due to the language barrier and initial confusion. She has severe hypercalcaemia (4.14mmol/L), renal insufficiency, cardiac arrhythmia later complicated by an ischemic cardiac episode. Clinic and biologic examinations initially guided the research towards a hematological and neoplasic pathology. The iatrogenic etiology will be permitted by the contribution of details on its medical history and treatment learnt secondly. She was treated for post-surgical hypoparathyroidism by dihydrotachysterol, a vitamin D derivative. The cessation of substitution, treatment with hydration and biphosphonates allowed the rapid correction of hypercalcemia. DISCUSSION: Dihydrotachysterol intoxication is a rare etiology of hypercalcemia. Because of the longer half-life of this molecule, the risk of hypercalcemia seems to be greater than with other vitamin D derivatives. This molecule, withdrawn from the French market in 1982, is not detected by the dosage of 25 and 1.25 OH vitamin D. CONCLUSION: We report an original case of intoxication by dihydrotachysterol. The risk of hypercalcemia encountered with this molecule must be known. The close medical follow-up recommended in case of hypoparathyroidism seems to be particularly necessary in case of supplementation by this molecule.

Emotional overactivity in patients with irritable bowel syndrome.

BACKGROUND: Negativity is often observed in patients with irritable bowel syndrome (IBS). No study has examined their emotional expressiveness as a marker of emotional reactivity. We investigated IBS patients' vulnerability to an emotional load by associating their expressiveness with psychological and neurophysiological assessments. We hypothesized that IBS would be characterized by a lack of expressiveness coupled with high scores in psychological and neurophysiological parameters. METHODS: We assessed the emotional facial expressions (EMFACS), psychological (anxiety, depression, alexithymia), and neurophysiological (cortisol, heart rate variability (HRV)) parameters of 25 IBS patients and 26 healthy controls (HC) while they watched fear-eliciting movie extracts. KEY RESULTS: Overall, the task elicited an increase in state anxiety and consistent HRV responses. However, IBS patients differed from HC as they displayed more sadness and tended to display more rage. Contrary to HC, IBS patients showed an increase in heart rate and a decrease in parasympathetic regulation, reflecting an enhanced responsiveness corroborated by higher scores in depression and state anxiety. Consistent with their higher difficulty in identifying feelings, a component of alexithymia positively correlated with their expressions of rage, they were not aware of their increase in anxiety during the task, whereas HC were. No linear relationship between patients' expressions and their neurophysiological responses was found. CONCLUSIONS & INFERENCES: Irritable bowel syndrome patients displayed greater emotional expressiveness with negative prevalence. This reflects an emotional vulnerability potentially related to low regulation skills and underscores the importance of considering the central dysregulation hypothesis in IBS as a promising avenue of research.

[Early detection of leptomeningeal metastasis in patients with metastatic breast carcinoma: validation of CA 15-3 measurement in cerebrospinal fluid]. / Détection précoce des métastases leptoméningées chez les patientes atteintes de cancer du sein métastatique: validation du dosage du CA 15-3 dans le liquide céphalorachidien.

Fifteen per cent of metastatic breast cancer will develop symptomatic leptomeningeal metastases. The introduction of trastuzumab (Herceptin) therapy has improved the response rates of survival of patients with metastatic breast cancer overexpressing HER2. Although previous studies are retrospective and of limited number, involving small study groups and different types of patient management, several authors have reported a 30% incidence of leptomeningeal metastases in patients with metastatic breast cancer overexpressing HER2 who were treated with trastuzumab, while 70 to 80% of cases of the disease were controlled systemically. In order to improve control of the disease at the level of the central nervous system (CNS), routine detection of leptomeningeal metastases in high-risk patients could be offered. CA 15-3 in cerebrospinal fluid (CSF) detection might be useful in helping to diagnose CNS metastases, particularly where cytology results are negative--which applies to 30% of cases--because tumor markers are more sensitive in detecting the tumor process. Our study validate CA 15-3 measurement in CSF and reference values were given.

Potential use of radiolabeled antisense oligonucleotides in oncology.

Antisense oligodeoxynucleotides (ODNs) have great promise for therapy. Oligomers labeled with gamma-emitting radioelements have great promise for diagnosis. These radiolabeled oligomers can be used to identify the presence of a particular messenger RNA through simple external detection of radioactivity by means of scintigraphy. This review evaluates the progress in the development of antisense oligodeoxynucleotides for non-invasive imaging of chemoresistance. As nominated by H.N. Wagner at the final session of Nuclear Medicine congress in Denver, the deoxyribonucleic acid is "the molecule of the millennium".

Effect of oestrone on the natural killer (NK) cell activity, antioxidant status and tumour growth in athymic mice xenografted with human tumours.

Natural killer (NK) cells have been described as being very sensitive to oxidative stress. Thus it has been previously shown that chronic administration of oestrone in drinking water of athymic mice xenografted with a wide variety of human tumours, increases their growth and development. In this study an investigation was made to see whether oestrone supplementation could influence the NK cell activity by changes in the antioxidant defences which result in an oxidative stress and influence the proliferation of tumours. Supplementary oestrone was administered in drinking water of athymic mice xenografted with two different human tumours which lack oestrogen receptors: a bladder carcinoma and a small-cell lung carcinoma. The growth of the urothelial carcinoma was poorly affected by oestrone, but oestrone significantly (p<0.01) increased the proliferation of the small-cell lung carcinoma. The average uterus weight was increased by 62% in oestrone treated mice with no modifications in plasma zinc and selenium status, nor in erythrocyte copper zinc superoxide dismutase level. Nevertheless a slight decrease in erythrocyte glutathione peroxidase activity was noted. Trace elements and antioxidant enzymes in liver homogenates remained unchanged. Oestrone treatment also had no effect on plasma and liver lipid peroxides. The immune response was evaluated by measuring NK activity of splenocytes against 51Cr labelled YAC-I target cells. A 35.5% decrease in the NK activity (p<0.001) was observed after oestrone treatment and may be responsible for graft tolerance. However, the results of these experiments seem to exclude the role of oxidative stress in the modulation of NK activity.

Detection of chemoresistance profile of cell lines K562, KB, GLC4 and HL60 through characterisation of the hmdr1, mrp and lrp transcripts.

The current trend in innovative cancer therapy is moving towards targeting the genes of interest by means of oligonucleotides developed for therapeutic or diagnostic use. These new approaches are of particular interest in oncology, and it would therefore be extremely useful to characterise all the biological tools currently available in this field. The chemoresistance profiles of four human cancer cell lines were determined by identifying of the operating conditions needed to characterise the presence of hmdr1, mrp and lrp mRNA by gene amplification.

Antioxidant status and lipid peroxidation in athymic mice xenografted with two types of human tumors.

Antioxidants and reactive oxygen species are considered to play an important role in experimental in vivo carcinogenesis studies. We attempted in this study to evaluate the repercussions on the antioxidant and lipid peroxide status of the growth of human malignant tumors xenografted into athymic mice. We selected three tumor models: two urothelial carcinomas (bladder tumors stage 3) and one brain tumor (glioblastoma stage 4). All these tumors exhibited a fast growth pattern when xenografted into athymic mice. Tumoral tissue was implanted subcutaneously. After growth establishment each tumor size was measured at regular intervals: every 2 d for bladder tumor and twice a week for glioblastoma. The period of observation was 3 wk for bladder tumors and 5 wk for glioblastoma. At the end of the observation period, all mice were sacrificed; tumoral tissue was taken and blood collected. Superoxide dismutase activity (SOD), glutathione peroxidase activity (GSH-Px), zinc (Zn), selenium (Se), and thiobarbituric acid reactive substances (TBARS) were measured in blood. TBARS alone were measured into tumoral tissue. A modification of the antioxidant blood status was observed in mice xenografted with bladder tumors with decrease in Se status and GSH-Px activities, and increase in TBARS. Such an effect was absent in mice xenografted with glioblastoma. It would appear that an oxygen-mediated stress exists in the animal bearing an implanted tumor compared with the control group, and that tumoral tissue itself is able to induce an oxidative stress into its host. All this leads to a disturbance of the antioxidant defense system.

Evaluation of LOCI technology-based thyroid blood tests on the Dimension Vista analyzer.

OBJECTIVES: To assess the performance of thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) determinations by luminescent oxygen channeling immunoassay (LOCI) technology on the Dimension Vista analyzer (Siemens Healthcare Diagnostics). DESIGN & METHODS: We assessed 1) functional sensitivity for TSH (FSe-TSH), and intra- and inter-assay variations for TSH, FT4 and FT3 on Vista; 2) comparisons of serum and heparin-treated plasma on Vista; 3) comparisons of a) plasma TSH by Vista versus electrochemiluminescence (ECLIA) on Roche Modular analyzer, and b) plasma FT4 and FT3 by Vista versus Immunotech-Beckman radioimmunoassay (RIA); and 4) association of albumin and prealbumin levels with free thyroid hormone concentrations on Vista. RESULTS: 1) FSe-TSH concentration was below 0.005 mIU/L. Maximum intra-assay CVs (2.1%, 1.4%, 5.2%) and inter-assay CVs (16.5%, 5.1%, 5.8%) were good for TSH, FT4 and FT3 respectively. 2) Heparin-treated plasma samples consistently gave slightly higher values than serum for TSH, FT4 and FT3. 3) Passing-Bablok regression gave: TSH: [LOCI]=0.91[ECLIA]-0.08 (concordance correlation coefficient ρ(c)=0.95); FT4: [LOCI]=1.05[RIA]-1.55 (ρ(c)=0.80); and FT3: [LOCI]=1.05[RIA]-0.06 (ρ(c)=0.81). 4) Both serum albumin and prealbumin concentrations were positively associated with FT3 levels and negatively associated with FT4 levels in patients. CONCLUSION: LOCI is accurate for TSH, FT4 and FT3 analysis. Despite a slight significant bias compared to ECLIA, LOCI is precise for TSH and fulfills the third-generation criteria. However, the poor concordance between LOCI and RIA for FT4 and FT3, and the dependence of these hormones on binding proteins require further investigation.

Characteristics of medication errors in pediatrics.

A six-month prospective study was carried out by 16 poison control centers in France to assess the epidemiology of medication errors in pediatrics. In this study, 1108 medication errors were analyzed. Mean population age was 3.2 years (median 2 years, range 3 days-15 years), and 30 percent of the children were under 1 year of age. The most frequent error characteristics were family responsibility, 87 percent (a member of the patient's family most often committed the error in medication use); parental prescribing decision, 31.5 percent (medication administered to the child by the parents without medical consultation or the advice of a pharmacist); incorrect execution of the prescription by the parents, 30 percent (error in dispensing, route of administration, etc.); oral forms, 52 percent (errors occurred most frequently with oral as opposed to other forms); incorrect dosage, 31.5 percent; and drug error, 30 percent (the drug dispensed was not the one prescribed). Iatrogenic injury occurred in 186 patients (17 percent) and 161 were hospitalized (15 percent). The majority of these were for surveillance only. The clinical outcome caused by medication error was unfavorable in two cases. The types of drugs most frequently misused included morphinic cough suppressants (9.5 percent), salicylates (9.1 percent), and ear, nose, and throat drops (9 percent); 459 proprietary medicines were specified. Prevention of medication errors should involve certain main requirements: formulations and package instructions specific to pediatric patients to ensure appropriateness and accuracy, detailed information given to patients by physicians and pharmacists about their prescriptions, and more public information concerning the risks of remedies or medication administered to children by parents who do not seek medical advice.

Can tumour marker assays be a guide in the prescription of bone scan for breast and lung cancers?

Considering the current need to improve cost-effectiveness in cancer patient management, a prospective study was undertaken in order to define the optimal combination of bone scan and tumour marker assays in breast and lung cancer strategies, as has been done in the case of prostate cancer. All patients with breast or lung cancer referred to the Nuclear Medicine Department of the Grenoble Teaching Hospital between December 1995 and April 1997 were included. A blood sample was drawn in each case for marker assay (CA15-3 or CEA and CYFRA 21-1) on the same day as the bone scan. Two hundred and seventy-five patients were included: 118 with lung cancer and 157 with breast cancer. With regard to lung cancer, no information useful for guiding bone scan prescription was obtained through CEA and CYFRA 21-1 assays. For breast cancer, the results suggest that in asymptomatic patients, a CA15-3 level of less than 25 U/ml (upper normal value chosen as the threshold) is strongly predictive of a negative bone scan; by contrast, high tumour marker levels are predictive of neoplastic bone involvement. When a doubtful bone scan is obtained in a patient with breast cancer, a normal marker level makes it highly probable that bone scan abnormalities are not related to malignancy.