[Making meaning of mental distress; discourse analysis of service-users' narratives]. / Betekenis geven aan psychische problematiek; discoursanalyse van ervaringsverhalen.

BACKGROUND: Processes of meaning-making are central to personal recovery in mental distress. Scientific inquiry of meaning-making is scarce within psychiatry, while it has the potential to better attune care to the lived-experience and views of service-users. AIM: To gain insight into how service-users make meaning of mental distress; how this meaning is shaped by mental health discourses, and how these discourses influence the search for identity and recovery. METHODS: Qualitative study of service-users’ narratives (N = 25) from the Psychiatry Story Bank. Narratives were collected through an open interview and analyzed with discourse analysis. RESULTS: We identified four patterns of meaning: Mental distress as ‘weakness’, as ‘social isolation’, as ‘necessity for care’ and as ‘disconnection’. Disposal - and integration - of various discourses apparently helped participants to find meaning, attuned to their recovery phase and the particular recognition they pursued. The quest for recovery was complicated when they experienced a clash between their own meaning-making and dominant ideals in care. CONCLUSION: Caretakers can stimulate the creation of helpful meaning, by attuning to their patients’ context, recovery phase and plea for recognition. Awareness of the effects and limitations of their own assumptions on mental distress is of importance as well.

Bone tumor-targeted delivery of theranostic 195mPt-bisphosphonate complexes promotes killing of metastatic tumor cells.

Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum (195mPt) is a rich source of low-energy Auger electrons, which kills tumor cells by damaging DNA. Auger electrons damage cells over a very short range. Consequently, 195mPt-based radiopharmaceuticals should be targeted toward â€‹tumors to maximize radiotherapeutic efficacy and minimize Pt-based systemic toxicity. Herein, we show that systemically administered radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes specifically accumulate in intratibial bone metastatic lesions in mice. The 195mPt-BP complexes accumulate 7.3-fold more effectively in bone 7 days after systemic delivery compared to 195mPt-cisplatin lacking bone-targeting bisphosphonate ligands. Therapeutically, 195mPt-BP treatment causes 4.5-fold more γ-H2AX formation, a biomarker for DNA damage in metastatic tumor cells compared to 195mPt-cisplatin. We show that systemically administered 195mPt-BP is radiotherapeutically active, as evidenced by an 11-fold increased DNA damage in metastatic tumor cells compared to non-radioactive Pt-BP controls. Moreover, apoptosis in metastatic tumor cells is enhanced more than 3.4-fold upon systemic administration of 195mPt-BP vs. radioactive 195mPt-cisplatin or non-radioactive Pt-BP controls. These results provide the first preclinical evidence for specific accumulation and strong radiotherapeutic activity of 195mPt-BP in bone metastatic lesions, which offers new avenues of research on radiotherapeutic killing of tumor cells in bone metastases by Auger electrons.

New sensitive method for HEPES quantification in 68Ga-radiopharmaceuticals.

BACKGROUND: The introduction of a GMP-certified 68Ga-generator spurred the application of 68Ga-radiopharmaceuticals. Several radiosynthesis of 68Ga-radiopharmaceuticals are more efficient and robust when performed with 2-[4-(2-hydroxyethyl)piperazin-1-yl] ethanesulfonic acid (HEPES) buffer, which is considered as an impurity in the quality control (QC) procedure. Thus, prior to clinical use, QC must be conducted to ensure that HEPES does not exceed the maximum dose of 200 µg/V Injected as described in European Pharmacopoeia (Ph Eur) for edotreotide. However, when applying the thin-layer chromatography (TLC) method described in the Ph Eur to quantify the HEPES amount present in the 68Ga-octreotide or in the remaining 68Ga-radiopharmaceuticals that were tested, no amount was detectable after 4 min of iodine incubation. Here we tested our modified TLC method and validate a new high-performance liquid chromatography (HPLC) method to quantify HEPES in 68Ga-radiopharmaceuticals and compare it to the TLC-method described in Ph Eur. In addition, samples collected from various institutes were tested to evaluate whether the synthesis of different 68Ga-radiopharmaceuticals or the use of different synthesis methods could affect the amounts of HEPES. RESULTS: HEPES could not be detected by the TLC method described in the Ph Eur within 4 min incubation in an iodine-saturated chamber. As for our modified TLC method, only after 2 h, spots were only visible > 1 mg/mL. The HPLC method had a limit-of-quantification (LOQ) of 3 µg/mL and a limit-of-detection (LOD) of 1 µg/mL. From the three 68Ga-radiopharmaceuticals tested, only in the [68Ga]Ga-NODAGA-Exendin samples exceeding amounts of HEPES were found and its concentration in the [68Ga]Ga-NODAGA-Exendin was significantly higher, when compared to [68Ga]Ga-DOTATOC and [68Ga]Ga-PSMA-11. CONCLUSION: The TLC method described in Ph Eur and our modified TLC method may not be sufficiently sensitive and thus unsuitable to use for QC release. The new HPLC method was sensitive, quantitative, reproducible and suitable for QC release. With this method, we were able to determine that some 68Ga-radiopharmaceuticals may exceed the HEPES limit of 200 µg/ V Injected. This new analytical system would allow correcting for the maximum injected dose in order not to exceed this amount.

What is known about the quality of out-of-hospital emergency medical services in the Arabian Gulf States? A systematic review.

BACKGROUND: The Emergency Medical Services (EMS) have been developed in the Arabian Gulf States (AGS) in the last three decades. The EMS needs continuous quality assessment of their performance to improve and provide the best out-of-hospital care. This study aims to assess the quality of EMS in the AGS according to the six quality domains of the Institute of Medicine. METHODS: We searched four databases (i.e., PubMed, EMBASE, Web of Science, and CINAHL) for studies that reported on the quality of EMS in any of the AGS using clinical or non-clinical performance indicators. To quantify study quality and risk of bias, the adapted Newcastle Ottawa Scale was used. We focused on structural and functional indicators, clinical and non-clinical. RESULTS: Twenty-five studies were eligible for inclusion. One study contained result of safety, fifteen time-centeredness, twenty effectiveness, five patient-centeredness, and thirteen studies reported on equity of EMS. None of the studies reported on efficiency of EMS. A significant proportion of studies showed high scores on the Newcastle-Ottawa scale. Limited studies on EMS quality were available, not covering all relevant quality domains and not covering the whole AGS region. The equity domain showed the best outcome performance finding, whereas finding of the patient-centeredness domain showed room for improvement in the foreseeable future. CONCLUSION: This review highlights the need for more and better studies of sufficient quality about all domains of quality in EMS in all the AGS. EMS research in Kuwait and Bahrain is warranted, as currently studies of EMS quality are unavailable for these States. Moreover, efficiency researches exploring this discipline should be conducted specially no studies were found has been searching this domain. TRIAL REGISTRATION: PROSPERO registration number: CRD42019123896.

MDR1 inhibition increases sensitivity to doxorubicin and etoposide in adrenocortical cancer.

Chemotherapy for adrenocortical carcinoma (ACC) has limited efficacy and is accompanied by severe toxicity. This lack of effectiveness has been associated with high tumoral levels of the multidrug resistance (MDR) pump P-glycoprotein (P-gp), encoded by the MDR1 gene. In this study, effects of P-gp inhibition on the sensitivity of ACC cells to cytotoxic drugs were evaluated. MDR1 mRNA and P-gp expression were determined in human adrenal tissues and cell lines. H295R, HAC15 and SW13 cells were treated with mitotane, doxorubicin, etoposide, cisplatin and streptozotocin, with or without the P-gp inhibitors verapamil and tariquidar. Cell growth and surviving fraction of colonies were assessed. MDR1 mRNA and P-gp protein expression were lower in ACCs than in adrenocortical adenomas (P < 0.0001; P < 0.01, respectively). MDR1 and P-gp expression were positively correlated in ACC (P < 0.0001, ρ = 0.723). Mitotane, doxorubicin, cisplatin and etoposide dose dependently inhibited cell growth in H295R, HAC15 and SW13. Tariquidar, and in H295R also verapamil, increased the response of HAC15 and H295R to doxorubicin (6.3- and 7.5-fold EC50 decrease in H295R, respectively; all P < 0.0001). Sensitivity to etoposide was increased in H295R and HAC15 by verapamil and tariquidar (all P < 0.0001). Findings were confirmed when assessing colony formation. We show that cytotoxic drugs, except streptozotocin, used for ACC treatment, inhibit ACC cell growth and colony formation at clinically achievable concentrations. P-gp inhibition increases sensitivity to doxorubicin and etoposide, suggesting that MDR1 is involved in sensitivity to these drugs and could be a potential target for cytotoxic treatment improvement in ACC.

Recent developments in the diagnosis and therapy of well-differentiated neuroendocrine tumours.

Well-differentiated neuroendocrine tumours (NETs) of the digestive tract are being increasingly detected, which is partly explained by the increased use of endoscopic and cross-sectional imaging as well as improved recognition at histopathological evaluation. After the discovery of this relatively indolent type of epithelial malignancy over 100 years ago, their sporadic occurrence and divergent biological behaviour at multiple primary sites have hampered dedicated studies into NET pathogenesis and testing of drug efficacy in well-designed clinical trials. The last decade, however, has seen significant improvements in the NET field regarding our understanding of their pathophysiology. This has been substantiated by novel and exciting diagnostic and therapeutic options, including superior positron emission tomography imaging, treatment with unlabelled and radiolabelled somatostatin analogues and inhibitors of the mammalian target of rapamycin and vascular endothelial growth factor pathways. This review summarises contemporary studies within NET patients, which have enriched our clinical repertoire for this disease and have been instrumental in securing a remarkable improvement of overall survival within recent years.

Systematic review of surgical and medical treatment for tertiary hyperparathyroidism.

BACKGROUND: A significant proportion of patients with chronic kidney disease and secondary hyperparathyroidism (HPT) remain hyperparathyroid after kidney transplantation, a state known as tertiary HPT. Without treatment, tertiary HPT can lead to diminished kidney allograft and patient survival. Parathyroidectomy was commonly performed to treat tertiary HPT until the introduction of the calcimimetic drug, cinacalcet. It is not known whether surgery or medical treatment is superior for tertiary HPT. METHODS: A systematic review was performed and medical literature databases were searched for studies on the treatment of tertiary HPT that were published after the approval of cinacalcet. RESULTS: A total of 1669 articles were identified, of which 47 were included in the review. Following subtotal and total parathyroidectomy, initial cure rates were 98·7 and 100 per cent respectively, but in 7·6 and 4 per cent of patients tertiary HPT recurred. After treatment with cinacalcet, 80·8 per cent of the patients achieved normocalcaemia. Owing to side-effects, 6·4 per cent of patients discontinued cinacalcet treatment. The literature regarding graft function and survival is limited; however, renal graft survival after surgical treatment appears comparable to that obtained with cinacalcet therapy. CONCLUSION: Side-effects and complications of both treatment modalities were mild and occurred in a minority of patients. Surgical treatment for tertiary HPT has higher cure rates than medical therapy.

ENDOCRINOLOGY IN PREGNANCY: Pheochromocytoma in pregnancy: case series and review of literature.

Pheochromocytoma in pregnancy is extremely rare. Early recognition is crucial as antepartum diagnosis can largely decrease maternal and fetal mortality rates. As symptoms of pheochromocytoma are rather similar to those of other far more common causes of hypertension during pregnancy, timely diagnosis is a challenge. In pregnant patients, similar to non-pregnant patients, increased plasma and/or 24-h urine (nor)metanephrine concentrations most reliably confirm the diagnosis of pheochromocytoma. MRI and ultrasound are the only imaging modalities that can be used safely during pregnancy to localize the tumor. During pregnancy, pretreatment consists of alpha blockade as usual. However, dosing of α-adrenergic receptor blockers during pregnancy is a challenge as hypertension must be treated while preserving adequate uteroplacental circulation. When the diagnosis is made within the first 24 weeks of pregnancy, it is generally recommended to remove the tumor in the second trimester, while resection is generally postponed till after delivery when the diagnosis is made in the third trimester and medical pretreatment is sufficient. Both during and after pregnancy, laparoscopic surgery is the preferred approach for resection of the tumor. There is no consensus in literature about the preferred route and timing of delivery. Therefore, in our opinion, decisions should be made on an individual basis by an experienced and dedicated multidisciplinary team. Over the last decades, maternal and fetal prognosis has improved considerably. Further increasing awareness of this rare diagnosis and treatment of these patients by a dedicated team in a tertiary referral hospital are critical factors for optimal maternal and fetal outcome.

Inhibition of Human Adrenocortical Cancer Cell Growth by Temozolomide in Vitro and the Role of the MGMT Gene.

CONTEXT: Treatment of patients with adrenocortical carcinomas (ACC) with mitotane and/or chemotherapy is often associated with toxicity and poor tumor response. New therapeutic options are urgently needed. OBJECTIVE: The objectives of the study were to evaluate the therapeutic possibilities of temozolomide (TMZ) in ACC cells and to assess the potential predictive role of the DNA repair gene O6-Methylguanine-DNA methyltransferase (MGMT) in adrenocortical tumors. METHODS: Three human ACC cell lines and eight primary ACC cultures were used to assess effects of TMZ in vitro. In the cell lines, 11 normal adrenals, 16 adrenocortical adenomas, and 29 ACC, MGMT promoter methylation and expression were determined. RESULTS: IC50 values of TMZ on cell growth were 39 µM, 38 µM, and 44 µM for H295R, HAC15, and SW13, respectively. TMZ induced apoptosis and provoked cytotoxic and cytostatic effects by reducing the surviving fraction of ACC colonies and the colony size. TMZ thereby induced cell cycle arrests in ACC cell lines. TMZ and mitotane both inhibited growth of ACC cells cultured as three-dimensional spheroids. TMZ inhibited cell amount in five of eight primary ACC cultures and induced apoptosis in seven of eight primary ACC cultures. In ACC cell lines and adrenal tissues, MGMT promoter methylation was low. In ACCs, methylation was inversely correlated with MGMT mRNA expression. MGMT protein expression was not correlated with MGMT methylation. CONCLUSIONS: For the first time, we show the therapeutic potential of temozolomide for ACC, offering an urgently needed potential alternative for patients not responding to mitotane alone or with etoposide, doxorubicin, and cisplatin. (Pre-)clinical studies are warranted to assess efficacy in vivo.

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas.

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients.

Thyroid hormone and its metabolites in relation to quality of life in patients treated for differentiated thyroid cancer.

BACKGROUND: Levothyroxine (LT4) is the standard of care in patients with hypothyroidism. Despite this replacement therapy, quality of life (QoL) remains impaired in a substantial amount of patients. The reasons for this are still a matter of debate. Suggested causes include lack of endogenous T3 secretion by the thyroid, changes in other thyroid hormone metabolites and interference by autoimmune processes. OBJECTIVE: To investigate the association between thyroid function tests (TFTs) and QoL in patients with a history of differentiated thyroid cancer on LT4 monotherapy. These patients lack endogenous thyroidal T3 secretion in the absence of autoimmune disease. MATERIALS AND METHODS: This is a cross-sectional study in 143 patients (69·2% female). Initial therapy consisted of total thyroidectomy followed by radioiodine ablation minimally one year before inclusion. We assessed health-related QoL (RAND-36), thyroid-specific QoL (ThyPRO) and fatigue with the Multidimensional Fatigue Inventory. Extensive TFTs were assessed, including 3,5-diiodo-L-thyronine (3,5-T2). RESULTS: Mean age was 50·2 years and mean time since diagnosis was 8·4 years. Median TSH was 0·042 mU/l, total T4 145·0 nmol/l, free T4 25·6 pmol/l, total T3 1·93 nmol/l, reverse T3 0·53 nmol/l and 3,5-T2 0·86 nmol/l. Multiple linear regression analyses did not show any association between QoL and the different TFTs, including T4/T3 and 3,5-T2/T3 ratios reflecting peripheral metabolism. CONCLUSION: We did not find any association between TFTs and QoL in athyreotic patients on LT4 monotherapy. Our data do not provide evidence that a slight increase in dose improves fatigue or well-being in hypothyroid patients on LT4 therapy.

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors.

OBJECTIVE: Several series report on the relative contribution of ectopic ACTH syndrome (EAS) in the spectrum of Cushing's syndrome. However, prevalence of EAS in patients with thoracic or gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is currently unknown. DESIGN: We assessed, in a tertiary referral center, the prevalence of EAS in a large cohort of thoracic and GEP-NET patients including clinical, biochemical, and radiological features; management; and treatment outcome. METHODS: In total, 918 patients with thoracic or GEP-NETs were studied (1993-2012). Multiple endocrine neoplasia type 1 and small cell lung carcinoma patients were excluded. Differentiation between synchronous, metachronous, and cyclic occurrence of EAS was made. RESULTS: Out of the 918 patients with thoracic and GEP-NETs (469 males and 449 females; median age 58.7 years (range: 17.3-87.3)), 29 patients (3.2%) had EAS (ten males and 19 females; median age 48.1 years (range: 24.7-77.9)). EAS occurred synchronously in 23 patients (79%), metachronously in four patients (14%), and cyclical in two patients (7%) respectively. NETs causing EAS included lung/bronchus (n=9), pancreatic (n=9), and thymic (n=4). In four patients, the cause of EAS was unknown (n=4). Median overall survival (OS) of non-EAS thoracic and GEP-NET patients was 61.2 months (range: 0.6-249.4). Median OS of EAS patients was 41.4 months (range: 2.2-250.9). After comparison, only the first 5-year survival was significantly shorter (P=0.013) in EAS patients. CONCLUSION: Prevalence of EAS in this large cohort of patients with thoracic and GEP-NETs was 3.2%. EAS was mostly caused by thoracic and pancreatic NETs. First 5-year survival of EAS patients was shorter compared with non-EAS patients.

Anti-CEA antibody fragments labeled with [(18)F]AlF for PET imaging of CEA-expressing tumors.

A facile and rapid method to label peptides with (18)F based on chelation of [(18)F]AlF has been developed recently. Since this method requires heating to 100 °C, it cannot be used to label heat-sensitive proteins. Here, we used a two-step procedure to prepare (18)F-labeled heat-labile proteins using the [(18)F]AlF method based on hot maleimide conjugation. 1,4,7-Triazacyclononae-1,4-diacetate (NODA) containing a methyl phenylacetic acid group (MPA) functionalized with N-(2-aminoethyl)maleimide (EM) was used as a ligand which was labeled with [(18)F]AlF and then conjugated to the humanized anti-CEA antibody derivatives hMN-14-Fab', hMN-14-(scFv)2 (diabody), and a Dock-and-Lock engineered dimeric fragment hMN-14 Fab-AD2 at room temperature. The in vivo tumor targeting characteristics of the (18)F-labeled antibody derivatives were determined by PET imaging of mice with s.c. xenografts. NODA-MPAEM was radiolabeled with [(18)F]AlF at a specific activity of 29-39 MBq/nmol and a labeling efficiency of 94 ± 2%. The labeling efficiencies of the maleimide conjugation ranged from 70% to 77%, resulting in [(18)F]AlF-labeled hMN14-Fab', hMN14-Fab-AD2, or hMN14-diabody with a specific activity of 15-17 MBq/nmol. The radiolabeled conjugates were purified by gel filtration. For biodistribution and microPET imaging, antibody fragments were injected intravenously into BALB/c nude mice with s.c. CEA-expressing LS174T xenografts (right flank) and CEA-negative SK-RC-52 xenografts (left flank). All [(18)F]AlF-labeled conjugates showed specific uptake in the LS174T xenografts with a maximal tumor uptake of 4.73% ID/g at 4 h after injection. Uptake in CEA-negative SK-RC-52 xenografts was significantly lower. Tumors were clearly visualized on microPET images. Using a [(18)F]AlF-labeled maleimide functionalized chelator, antibody fragments could be radiofluorinated within 4 h at high specific activity. Here, we translated this method to preclinical PET imaging studies and showed feasibility of [(18)F]AlF-fluorinated hMN-14-Fab', [(18)F]AlF-hMN-14-Fab-AD2, and [(18)F]AlF-hMN-14-diabody for microPET imaging of CEA-expressing colonic cancer.

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results.

BACKGROUND: Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC). METHODS: Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 µg). After confirmation of tumour targeting by (111)In-IMP288, patients were treated with a bsMAb/(177)Lu-IMP288 cycle. RESULTS: Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-µg peptide dose. High (177)Lu-IMP288 doses (2.5-7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3-4 thrombocytopaenia in 10% of the patients who received (177)Lu-IMP288. CONCLUSION: This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.

Adjuvant radioimmunotherapy after radiofrequency ablation of colorectal liver metastases in an experimental model.

PURPOSE: Radiofrequency ablation (RFA) has shown to improve survival in patients not eligible for surgical resection of colorectal liver metastases. However, recurrences after RFA are a major problem. Adjuvant radioimmunotherapy (RIT) after surgical resection of liver metastases has shown to improve survival. The aim of the present study was to test the hypothesis that adjuvant RIT might be an effective way to prevent recurrent liver metastases after RFA in an experimental model. METHODS: Tumours in the liver were induced by intrahepatic injection of 300,000 CC531 cells in male Wag/Rij rats (n = 60). Ten days later, the intrahepatic tumours were treated with RFA. Adjuvant RIT ((177)Lu-labelled monoclonal antibody MG1 at 300 MBq/kg) was administered intravenously either at the day of RFA (day 10) or 7 days later. Control rats received no treatment. Primary endpoint was survival. RESULTS: Administration of (177)Lu-MG1 resulted in a transient decrease in body weight, compared to no adjuvant treatment. However, no other signs of clinical discomfort were registered. Log rank test showed that the survival curves of the groups treated with RIT, either at day 10 or day 17, did not differ significantly from the survival curve of the rats that did not receive adjuvant treatment (P = 0.902). CONCLUSION: This study shows that adjuvant RIT does not increase survival after RFA of colorectal liver metastases in rats.

Divided-dose kinetics of mefloquine in man.

The kinetics of mefloquine was investigated following oral divided-doses in 10 healthy Caucasian volunteers. They received 500 or 750 mg followed by 500 mg 8 h later. Unchanged mefloquine (M) and its carboxylic acid metabolite (MM) were measured in whole blood and plasma for 50 days by h.p.l.c. Maximum blood and plasma M concentrations of 1872 +/- 362 ng ml-1 (mean +/- s.d.) and 1900 +/- 434 ng ml-1, respectively, were found within 6-10 h after the second dose. The terminal plasma elimination half-life was 20.1 +/- 3.7 days (mean +/- s.d.) and the oral clearance was 22.3 +/- 6.7 ml h-1 kg-1 (mean +/- s.d.). Plasma concentrations of MM exceeded those of M by 2-3 fold within 2 days. The whole blood concentration of MM was lower than that in plasma but also exceeded the whole blood concentration of M.