A systematic review and meta-analysis of the clinimetric properties of the core outcome measurement instruments for clinical effectiveness trials of nutritional and metabolic interventions in critical illness (CONCISE).

BACKGROUND: CONCISE is an internationally agreed minimum set of outcomes for use in nutritional and metabolic clinical research in critically ill adults. Clinicians and researchers need to be aware of the clinimetric properties of these instruments and understand any limitations to ensure valid and reliable research. This systematic review and meta-analysis were undertaken to evaluate the clinimetric properties of the measurement instruments identified in CONCISE. METHODS: Four electronic databases were searched from inception to December 2022 (MEDLINE via Ovid, EMBASE via Ovid, CINAHL via Healthcare Databases Advanced Search, CENTRAL via Cochrane). Studies were included if they examined at least one clinimetric property of a CONCISE measurement instrument or recognised variation in adults ≥ 18 years with critical illness or recovering from critical illness in any language. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for systematic reviews of Patient-Reported Outcome Measures was used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were used in line with COSMIN guidance. The COSMIN checklist was used to evaluate the risk of bias and the quality of clinimetric properties. Overall certainty of the evidence was rated using a modified Grading of Recommendations, Assessment, Development and Evaluation approach. Narrative synthesis was performed and where possible, meta-analysis was conducted. RESULTS: A total of 4316 studies were screened. Forty-seven were included in the review, reporting data for 12308 participants. The Short Form-36 Questionnaire (Physical Component Score and Physical Functioning), sit-to-stand test, 6-m walk test and Barthel Index had the strongest clinimetric properties and certainty of evidence. The Short Physical Performance Battery, Katz Index and handgrip strength had less favourable results. There was limited data for Lawson Instrumental Activities of Daily Living and the Global Leadership Initiative on Malnutrition criteria. The risk of bias ranged from inadequate to very good. The certainty of the evidence ranged from very low to high. CONCLUSIONS: Variable evidence exists to support the clinimetric properties of the CONCISE measurement instruments. We suggest using this review alongside CONCISE to guide outcome selection for future trials of nutrition and metabolic interventions in critical illness. TRIAL REGISTRATION: PROSPERO (CRD42023438187). Registered 21/06/2023.

Core outcome measures for clinical effectiveness trials of nutritional and metabolic interventions in critical illness: an international modified Delphi consensus study evaluation (CONCISE).

BACKGROUND: Clinical research on nutritional and metabolic interventions in critically ill patients is heterogenous regarding time points, outcomes and measurement instruments used, impeding intervention development and data syntheses, and ultimately worsening clinical outcomes. We aimed to identify and develop a set of core outcome domains and associated measurement instruments to include in all research in critically ill patients. METHODS: An updated systematic review informed a two-stage modified Delphi consensus process (domains followed by instruments). Measurement instruments for domains considered 'essential' were taken through the second stage of the Delphi and a subsequent consensus meeting. RESULTS: In total, 213 participants (41 patients/caregivers, 50 clinical researchers and 122 healthcare professionals) from 24 countries contributed. Consensus was reached on time points (30 and 90 days post-randomisation). Three domains were considered 'essential' at 30 days (survival, physical function and Infection) and five at 90 days (survival, physical function, activities of daily living, nutritional status and muscle/nerve function). Core 'essential' measurement instruments reached consensus for survival and activities of daily living, and 'recommended' measurement instruments for physical function, nutritional status and muscle/nerve function. No consensus was reached for a measurement instrument for Infection. Four further domains met criteria for 'recommended,' but not 'essential,' to measure at 30 days post-randomisation (organ dysfunction, muscle/nerve function, nutritional status and wound healing) and three at 90 days (frailty, body composition and organ dysfunction). CONCLUSION: The CONCISE core outcome set is an internationally agreed minimum set of outcomes for use at 30 and 90 days post-randomisation, in nutritional and metabolic clinical research in critically ill adults.

A collective review of biological versus synthetic mesh-reinforced cruroplasty during laparoscopic Nissen fundoplication.

BACKGROUND: Laparoscopic cruroplasty and fundoplication have become the gold standard in the treatment of hiatal hernia and gastro-oesophageal reflux disease (GERD). The use of a mesh-reinforcement of the cruroplasty has been proven effective; although, there is a lack of evidence considering which type of mesh is superior. The aim of this study was to compare recurrence rates after mesh reinforced cruroplasty using biological versus synthetic meshes. METHODS: We performed a systematic review of all clinical trials published between January 2004 and September 2015 describing the application of a mesh in the hiatal hernia repair during Nissen fundoplication for both GERD and hiatal hernia. The primary outcome was the recurrence rate, and secondary outcomes were complication rate, mortality and symptomatic outcome. RESULTS: We included 16 studies and extracted data regarding 1089 mesh operated patients of whom 385 received a biological mesh and 704 a synthetic mesh. The mean follow-up was 53.4 months. The recurrence rate in the synthetic mesh group was 6.8% compared to 16.1% in the biological mesh group (P < 0.05). The complication rate was 5.1% and 4.6% (P = 0.694), respectively, and there were 12 mesh-related complications. No mesh-related mortality was reported. CONCLUSION: Mesh reinforcement of hiatal hernia repair seems safe in the short-term follow-up. The available literature suggests no clear advantage of biological over synthetic meshes. Regarding cost-efficiency and short-term results, the use of synthetic nonabsorbable meshes might be advocated.

Subjective outcome after laparoscopic hiatal hernia repair for intrathoracic stomach.

PURPOSE: For decades, an intrathoracic stomach (ITS) has been a definite indication for surgery due to the perceived risk of an acute volvulus with perforation, gangrene, or hemorrhage. At the present time, elective laparoscopic repair is the first choice for treatment of ITS. There is a lack of evidence in the long-term quality of life after a hiatal hernia repair for an intrathoracic stomach. METHODS: A retrospective analysis was performed on all patients undergoing a hiatal hernia repair for an intrathoracic stomach between January 2004 and January 2015. Additionally, to a hiatal closure, the patients received an antireflux procedure. Outcome measures included patient characteristics, operative details, complications, and postoperative morbidity and mortality. All patients were sent a quality of life questionnaire to assess long-term quality of life and patient satisfaction. A higher quality of life score represents a better quality of life. RESULTS: Eighty-six patients underwent laparoscopic repair for ITS, from which, one patient died during surgery. Eighty-five patients were contacted and 81 completed the questionnaire, resulting in a response rate of 95.3 %. At a median follow-up of 2.7 years (range 0.1-9.6), the mean quality of life score was 13.5 (standard deviation 2.8). The mean overall satisfaction was 8.4. There were four recurrences: three in the first 12 days after surgery and one in 2.4 years. CONCLUSIONS: Very good results in patient satisfaction and symptom reduction were achieved after a median follow-up of 2.7 years in this laparoscopic repair of the intrathoracic stomach single center experience study. The symptomatic recurrence rate was very low.

Drug dispensings among elderly in the year before colon cancer diagnosis versus matched cancer-free controls.

WHAT IS KNOWN AND OBJECTIVE: The concomitant use of multiple drugs is common among the general population of elderly. The aim of this study was to provide an overview of which drugs are dispensed to elderly in the year before colon cancer diagnosis and to compare this with cancer-free controls. METHODS: Data from the Eindhoven Cancer Registry were linked to the PHARMO Database Network. Patients with colon cancer aged ≥70 years were included and matched with controls on gender, year of birth and postal code. Proportions of cases and controls with ≥1 dispensing of each WHO ATC-2-level drug during the total year and during each quarter of the year were calculated and differences between cases and controls tested. RESULTS AND DISCUSSION: Proportion of cases with ≥1 drug dispensing was highest for drugs for constipation (cases vs. controls 58% vs. 10%), antithrombotics (42% vs. 33%), drugs for acid-related disorders (35% vs. 22%), antibacterials (34% vs. 24%), agents acting on the renin-angiotensin system (33% vs. 27%), beta-blockers (33% vs. 23%), lipid-modifying agents (29% vs. 22%), diuretics (29% vs. 21%), psycholeptics (25% vs. 18%) and antianaemics (23% vs. 6%). The proportion of cases with ≥1 drug dispensing increased from the first to the last quarter of the year for drugs for constipation (7%-53%), drugs for acid-related disorders (16%-27%), antibacterials (12%-16%), beta-blockers (26%-28%), psycholeptics (15%-19%) and antianaemics (6%-18%). Elevated proportions of cases with ≥1 drug dispensing for several drugs are mostly related to comorbidity, although increasing proportions of cases with ≥1 drug dispensing for certain drugs during the year can be attributed to the incidence of colon cancer. WHAT IS NEW AND CONCLUSION: We have provided insight into which drugs are commonly used in the year preceding colon cancer diagnosis. This may trigger general practitioners and medical specialists to further evaluate the patient.

Variability of microcirculatory measurements in healthy volunteers.

Reliable assessment of the microcirculation is important to investigate microcirculatory properties in various disease states. The GlycoCheck system automatically analyzes sublingual sidestream dark field images to determine the perfused boundary region (PBR; a measure of glycocalyx thickness), red blood cell filling percentage, and microvascular vessel density. Although GlycoCheck has been used to study the microcirculation in patients, little is known about the reproducibility of measurements in healthy volunteers. We assessed intra- and interobserver agreement by having two experienced observers perform three consecutive microcirculation measurements with the GlycoCheck system in 49 healthy volunteers. Intraobserver agreement of single measurements were poor (intraclass correlation coefficients (ICCs) < 0.4) for PBR, red blood cell filling percentage and microvascular vessel density. ICCs increased to values > 0.6 (indicating good reproducibility) for all parameters when performing and averaging three consecutive measurements. No systematic differences were observed between observers for any parameter. Interobserver variability was fair for PBR (ICC = 0.53) and red blood cell filling percentage (ICC = 0.58) and poor for perfused vessel density (ICC = 0.20). In conclusion, GlycoCheck software can be used with acceptable reliability and reproducibility for microcirculation measurements on a population level when averaging three consecutive measurements. Repeated measurements are preferably performed by the same observer.

Multimodal measurement of glycocalyx degradation during coronary artery bypass grafting.

Background: Glycocalyx shedding and subsequent endothelial dysfunction occur in many conditions, such as in sepsis, in critical illness, and during major surgery such as in coronary artery bypass grafting (CABG) where it has been shown to associate with organ dysfunction. Hitherto, there is no consensus about the golden standard in measuring glycocalyx properties in humans. The objective of this study was to compare different indices of glycocalyx shedding and dysfunction. To this end, we studied patients undergoing elective CABG surgery, which is a known cause of glycocalyx shedding. Materials and methods: Sublingual glycocalyx thickness was measured in 23 patients by: 1) determining the perfused boundary region (PBR)-an inverse measure of glycocalyx thickness-by means of sidestream dark field imaging technique. This is stated double, 2) measuring plasma levels of the glycocalyx shedding products syndecan-1, hyaluronan, and heparan sulfate and 3) measuring plasma markers of impaired glycocalyx function and endothelial activation (Ang-2, Tie-2, E-selectin, and thrombomodulin). Measurements were performed directly after induction, directly after onset of cardiopulmonary bypass (CPB), and directly after cessation of CPB. We assessed changes over time as well as correlations between the various markers. Results: The PBR increased from 1.81 ± 0.21 µm after induction of anesthesia to 2.27 ± 0.25 µm (p < 0.0001) directly after CPB was initiated and did not change further during CPB. A similar pattern was seen for syndecan-1, hyaluronan, heparan sulfate, Ang-2, Tie-2, and thrombomodulin. E-selectin levels also increased between induction and the start of CPB and increased further during CPB. The PBR correlated moderately with heparan sulfate, E-selectin, and thrombomodulin and weakly with Syndecan-1, hyaluronan, and Tie-2. Shedding markers syndecan-1 and hyaluronan correlated with all functional markers. Shedding marker heparan sulfate only correlated with Tie-2, thrombomodulin, and E-selectin. Thrombomodulin correlated with all shedding markers. Conclusion: Our results show that glycocalyx thinning, illustrated by increased sublingual PBR and increased levels of shedding markers, is paralleled with impaired glycocalyx function and increased endothelial activation in CABG surgery with CPB. As correlations between different markers were limited, no single marker could be identified to represent the glycocalyx in its full complexity.

Switching from infliximab innovator to biosimilar in patients with inflammatory bowel disease: a 12-month multicentre observational prospective cohort study.

BACKGROUND: Infliximab biosimilars have become available for treatment of inflammatory bowel disease (IBD). However, data showing long-term safety and effectiveness of biosimilars in IBD patients are limited. AIM: To study prospectively the switch from infliximab innovator to biosimilar in an IBD cohort with 12 months follow-up to evaluate safety and effectiveness. METHODS: Adult IBD patients from two hospitals treated with infliximab innovator (Remicade; Janssen Biotech,  Horsham ,  Pennsylvania, USA) were switched to infliximab biosimilar (Inflectra; Hospira, Lake Forest, Illinois, USA) as part of routine care, but in a controlled setting. Blood samples were taken just before the first, second, fourth and seventh infusion of biosimilar. Infliximab trough levels, antibodies-to-infliximab (ATI), CRP and ESR were measured and disease activity scores were calculated. RESULTS: Our cohort consisted of 133 IBD patients (64% CD, 36% UC). Before switching we found widely varying infliximab levels (median 3.5 µg/mL). ATI were detected in eight patients (6%). Most patients were in remission or had mild disease (CD: 82% UC: 90%). After switching to biosimilar, 35 patients (26%) discontinued therapy within 12 months, mostly due to subjective higher disease activity (9%) and adverse events (AE, 9.8%). AE included general malaise/fatigue (n = 7), arthralgia (n = 2), skin problems (n = 2) and infusion reactions (n = 2). No differences in IFX levels, CRP, and disease activity scores were found between the four time points (P ≥ .0917). CONCLUSIONS: We found no differences in drug levels and disease activity between infliximab innovator and biosimilar in our IBD cohort, indicating that biosimilars are safe and effective. The high proportions of discontinuers were mostly due to elective withdrawal or subjective disease worsening.

Alliance and Treatment Outcome in Family-Involved Treatment for Youth Problems: A Three-Level Meta-analysis.

Alliance has been shown to predict treatment outcome in family-involved treatment for youth problems in several studies. However, meta-analytic research on alliance in family-involved treatment is scarce, and to date, no meta-analytic study on the alliance-outcome association in this field has paid attention to moderating variables. We included 28 studies reporting on the alliance-outcome association in 21 independent study samples of families receiving family-involved treatment for youth problems (N = 2126 families, M age youth ranging from 10.6 to 16.1). We performed three multilevel meta-analyses of the associations between three types of alliance processes and treatment outcome, and of several moderator variables. The quality of the alliance was significantly associated with treatment outcome (r = .183, p < .001). Correlations were significantly stronger when alliance scores of different measurement moments were averaged or added, when families were help-seeking rather than receiving mandated care and when studies included younger children. The correlation between alliance improvement and treatment outcome just failed to reached significance (r = .281, p = .067), and no significant correlation was found between split alliances and treatment outcome (r = .106, p = .343). However, the number of included studies reporting on alliance change scores or split alliances was small. Our findings demonstrate that alliance plays a small but significant role in the effectiveness of family-involved treatment. Future research should focus on investigating the more complex systemic aspects of alliance to gain fuller understanding of the dynamic role of alliance in working with families.

Location of genes involved in invasion and metastasis on human chromosome 7.

We have obtained evidence for the existence of genes controlling invasion and metastasis by somatic cell fusion studies. Noninvasive, nonmetastatic mouse BW5147 T-lymphoma cells were fused with invasive human T-cells. The human cells were either activated normal peripheral blood lymphocytes or leukemic T-lymphoblasts. Both fusions resulted in highly invasive human-mouse T-cell hybrids which metastasized in nude mice. Thus the genes derived from either malignant or nonmalignant but inherently invasive cells enable the T-cell hybridomas to metastasize. By continued in vitro selection for invasive cells employing monolayers of rat embryo fibroblasts followed by subcloning, we were able to isolate invasive hybrids that had lost all human chromosomes except chromosome 7. We present evidence that one or more genes residing on human chromosome 7 are necessary and sufficient for both the establishment and maintenance of invasiveness and metastatic potential of the interspecies T-cell hybrids.

The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin.

The ErbB-1 receptor tyrosine kinase binds to six different growth factors, whose prototype is the epidermal growth factor (EGF). Two homologous epithelial receptors, ErbB-3 and ErbB-4, bind all isoforms of another family of growth factors, the Neu differentiation factors (NDFs/neuregulins). The fourth member of the ErbB family, ErbB-2, acts as the preferred heterodimeric partner of ligand-occupied complexes of the three other ErbB proteins. Here we report that at high concentrations, EGF can induce cell growth and differentiation in the absence of ErbB-1. This function is shared by betacellulin, but not by three other ligands, including the transforming growth factor alpha (TGFalpha). The functional receptor was identified as a heterodimer between ErbB-3 and ErbB-2, a previously identified oncogenic complex. When singly expressed, neither ErbB-3 nor ErbB-2 can mediate signaling by EGF. In addition, when co-expressed, blocking either receptor by using site-specific antibodies inhibited EGF and betacellulin activities, indicating strict cooperativity between ErbB-3 and ErbB-2. Through analysis of chimeras between EGF and TGFalpha, we identified the middle portion of EGF (loop B) as the site that enables activation of ErbB-2/ErbB-3. In conclusion, cooperative and promiscuous binding of stroma-derived growth factors by the epithelium-expressed ErbB-2/ErbB-3 heterodimer may be significant to cancer development. The mechanistic implications of our results for a model that attributes receptor dimerization to ligand bivalency, as well as to a recently proposed mechanism of secondary dimerization, are discussed.

Identification of three amino acid residues in the B-chain of platelet-derived growth factor with different importance for binding to PDGF alpha- and beta-receptors.

The B-chain homodimer isoform of platelet-derived growth factor (PDGF) binds with high affinity both to alpha- and to beta-receptors. In order to localize amino acid residues in PDGF-BB of differential importance for the binding to the two receptors, PDGF-BB mutants were analyzed in which single amino acid residues were changed to alanine residues. We found that Phe-118 in loop 1 of the PDGF B-chain is crucial for binding to both receptors, and that the surrounding amino acids, Asn-117 and Leu-119, appear to be important primarily for binding to the beta-receptor. In contrast, Lys-161 in loop 3 was found to be more important for binding to alpha-receptors than beta-receptors. Previous studies have shown that the receptor binding epitope of PDGF-BB is composed mainly of loops 1 and 3; the findings of the present study show that the alpha- and beta-receptors interact with different amino acid residues in these regions.

Metabolic activation routes of arylamines and their genotoxic effects.

Two different types of DNA adducts are formed from many aromatic amines by bioactivation: N-acetylated and nonacetylated, arylamine DNA adducts. It has become clear from experiments using N-acetyl-2-aminofluorene and 2-aminofluorene adducts to C8 of deoxyguanosine that these two types of adducts may have different effects on DNA structure and DNA replication. We have determined blocking of DNA replication by various other N-acetylarylamine and arylamine deoxyguanosine adducts. It was found that the N-acetyl group in general is required for blocking of DNA replication; the nature of the aromatic moiety seems to be of minor importance. Little information is available on the genotoxic effects of these adducts in mammalian cells in vivo. We have tried to get more insight in this by investigating the clastogenicity, the initiation of preneoplastic cells, and the promotional effects of various aromatic amines from which different ratios of N-acetylarylamine DNA adducts to arylamine DNA adducts are formed in the rat liver. Our results show that formation of N-acetylarylamine adducts to C8 of deoxyguanosine in the liver is correlated with clastogenicity and hepatic promoting effect. Initiation capacities, however, seem to be correlated with formation of nonacetylated, arylamine adducts. Mechanisms by which formation of N-acetylarylamine DNA adducts may generate a promoting effect in the liver are discussed.

The effect of atovaquone on etoposide pharmacokinetics in children with acute lymphoblastic leukemia.

PURPOSE: The use of trimethoprim/sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia in patients with acute lymphoblastic leukemia (ALL) may cause undesirable adverse effects: fungal overgrowth, neutropenia, and drug resistance. A possible alternative is atovaquone, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity. However, it is not known if atovaquone alters the disposition or adverse effects of antileukemic drugs. METHODS: Using a crossover study design, we compared the pharmacokinetics of etoposide and its CYP3A4-formed catechol metabolite when given as a 300 mg/m2 i.v. infusion following daily atovaquone versus trimethoprim/sulfamethoxazole in nine patients. RESULTS: The area under the concentration time curve (AUC) of etoposide, etoposide catechol and the catechol to etoposide AUC ratio were slightly higher (a median of 8.6%, 28.4%, and 25.9%) following atovaquone as compared to trimethoprim/sulfamethoxazole (P=0.055, P= 0.031 and P=0.023), respectively. In vitro analysis in human liver microsomes showed modest inhibition of etoposide catechol formation in the presence of atovaquone. Using uptake of 3H-vinblastine in L-MDR1 cells, atovaquone was shown to inhibit P-glycoprotein with an apparent Ki of 95.6 microM. CONCLUSIONS: Although the effect of atovaquone on etoposide disposition was modest, in light of the fact that the risk of etoposide-related secondary acute myeloid leukemia has been linked to minor changes in schedule and concurrent therapy, we suggest caution with the simultaneous administration of atovaquone and etoposide, particularly if used with other CYP3A4/P-glycoprotein substrates.

Inhibitory effects of the phorbolester TPA and cigarette smoke condensate on the mutagenicity of benzo[a]pyrene in a co-cultivation system.

The transport of reactive intermediates was studied in a co-cultivation system of primary chick embryo hepatocytes and V79 Chinese hamster cells. Two test systems with different genetic endpoints--sister-chromatid exchange (SCE) and gene mutation at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus--were used. Benzo[a]pyrene (B[a]P) was positive in both test systems. When the V79 cells were co-cultivated with the hepatocytes at a distance of 1 mm, only a slight increase in the number of SCEs was observed after exposure to benzo[a]pyrene. When the two cell types were in direct contact, addition of the phorbolester TPA or cigarette smoke condensate inhibited the mutagenic effects of B[a]P in both assays by 50%. No influence of TPA on the number of SCEs induced by B[a]P was observed in a preincubation assay using Aroclor-1254-induced rat liver homogenate. The results indicate that metabolic co-operation may play a role in the transport of reactive intermediates in this co-cultivation system. The mutagenic potential of compounds may be underestimated in systems using intact cells for metabolic activation if the compounds or their metabolites are capable of inhibiting metabolic co-operation.

Rational design for the development of epidermal growth factor receptor antagonists.

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) bind with similar high affinity to the human EGF receptor. Using a domain-exchange strategy we have shown that the C-terminal linear region of these molecules is involved in high affinity receptor binding. By further single amino acid substitution in this linear C-terminal region, a putative interaction site of these ligands with their receptor has been identified. This identification of a receptor binding domain in EGF/TGF alpha provides an important initial step in the development of EGF receptor antagonists with significant clinical potential.

Labelling of bleomycin with cobalt-57, indium-111, technetium-99m, mercury-197, lead-203, and copper-67.

The radiochemical purity of the cobalt-57 complex of bleomycin could be enhanced by adjusting the pH of the final product to a value between 5 and 6. This radiopharmaceutical appeared to have better tumor visualizing properties compared to the not neutralized preparation. The clinical use of the cobalt-57 bleomycin complex is however limited by the long physical half-life of the label, causing a risk of radioactive contamination. It appeared to be possible to label bleomycin with radioactive cations (111In3+, 99mTc4+, 197Hg2+ and 67Cu2+) having suitable gamma ray energies and short half-lifes. These bleomycin complexes showed a high radio-chemical purity judged by their behaviour on thin layer chromatography, paper chromatography, and electrophoresis, but their application as tumor visualizing radiopharmaceutical turned out to be disappointing compared with cobalt-57 bleomycin.

Clinical evaluation of radio-labelled bleomycin for tumor detection.

Investigations with bleomycin labelled with radionuclides other than 57Co in patients with cancer and in tumor-bearing animals are described. In patients 57Co-bleo appears to be a better tumor-seeking radiopharmaceutical than 111In-bleo, 99mTc-bleo or 197Hg-bleo. This can be explained by a higher stability in vivo and a better tumor-seeking property of 57Co-bleo and less disturbing activity in the cardiac pool and in bone and other normal tissues when assessing the scintigram. Results with 111In-bleo labelled in acidic solution are not essentially different from those with 111In-bleo labelled in neutral solution. Results of 197Hg-bleo are almost identical with those of 197HgCl2 regarding the tumor-seeking effect as well as the distribution in normal tissues and organs. Probably the complex of 197Hg to bleomycin is not stable in vivo. The superiority of 57Co-bleo over 99mTc-bleo, 197Hg-bleo and also over 67Cu-bleo is confirmed by experiments on tumor bearing animals. We may conclude that the indication for use of bleomycin as a tumor-seeking pharmaceutical labelled with 111In, 99mTc, 197Hg or 67Cu seems to be very limited.