Priority recommendations for the implementation of patient-reported outcomes in clinical cancer care: a Delphi study.

PURPOSE: The aim of this study was to develop priority recommendations for the service level implementation of patient-reported outcomes (PROs) into clinical cancer care. METHODS: Development of draft guidance statements was informed by a literature review, the Knowledge to Action (KTA) implementation framework, and discussion with PRO experts and cancer survivors. A two-round modified Delphi survey with key stakeholders including cancer survivors, clinical and research experts, and Information Technology specialists was undertaken. Round 1 rated the importance of the statements and round 2 ranked statements in order of priority. RESULTS: Round 1 was completed by 70 participants with round 2 completed by 45 participants. Forty-seven statements were rated in round 2. In round 1, the highest agreement items (>90% agreement) included those that focused on the formation of strong stakeholder partnerships, ensuring ongoing communication within these partnerships, and the use of PROs for improvement and guidance in clinical care. Items ranked as the highest priorities in round 2 included assessment of current staff capabilities and service requirements, mapping of workflows and processes to enable collection, and using collected PROs to guide improved health outcomes. CONCLUSIONS: This stakeholder consultation process has identified key priorities in PRO implementation into clinical cancer care that include clinical relevance, stakeholder engagement, communication, and integration within the existing processes and capabilities. IMPLICATION FOR CANCER SURVIVORS: Routine adoption of PRO collection by clinical cancer services requires multiple implementation steps; of highest priority is strong engagement and communication with key stakeholders including cancer survivors.

Real-world deployment of lateral flow SARS-CoV-2 antigen detection in the emergency department to provide rapid, accurate and safe diagnosis of COVID-19.

BACKGROUND: Point-of-care (POC) SARS-CoV-2 lateral-flow antigen detection (LFD) testing in the emergency department (ED) could inform rapid infection control decisions but requirements for safe deployment have not been fully defined. METHODS: Review of LFD test results, laboratory and POC-RT-PCR results and ED-performance metrics during a two-week high SARS-CoV-2 prevalence period followed by several months of falling prevalence. AIM: Determine whether LFD testing can be safely deployed in ED to provide an effective universal SARS-CoV-2 testing capability. FINDINGS: 93% (345/371) of COVID-19 patients left ED with a virological diagnosis during the 2-week universal LFD evaluation period compared to 77% with targeted POC-RT-PCR deployment alone, on background of approximately one-third having an NHS Track and Trace RT-PCR test-result at presentation. LFD sensitivity and specificity was 70.7% and 99.1% respectively providing a PPV of 97.7% and NPV of 86.4% with disease prevalence of 34.7%. ED discharge-delays (breaches) attributable to COVID-19 fell to 33/3532 (0.94%) compared with the preceding POC-RT-PCR period (107/4114 (2.6%); p=<0.0001). Importantly, LFD testing identified 1 or 2 clinically-unsuspected COVID-19 patients/day. Three clinically-confirmed LFD false positive patients were appropriately triaged based on LFD action-card flowchart, and only 5 of 95 false-negative LFD results were inappropriately admitted to non-COVID-19 areas where no onward-transmission was identified. LFD testing was restricted to asymptomatic patients when disease prevalence fell below 5% and detected 1-3 cases/week. CONCLUSION: Universal SARS-CoV-2 LFD testing can be safely and effectively deployed in ED alongside POC-RT-PCR testing during periods of high and low disease prevalence.

Genetic associations of fatigue and other symptoms following breast cancer treatment: A prospective study.

BACKGROUND: Cancer-related fatigue, mood disturbances, pain and cognitive disturbance are common after adjuvant cancer therapy, but vary considerably between individuals despite common disease features and treatment exposures. A genetic basis for this variability was explored in a prospective cohort. METHODS: Physical and psychological health of women were assessed prospectively following therapy for early stage breast cancer with self-report questionnaires. Participation in a genetic association sub-study was offered. Indices for the key symptom domains of fatigue, pain, depression, anxiety, and neurocognitive difficulties were empirically derived by principal components analysis from end-treatment questionnaires, and then applied longitudinally. Genetic associations were sought with functional single nucleotide polymorphisms (SNPs) in pro- and anti-inflammatory cytokine genes - tumour necrosis factor (TNF)-α (-308 â€‹GG), interferon (IFN)-É£ (+874 â€‹TA), interleukin (IL)-10 (1082 â€‹GA and -592 CA), IL-6 (-174 â€‹GC), IL-1ß (-511 â€‹GA). RESULTS: Questionnaire data was available for 210 participants, of whom 111 participated in the genetic sub-study. As expected, symptom domain scores generally improved over several months following treatment completion. Tumour and adjuvant treatment related factors were unassociated with either severity or duration of the individual symptom domains, but severity of symptoms at end-treatment was strongly associated with duration for each domain (all p â€‹< â€‹0.05). In multivariable analyses, risk genotypes were independently associated with: fatigue with IL-6 -174 â€‹GG/GC and IL-10 -1082 GG; depression and anxiety with IL-10 -1082 AA; neurocognitive disturbance: TNF-α -308 GG; depression IL-1ß (all p â€‹< â€‹0.05). The identified SNPs also had cumulative effects in prolonging the time to recovery from the associated symptom domain. CONCLUSIONS: Genetic factors contribute to the severity and duration of common symptom domains after cancer therapy.

Evaluation of the age-dependent dosing recommendations for the administration of daily tinzaparin in children with thrombosis.

Essentials The once-daily dosing of tinzaparin provides an advantage over other low molecular weight heparins. The recommended age-dependent doses of tinzaparin in children have not previously been validated. Once-daily administration of tinzaparin is a safe and effective treatment of childhood thrombosis. Recommended doses are appropriate but monitoring may be required due to inter-individual variation. SUMMARY: Background The recommended starting doses of tinzaparin for the treatment of thrombosis in children have not previously been validated. There are few data to support the efficacy and safety of once-daily tinzaparin dosing in children with thrombosis. Objectives To investigate the use of tinzaparin for the treatment of childhood thrombosis, and to evaluate the age-dependent dosing recommendations and define outcomes in terms of efficacy and safety. Methods This was a retrospective cohort study of children aged 0 to < 16 years treated for thrombosis at a large teaching hospital in the UK between 2008 and 2015. Medical records were reviewed to evaluate tinzaparin dosing, anti-activated factor X (FXa) levels, and patient outcomes. Results Seventy-nine children were identified as having received tinzaparin. Dosing information was available for 57. Younger children required higher doses to reach a therapeutic level. The therapeutic dose requirement varied within age groups, supporting the use of anti-FXa monitoring. Over a median follow-up of 35 months, there were 13 (16%) bleeding episodes (two major; seven clinically relevant but non-major; and four minor). There were two (3%) recurrent episodes of thrombosis. Children were treated for a median duration of 3 months, and the majority (86%) remained on tinzaparin for the duration of their anticoagulant therapy. Conclusion Once-daily tinzaparin is a safe and effective treatment for childhood thrombosis, with rates of recurrence and bleeding similar to those for other anticoagulants used in children. The recommended starting doses are appropriate, but anti-FXa monitoring may be required, owing to interindividual variability in the therapeutic dose requirement.

Management of metastatic renal cell carcinoma in the era of targeted therapies.

BACKGROUND: Metastatic renal cell cancer is associated with poor prognosis and survival and is resistant to conventional chemotherapy. Therapeutic targeting of molecular pathways for tumour angiogenesis and other specific activation mechanisms offers improved tumour response and prolonged survival. AIMS: To conduct a retrospective audit of metastatic renal cell carcinoma patients treated with targeted therapies. METHODS: Data were extracted from clinical records of patients undergoing targeted treatment between 2005 and 2009 at two hospital sites. Data collected included pathology, systemic therapy class, toxicity and survival. Univariate and multivariate survival analyses were performed. RESULTS: Sixty-one patients were treated with 102 lines of therapy with a median overall survival (OS) of 23 months, median time to failure of first-line treatment (TTF1) of 10 months and median time to failure of second-line treatment (TTF2) of 5.2 months. Time from first diagnosis to treatment >12 months was significantly associated with improved OS, longer TTF1, TTF2 and response to first-line anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGF TKI) therapy. Variables associated with tumour biology, natural history and the systemic inflammatory response were associated with improved OS and TTF1. Development of hypertension was predictive of anti-VEGF TKI outcome. Toxicities were as expected for each drug class. CONCLUSIONS: Survival and toxicity outcomes from two Australian sites are comparable to published data. The adverse event profile differs to conventional chemotherapy. Clinicians caring for patients with metastatic renal cancer will need to become familiar with these toxicities and their management as these agents enter widespread use.

The diet quality of adult women participating in a behavioural weight-loss programme.

BACKGROUND: Diet quality plays an important role in health and has been shown to impact the risk of heart disease and certain cancers. The present study aimed to examine baseline and 16-week follow-up levels of energy intake, energy density and diet quality, as measured by the Healthy Eating Index 2005 (HEI-2005), in overweight and obese women participating in a behavioural weight-loss programme. METHODS: Sixty-six women [mean (SD) age 48.6 (10.8) years; body mass index 31.8 (3.7) kg m(-2) ; 92% Caucasian] completed dietary measures at baseline and follow-up. All participants received a 16-week Internet Behavioural weight-loss programme based on the core of the Diabetes Prevention Program. Dietary intake was measured using the 2005 Block food frequency questionnaire. Diet quality was calculated using the HEI-2005. Paired t-tests were used to determine changes over time. RESULTS: There was a reduction in reported energy intake [7.867 (3.232) MJ versus 5.748 (1.775) MJ, P < 0.001] over the 16 weeks. Participants had an increase in diet quality [HEI score = 53.9 (9.9) versus 57.4 (10.6), P = 0.002] as well as a reduction in energy density [0.0088 (0.0021) MJ g(-1) to 0.0080 (0.0021) MJ g(-1) (P = 0.002)]. All micronutrient intakes decreased over the 16 weeks. CONCLUSIONS: Participation in a 16-week behavioural weight-loss programme significantly improved diet quality and reduced dietary energy density and energy intake in adult women. However, despite the overall increase in diet quality score, there were deficiencies in key micronutrients in the diets of most women at the conclusion of the 16-week study.

A survey of prelicensure pain curricula in health science faculties in Canadian universities.

OBJECTIVE: The present exploratory, descriptive study aimed to determine the designated time for mandatory pain content in curricula of major Canadian universities for students in health science and veterinary programs before being licensed. METHOD: Major Canadian university sites (n=10) were chosen where health science faculties included at least medicine (n=10) and nursing (n=10); many also included dentistry (n=8), pharmacy (n=7), physical therapy (n=8) and/or occupational therapy (n=6). These disciplines provide the largest number of students entering the workforce but are not the only ones contributing to the health professional team. Veterinary programs (n=4) were also surveyed as a comparison. The Pain Education Survey, developed from previous research and piloted, was used to determine total mandatory pain hours. RESULTS: The majority of health science programs (67.5%) were unable to specify designated hours for pain. Only 32.5% respondents could identify specific hours allotted for pain course content and/or additional clinical conferences. The average total time per discipline across all years varied from 13 h to 41 h (range 0 h to 109 h). All veterinary respondents identified mandatory designated pain content time (mean 87 h, range 27 h to 200 h). The proportion allotted to the eight content categories varied, but time was least for pain misbeliefs, assessment and monitoring/follow-up planning. CONCLUSIONS: Only one-third of the present sample could identify time designated for teaching mandatory pain content. Two-thirds reported 'integrated' content that was not quantifiable or able to be determined, which may suggest it is not a priority at that site. Many expressed a need for pain-related curriculum resources.

Domains in ferroelectric nanodots.

Almost free-standing single crystal mesoscale and nanoscale dots of ferroelectric BaTiO(3) have been made by direct focused ion beam patterning of bulk single crystal material. The domain structures which appear in these single crystal dots, after cooling through the Curie temperature, were observed to form into quadrants, with each quadrant consisting of fine 90 degrees stripe domains. The reason that these rather complex domain configurations form is uncertain, but we consider and discuss three possibilities for their genesis: first, that the quadrant features initially form to facilitate field-closure, but then develop 90 degrees shape compensating stripe domains in order to accommodate disclination stresses; second, that they are the result of the impingement of domain packets which nucleate at the sidewalls of the dots forming "Forsbergh" patterns (essentially the result of phase transition kinetics); and third, that 90 degrees domains form to conserve the shape of the nanodot as it is cooled through the Curie temperature but arrange into quadrant packets in order to minimize the energy associated with uncompensated surface charges (thus representing an equilibrium state). While the third model is the preferred one, we note that the second and third models are not mutually exclusive.

Evidence for the role of gonadotropin hormones in the development of Alzheimer disease.

Differences in the prevalence and age of onset of Alzheimer disease (AD) in men and women, and observations that hormone replacement therapy (HRT) may prevent the development of AD, caused many to hypothesize that estrogen deficiency contributes to AD. However, recent trials using estrogen failed to show any benefit in preventing or alleviating the disease. To address this and other inconsistencies in the estrogen hypothesis, we suspect that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone (LH), as a major factor in AD pathogenesis. Individuals with AD have elevated levels of LH when compared with controls, and both LH and its receptor are present in increased quantities in brain regions susceptible to degeneration in AD. LH is also known to be mitogenic, and could therefore initiate the cell cycle abnormalities known to be present in AD-affected neurons. In cell culture, LH increases amyloidogenic processing of amyloid-beta protein precursor, and in animal models of AD, pharmacologic suppression of LH and FSH reduces plaque formation. Given the evidence supporting a pathogenic role for LH in AD, a trial of leuprolide acetate, which suppresses LH release, has been initiated in patients.

Mitotic and gender parallels in Alzheimer disease: therapeutic opportunities.

In this review, we discuss the role of cell cycle dysfunction in the pathogenesis of Alzheimer disease and propose that such mitotic catastrophe, as one of the earliest events in neuronal degeneration, may, in fact, be sufficient to initiate the neurodegenerative cascade. The question as to what molecule initiates cell cycle dysfunction is now beginning to become understood and, in this regard, the gender-predication, age-related penetrance and regional susceptibility of specific neuronal populations led us to consider luteinizing hormone as a key mediator of the abnormal mitotic process. As such, agents targeted toward luteinizing hormone or downstream sequelae may be of great therapeutic value in the treatment of Alzheimer disease.

The regulation of biologic products derived from bioengineered plants.

Recently, there has been a large increase in the number and types of biological products--from therapeutic antibodies to vaccines for the prevention of infectious diseases--that are produced in bioengineered plant systems. We anticipate that this technology will be used increasingly on a commercial scale for the manufacture of human and animal products. These production systems have the capacity to produce very large quantities of products at lower costs and with reduced risks compared with mammalian systems.

Imaging and phase I study of 111In- and 90Y-labeled anti-LewisY monoclonal antibody B3.

B3 is a murine monoclonal antibody (mAb) that recognizes a LewisY carbohydrate antigen present on the surface of many carcinomas. An imaging and Phase I trial was performed to study the ability of 111In-mAb B3 to image known metastasis and determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), kinetics, and biodistribution of 90Y-mAb B3. Patients (n = 26) with advanced epithelial tumors that express the LewisY antigen were entered. All patients received 5 mCi of 111In-mAb B3 for imaging. 90Y-mAb B3 doses were escalated from 5 to 25 mCi in 5-mCi increments. 111In-mAb B3 and 90Y-mAb B3 were coadministered over a 1-h infusion. Definite tumor imaging was observed in 20 of 26 patients. Sites imaged included lung, liver, bone, and soft tissues. The MTD of 90Y-mAb B3 was determined to be 20 mCi. The DLTs were neutropenia and thrombocytopenia. Tumor doses ranged from 7.7 to 65.1 rad/mCi. 111In- and 90Y-mAb B3 serum pharmacokinetics (n = 23) were found to be similar. The amount of B3 administered (5, 10, and 50 mg) did not alter the pharmacokinetics. Bone marrow biopsies (n = 23) showed 0.0038+/-0.0016% of injected dose/gram for 111In-mAb B3 compared to 0.0046+/-0.0017% of injected dose/gram for 90Y-mAb B3 (P = 0.009). When given to patients with carcinomas that express the LewisY antigen, 111In-mAb B3 demonstrated good tumor localization. The MTD of 90Y-mAb B3 is 20 mCi, with myelosuppression as the DLT. Higher doses of radioactivity need to be delivered to achieve an antitumor effect. Humanized mAb B3 is being developed for evaluation in radioimmunotherapy. A clinical trial to explore the use of higher doses of 90Y-mAb B3 with autologous stem cell support is planned.

Endothelin and dopamine release.

Endothelins and endothelin receptors are widespread in the brain. There is increasing evidence that endothelins play a role in brain mechanisms associated with behaviour and neuroendocrine regulation as well as cardiovascular control. We review the evidence for an interaction of endothelin with brain dopaminergic mechanisms. Our work has shown that particularly endothelin-1 and ET(B) receptors are present at significant levels in typical brain dopaminergic regions such as the striatum. Moreover, lesion studies showed that ET(B) receptors are present on dopaminergic neuronal terminals in striatum and studies with local administration of endothelins into the ventral striatum showed that activation of these receptors causes dopamine release, as measured both with in vivo voltammetry and behavioural methods. While several previous studies have focussed on the possible role of very high levels of endothelins in ischemic and pathological mechanisms in the brain, possibly mediated by ET(A) receptors, we propose that physiological levels of these peptides play an important role in normal brain function, at least partly by interacting with dopamine release through ET(B) receptors.

Maternal infant-feeding decisions: reasons and influences.

The purpose of this prospective longitudinal study was to determine the reasons for and influences on mothers' infant-feeding decisions over the 6 months post-birth. The breastfeeding initiation rate of 41.7% had declined to 11.4% at 6 months. The major reasons for not choosing breastfeeding were embarrassment and discomfort with the idea. Younger, less-educated mothers with lower incomes were less likely to start breastfeeding, more likely to discontinue breastfeeding early, and more likely to feed their babies cheaper evaporated milks. Mothers gave up breastfeeding early because it was too difficult or because they were returning to work. Reasons given by both breastfeeding and bottle-feeding mothers for switching milks were that the baby was "not satisfied" on the milk or that it was "not agreeing with" the baby. Generally, the social network, rather then health professionals, had greater influence on mothers' decisions.

Endothelin induces dopamine release from rat striatum via endothelin-B receptors.

The aim of the present study was to determine whether local administration of endothelin induces the release of dopamine in the rat striatum and to characterize and localize endothelin receptors in this brain region. Local injection of endothelin-1 (10 pmol) into the ventral striatum of urethane-anaesthetized rats caused an increase of 8 microM in the extracellular concentration of dopamine as measured by in vivo chronoamperometry. The peak increase in dopamine concentration occurred within 5 min of endothelin injection. Injection of the selective endothelin-B receptor agonist [Ala1.3,11.15]endothelin-1 (10 pmol) also caused an increase in extracellular dopamine concentration, suggesting that endothelin is acting at the endothelin-B receptor to elicit its effect. In rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway, the response to local injection of endothelin-1 (10 pmol) was significantly inhibited on the lesioned side as compared to the non-lesioned side. In contrast, pretreatment of the rats with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate (5 mg/kg, i.p.) or the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 mg/kg, i.p.) did not alter the endothelin-induced release of dopamine. In binding studies, addition of endothelin-1 displaced [125I]endothelin-1 with a Ki of 220 pM. The endothelin-B receptor antagonist BQ788 displaced [125I]endothelin-1 with a Ki of 120 nM, whereas the endothelin-A receptor antagonist BQ123 produced only a 25% displacement at 10 microM, suggesting that endothelin receptors in the striatum are of the endothelin-B subtype. In rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine system, [125I]endothelin-1 binding was reduced by 53% in lesioned striatum compared to non-lesioned striatum, with no difference in the Kd. These data provide evidence that endothelin acts on a homogeneous population of endothelin-B receptors within the striatum to cause the release of dopamine and that a significant proportion of these receptors is located on dopaminergic neurons.

Endothelin interactions with brain dopamine systems.

We examined the interactions of endothelin (ET) with dopaminergic systems in rat brain. Using HPLC and radioimmunoassay, we found that striatum contained the highest levels of predominantly ET-1, whereas highest levels of predominantly ET-3 were found in the pituitary. Dopamine depletion in the striatum did not change the levels of immunoreactive ET, even though we have previously found a decrease in the density of ET receptors. In a comparison of spontaneously hypertensive rats (SHR) with Wistar-Kyoto (WKY) rats, ET levels were lower in cerebellum and medulla, with no difference in striatum or in other brain areas. In conclusion, ET is present in high levels in striatum, but these levels are not affected by dopamine depletion or in SHR.

Biodistribution and catabolism of Ga-67-labeled anti-Tac dsFv fragment.

The disulfide-linked fragment (dsFv) of the antibody to the alpha subunit of the IL2 receptor has been radiolabeled with a [Ga-67] Ga-2-(p-SCN-Bz)-NOTA derivative linked through an isothiocyanato group to either the epsilon-amino group of lysine or the alpha-amino group of the N-terminal amino acids. This low molecular weight protein (LMWP) has been proposed as a tumor diagnostic agent. However, > 60% of the injected dose localized in the mouse kidney. The major catabolites (> 95%) in the kidney were identified as the Ga-2-(p-SCN-Bz)-NOTA conjugate with either lysine or methionine, with no evidence of transchelation of Ga-67. Since different amino acids in the dsFv were radiolabeled according to this procedure, it was possible to study the relative residence times of the various catabolites. The methionine conjugate had a significantly shorter residence time than the lysine conjugate in the same kidney. Labeling the appropriate amino acid in a LMWP may lead to reduced residence times and increased diagnostic or therapeutic ratios.

Cloning and expression of the recombinant FAb fragment of monoclonal antibody K1 that reacts with mesothelin present on mesotheliomas and ovarian cancers.

The monoclonal antibody (MAb) K1 recognizes an approximate 40 kDa glycoprotein, mesothelin, that is present on the surface of human mesothelial cells, mesotheliomas and ovarian cancers. We have cloned the cDNAs encoding the variable regions of MAb K1 and constructed plasmids for expression of recombinant K1(FAb). Recombinant FAb was produced in Escherichia coli in inclusion bodies that were solubilized and refolded to active protein. Binding of K1 MAb and FAb was compared by radioactive binding and competition assays and by surface plasmon resonance (BIAcore). Recombinant K1(FAb) binds to cells expressing K1-antigen with a similar affinity as papain derived FAb from K1(IgG) and with a 4- to 10-fold reduced affinity compared with bivalent IgG. The cloned FAb can be used to make higher affinity antibodies and immunoconjugates that could be useful for various types of immunotherapies.

Improved biodistribution of 125I-labeled anti-Tac disulfide-stabilized Fv fragment by blocking its binding to the alpha subunit of the interleukin 2 receptor in the circulation with preinjected humanized anti-Tac IgG.

Animal studies using radiolabeled anti-Tac disulfide-stabilized Fv (dsFv) monoclonal antibody have shown formation of complexes in serum with the soluble alpha subunit of the interleukin 2 receptor alpha (sIL-2R alpha). In this study, we improved the targeting of 125I-labeled anti-Tac dsFv to receptor-positive tumors in the presence of circulating receptor by preinjecting unlabeled humanized anti-Tac IgG antibody (HuTac IgG). We used mice bearing SP2/Tac tumor xenografts that express the IL-2R alpha. A positive correlation was seen between tumor size and the concentration of circulating receptor. Tumor-bearing mice were injected with 125I-labeled anti-Tac dsFv (400 ng), either alone or 15 min after injection of HuTac IgG. The 125I-labeled anti-Tac dsFv formed high molecular weight complexes with the sIL-2R alpha. The fraction of the dsFv present in the complexes increased as tumor size increased (greater sIL-2R alpha levels). The fractions of dsFv in the complexes were 9.9- to 11.6-fold higher when sIL-2R alpha was not blocked with preinjected HuTac IgG. The administration of a 12-fold molar excess of HuTac IgG over sIL-2R alpha resulted in >80% of the 125I activity present as the dsFv rather than in the complexes. Furthermore, the biodistribution of 125I-labeled anti-Tac dsFv was improved by blocking its binding to sIL-2R alpha by preinjecting HuTac IgG. Specifically, in the preinjected group, at 15 min postinjection, the 125I-labeled anti-Tac dsFv levels in tumor increased to 10.8% compared to 5.6% injected dose per gram in the non-preinjected group. In summary, our studies showed that preinjection of HuTac IgG can block the formation of complexes of circulating sIL-2R alpha and 125I-labeled anti-Tac dsFv. This blockade is associated with faster blood clearance, higher tumor uptake, and greater tumor:nontumor ratios of the radiolabeled antibody fragment.

Technetium-99m labeling and biodistribution of anti-TAC disulfide-stabilized Fv fragment.

UNLABELLED: We used a preformed 99mTc chelate approach to label a genetically engineered disulfide-bonded Fv fragment of anti-Tac monoclonal antibody (dsFv). The biodistribution of this 99mTc-labeled dsFv was evaluated in athymic mice with IL-2 alpha-receptor-positive ATAC4 tumor xenografts. METHODS: Benzoylmercaptoacetyl-triglycine (BzMAG3) was first labeled with 99mTc, and the carboxy group of 99mTc-MAG3 was then activated to the corresponding tetrafluorophenyl ester. This activated ester was purified with a Sep-Pak C18 column and conjugated to dsFv. The resulting 99mTc-MAG3-dsFv was purified with PD-10 size-exclusion chromatography. The immunoreactivity of 99mTc-MAG3-dsFv was 76% +/- 9%. When incubated in serum at 37 degrees C for 24 hr, there was no appreciable dissociation of 99mTc. The mice were co-injected with 125I-dsFv labeled by the Iodo-Gen method as a control. The mice were killed at 15 to 720 min for analysis of biodistribution and radiocatabolites. RESULTS: The tumor uptake of 99mTc-MAG3-dsFv was similar to that of 125I-dsFv. The tumor uptake of 99mTc-MAG3-dsFv was rapid with tumor-to-blood or tumor-to-organ ratio higher than 1 for all organs except the kidneys. The peak tumor value of 5.1% injected dose per gram was obtained at 45 min, and the tumor-to-organ ratios increased steadily over time; a ratio of 15, 11, 7, 95 and 0.10 resulted at 6 hr for blood, liver, stomach, muscle and kidney. The radioactivity was primarily excreted through kidneys. CONCLUSION: The rapid achievement of high tumor-to-blood and -tissue ratios makes 99mTc-MAG3-dsFv a promising agent for scintigraphic detection of various hematological malignancies that express IL-2 alpha receptors.