Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety.

Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates' capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.

Feasibility of a Composite Measure of Pulmonary Vascular Impedance and Application to Patients with Chronic RV Failure Post LVAD Implant.

Pulmonary vascular impedance (PVZ) describes RV afterload in the frequency domain and has not been studied extensively in LVAD patients. We sought to determine (1) feasibility of calculating a composite (c)PVZ using standard of care (SoC), asynchronous, pulmonary artery pressure (PAP) and flow (PAQ) waveforms; and (2) if chronic right ventricular failure (RVF) post-LVAD implant was associated with changes in perioperative cPVZ.PAP and PAQ were obtained via SoC procedures at three landmarks: T(1), Retrospectively, pre-operative with patient conscious; and T(2) and T(3), prospectively with patient anesthetized, and either pre-sternotomy or chest open with LVAD, respectively. Additional PAP's were taken at T(4), following chest closure; and T(5), 4-24 h post chest closure. Harmonics (z) were calculated by Fast Fourier Transform (FFT) with cPVZ(z) = FFT(PAP)/FFT(PAQ). Total pulmonary resistance Z(0); characteristic impedance Zc, mean of cPVZ(2-4); and vascular stiffness PVS, sum of cPVZ(1,2), were compared at T(1,2,3) between +/-RVF groups.Out of 51 patients, nine experienced RVF. Standard hemodynamics and changes in cPVZ-derived parameters were not significant between groups at any T.In conclusion, cPVZ calculated from SoC measures is possible. Although data that could be obtained were limited it suggests no difference in RV afterload for RVF patients post-implant. If confirmed in larger studies, focus should be placed on cardiac function in these subjects.

Quantitative genetics of costly neonatal sexual size dimorphism in squirrel monkeys (Saimiri boliviensis).

Offspring size is often an intimate link between the fitness of parents and offspring. Among mammals, neonate mass is also related to adult levels of dimorphism and intrasexual competitive mating. We describe the sex-specific genetic architecture of neonate mass in captive squirrel monkeys (Saimiri boliviensis), a small Neotropical primate. Best fitting quantitative genetic models show strong maternal genetic effects with little difference between sexes offering limited opportunity for neonatal dimorphism to respond to observed or hypothetical selection. Heritabilities that are approximately zero also imply it is unlikely that neonatal dimorphism can evolve as a correlated response to selection on adult size. However, male mass is also more dependent on maternal condition (age and parity) making dimorphism plastic. Finally, we hypothesize that large maternal genetic effects reflect income breeding and tightly synchronized seasonal reproduction in squirrel monkeys, both of which require strong maternal control of offspring growth and timing of birth.

Changing epidemiology of methicillin-resistant Staphylococcus aureus colonization in paediatric intensive-care units.

Community-associated methicillin-resistant S. aureus (CA-MRSA) accounts for a growing proportion of hospital-onset infections, and colonization is a risk factor. This study aimed to determine changes in the prevalence of CA-MRSA colonization in paediatric intensive-care units (ICUs). A total of 495 paediatric patients colonized with MRSA from neonatal, medical, surgical, and cardiac ICUs between 2001 and 2009 were identified. Isolates were characterized by spa type, staphylococcal cassette chromosome (SCC) mec type and the presence of the genes encoding Panton­Valentine leukocidin (PVL). The proportion of patients colonized with MRSA remained stable (average 3·2%). The proportion of isolates with spa type 1, SCCmec type IV and PVL increased over time to maximums in 2009 of 36·1% (P < 0·001), 54·2% (P = 0·03) and 28·9% (P = 0·003), respectively. Antibiotic susceptibility patterns showed increasing proportions susceptible to clindamycin, gentamicin, tetracycline and trimethoprim-sulfamethoxazole (P values <0·001). In conclusion, the proportion of MRSA-colonized children in ICUs with CA-MRSA increased significantly over time.

Incidental Findings from 16,400 Brain MRI Examinations of Research Volunteers.

BACKGROUND AND PURPOSE: Incidental findings are discovered in neuroimaging research, ranging from trivial to life-threatening. We describe the prevalence and characteristics of incidental findings from 16,400 research brain MRIs, comparing spontaneous detection by nonradiology scanning staff versus formal neuroradiologist interpretation. MATERIALS AND METHODS: We prospectively collected 16,400 brain MRIs (7782 males, 8618 females; younger than 1 to 94 years of age; median age, 38 years) under an institutional review board directive intended to identify clinically relevant incidental findings. The study population included 13,150 presumed healthy volunteers and 3250 individuals with known neurologic diagnoses. Scanning staff were asked to flag concerning imaging findings seen during the scan session, and neuroradiologists produced structured reports after reviewing every scan. RESULTS: Neuroradiologists reported 13,593/16,400 (83%) scans as having normal findings, 2193/16,400 (13.3%) with abnormal findings without follow-up recommended, and 614/16,400 (3.7%) with "abnormal findings with follow-up recommended." The most common abnormalities prompting follow-up were vascular (263/614, 43%), neoplastic (130/614, 21%), and congenital (92/614, 15%). Volunteers older than 65 years of age were significantly more likely to have scans with abnormal findings (P < .001); however, among all volunteers with incidental findings, those younger than 65 years of age were more likely to be recommended for follow-up. Nonradiologists flagged <1% of MRIs containing at least 1 abnormality reported by the neuroradiologists to be concerning enough to warrant further evaluation. CONCLUSIONS: Four percent of individuals who undergo research brain MRIs have an incidental, potentially clinically significant finding. Routine neuroradiologist review of all scans yields a much higher rate of significant lesion detection than selective referral from nonradiologists who perform the examinations. Workflow and scan review processes need to be carefully considered when designing research protocols.

Functional hydraulic sectoring in grapevines as evidenced by sap flow, dye infusion, leaf removal and micro-computed tomography.

The supply of water to a plant canopy is dependent on the xylem pathway connecting roots to leaves. In some plants, sectored xylem pathways can restrict resource distribution, resulting in variable quality of organs in the shoots, yet little is known about the effects of sectoring in crop cultivars. In this study, we combined sap flow measurements and infusion of xylem-specific dyes to document functional conductive area and flow pathways from roots to shoots of 20-year-old Thompson Seedless and 8-year-old Chardonnay grapevines. Sap flow measurements and dye infusion demonstrated that water flowed predominantly in discrete xylem (visually identifiable from the trunk surface) sectors along the trunk axis, each supplying limited portions of the canopy. Functional conductive area in the trunk was proportional to that in the shoots even though sector size varied considerably between vines. Leaf area removal experiments further demonstrated sectoring in grapevines; sap flow decreased by >90 % in trunk sectors connected to excised shoots while it remained constant in trunk sectors supplying intact portions of the canopy. Despite the functional sectoring in grapevines, a high degree of interconnectivity of trunk xylem in the tangential direction was confirmed with synchrotron-based micro-computed tomography (microCT) and dye crossover infusion studies. Fruit attached to dyed canes was also similarly sectored; no clusters exhibited dye on non-dyed canes, while 97 % of clusters attached to dyed canes exhibited dye infusion. The dye travelled down the cluster rachis and appeared to accumulate at the pedicel/berry junction, but only on dyed canes. These findings suggest that xylem in grapevine trunks is integrated anatomically, but functions in a sectored manner due to high axial hydraulic conductivity. The functional sectoring of grapevine xylem documented here has important implications for management practices in vineyards and for fruit cluster uniformity within single grapevine.

Pattern of maternal circulating CRH in laboratory-housed squirrel and owl monkeys.

The anthropoid primate placenta appears to be unique in producing corticotropin-releasing hormone (CRH). Placental CRH is involved in an endocrine circuit key to the production of estrogens during pregnancy. CRH induces cortisol production by the maternal and fetal adrenal glands, leading to further placental CRH production. CRH also stimulates the fetal adrenal glands to produce dehydroepiandrostendione sulfate (DHEAS), which the placenta converts into estrogens. There are at least two patterns of maternal circulating CRH across gestation among anthropoids. Monkeys examined to date (Papio and Callithrix) have an early-to-mid gestational peak of circulating CRH, followed by a steady decline to a plateau level, with a possible rise near parturition. In contrast, humans and great apes have an exponential rise in circulating CRH peaking at parturition. To further document and compare patterns of maternal circulating CRH in anthropoid primates, we collected monthly blood samples from 14 squirrel monkeys (Saimiri boliviensis) and ten owl monkeys (Aotus nancymaae) during pregnancy. CRH immunoreactivity was measured from extracted plasma by using solid-phase radioimmunoassay. Both squirrel and owl monkeys displayed a mid-gestational peak in circulating CRH: days 45-65 of the 152-day gestation for squirrel monkeys (mean±SEM CRH=2,694±276 pg/ml) and days 60-80 of the 133-day gestation for owl monkeys (9,871±974 pg/ml). In squirrel monkeys, circulating CRH declined to 36% of mean peak value by 2 weeks before parturition and then appeared to increase; the best model for circulating CRH over gestation in squirrel monkeys was a cubic function, similar to previous results for baboons and marmosets. In owl monkeys, circulating CRH appeared to reach plateau with no subsequent significant decline approaching parturition, although a cubic function was the best fit. This study provides additional evidence for a mid-gestational peak of maternal circulating CRH in ancestral anthropoids that has been lost in the hominoid lineage.

Liposomal blockade of the reticuloendothelial system: improved tumor imaging with small unilamellar vesicles.

The reticuloendothelial system of mice bearing EMT6 tumors was effectively blocked by intravenous injections of small unilamellar vesicles that incorporated a 6-aminomannose derivative of cholesterol in the lipid bilayer. Neutral liposomes loaded with indium-111-nitrilotriacetic acid were then injected. Fifty percent more radioactivity was deposited in tumors of the animals with blocked reticuloendothelial systems than in controls. Twenty-four hours after the injection of radioactive vesicles, well-defined tumor images were observed in whole-body gamma camera scintigraphs. Biodistribution studies showed that tumors from animals with blocked reticuloendothelial systems had more than twice the radioactivity per gram than any other tissue analyzed.

Post-stroke tactile allodynia and its modulation by vestibular stimulation: a MEG case study.

BACKGROUND: There is behavioural evidence that caloric vestibular stimulation (CVS) can alleviate central pain. Several such patients have also noted that it reduces tactile allodynia, an especially ill-understood phenomenon in these patients. AIMS OF THE STUDY: The first aim is to use magnetoencephalography (MEG) to study neural activity associated with tactile allodynia in central post-stroke pain (CPSP). The second is to assess how this would be affected, if at all, by CVS. The third is to assess the ability of the VESTAL solution for MEG to detect anterior cingulate activation. METHODS: A 58-year-old woman with CPSP, and marked unilateral tactile allodynia, participated in a MEG study with imaging pre- and post-CVS. RESULTS: Tactile simulation within the patient's allodynic area resulted in contralateral activation of the primary motor and anterior cingulate cortices, which had normalized 24 h post-CVS. CONCLUSIONS: We suggest that the unexpected primary motor cortex activation in response to light touch in the allodynic area arises from inappropriate activation of a normal mechanism, which may occur when a threat to homeostasis is present, to lower motor thresholds and allow for more rapid performance of corrective actions. We propose this may be mediated by the interoceptive cortex in the dorsal posterior insula.

Adverse effects of concurrent carboplatin chemotherapy and radiation therapy in dogs.

BACKGROUND: Concurrent chemo- and radiotherapy improves outcome of certain human neoplasms but with increased signs of toxicity. Reports on adverse effects of concurrent chemo- and radiotherapy in the veterinary literature are scant. OBJECTIVE: To report adverse hematologic and gastrointestinal effects of combined carboplatin and radiation therapy in dogs. ANIMALS: Client-owned dogs with spontaneously occurring neoplasia. METHODS: Retrospective case study. Medical records of 65 dogs were reviewed. Criteria for inclusion were administration of radiation according to 1 of 3 fractionation schemes (19 x 3, 16 x 3, or 12 x 4 Gy) and administration of at least 1 concurrent carboplatin treatment at a dosage of 200-300 mg/m(2). Dog and treatment-related variables were analyzed for association with signs of intoxication. RESULTS: Median carboplatin dosage was 200 mg/m(2) (range, 200-250 mg/m(2)). Twelve of 58 dogs (21%) developed grade 3 or 4 neutropenia. Eleven of 56 dogs (20%) developed grade 3 or 4 thrombocytopenia. Six of 62 dogs (10%) developed grade 3, 4, or 5 gastrointestinal toxicosis. Analysis of association of dog and treatment-related variables with signs of intoxication was hampered by the small numbers of dogs in individual groups, and no statistically significant associations were found. CONCLUSIONS AND CLINICAL IMPORTANCE: Combined modality therapy resulted in myelosuppression and gastrointestinal toxicosis. Future studies are needed to determine whether the potential benefit of combined modality therapy outweighs the risk of decreasing chemotherapy and radiation treatment intensity.

Sequencing of the von Hippel-Lindau gene in canine renal carcinoma.

BACKGROUND: Similarities in human and canine renal cell carcinoma (RCC) epidemiology and biologic behavior suggest that molecular mechanisms of tumorigenesis may be similar in both species. Approximately 75% of RCC in people are of the clear cell subtype, up to 85% of which are associated with mutation of the von Hippel-Lindau (VHL) gene. The canine VHL coding deoxyribonucleic acid (DNA) shares 90% identity with the human VHL gene. OBJECTIVE: To determine whether or not RCC in dogs are associated with VHL mutations, and if so determine the prevalence, type, and location of these mutations. ANIMALS: Thirteen dogs with RCC, 2 dogs with primary renal sarcomas, and 10 dogs without neoplastic kidney disease. METHODS: DNA was extracted from paraffin-embedded RCC tissue; DNA extracts from paraffin-embedded and snap-frozen nonneoplastic canine kidneys and canine whole blood were used as negative controls. Polymerase chain reaction and sequencing of the 3 VHL exons was performed, and results compared with the accessioned canine sequence. RESULTS: All VHL exons were amplified from 9 of 13 canine RCC samples, both renal sarcomas, 8 of 10 nonneoplastic kidney samples, and canine whole blood; only exon 2 could be amplified from 2 RCC samples. Mutations were not identified in any exons. A maximal prevalence of 33.6% for VHL mutations in canine RCC was determined. CONCLUSION AND CLINICAL IMPORTANCE: Although similarities between canine and human RCC merit further investigation of the dog as a model for some subtypes of renal tumors, the lower prevalence of VHL mutations suggests that oncogenesis in these 2 species differs.

Behavioural evidence for vestibular stimulation as a treatment for central post-stroke pain.

BACKGROUND: Central post-stroke pain (CPSP) is often resistant to treatment. We have previously proposed that caloric vestibular stimulation might alleviate it. METHODS: We conducted a single blind placebo controlled investigational study of caloric vestibular stimulation (CVS) in nine patients with CPSP. Participants rated their pain levels before and after the procedure on a 10 point scale. RESULTS: We found a significant immediate treatment effect of the cold water caloric stimulation with an average pain reduction of 2.58 points (SEM 0.52) for the experimental condition compared with 0.54 points (SEM 0.49) for the placebo conditions. CONCLUSIONS: Participants who responded best to CVS had suffered strokes that spared and permitted activation of the dominant parieto-insular vestibular cortex (PIVC), which is known to be located in the non-dominant hemisphere. These findings tie in closely with the thermosensory disinhibition hypothesis for central pain, which leads us to propose that vestibular stimulation may alleviate CPSP from cross activation between the PIVC and the thermosensory cortex in the adjacent dorsal posterior insula. Alternatively, if one views vestibular function and thermoregulation as part of a larger interoceptive system that exists to maintain homeostasis, then it is possible they share a common integrative mechanism in the brainstem, which may act to reset the balance in central pain.

Bartonella DNA in the blood and lymph nodes of Golden Retrievers with lymphoma and in healthy controls.

BACKGROUND: Although lymphoma is the most common neoplastic process reported in dogs, its precise etiology is unknown. Golden Retrievers are more likely to develop lymphoma, suggesting a breed predisposition; however, other factors, including environment, immunity, and infection, are likely contributors to oncogenesis. HYPOTHESIS: We hypothesized that the development of lymphoma in Golden Retrievers may be associated with vector-borne infections, specifically Bartonella, Anaplasma, or Ehrlichia species infections. ANIMALS: Golden Retrievers with lymphoma and healthy Golden Retrievers from across the United States were recruited for study participation. METHODS: A matched, case-control study was performed to determine the association of lymphoma and the presence of Bartonella, Anaplasma, and Ehrlichia species in serum, blood, and lymph node aspirates. RESULTS: Using PCR analyses and DNA sequencing, single and coinfections with Bartonella henselae, Bartonella elizabethae, Bartonella quintana, and/or Bartonella vinsonii (berkhoffii) were detected in the blood and lymph node aspirates of Golden Retrievers with lymphoma (5/28 dogs, 18%) and in healthy Golden Retrievers (10/56 dogs, 18%); no Anaplasma or Ehrlichia DNA was detected in any dog. When compared with dogs with lymphoma, a higher (P <.001) proportion of healthy Golden Retrievers were receiving monthly acaricide treatments (2.6 times higher). CONCLUSIONS AND CLINICAL IMPORTANCE: Bartonella DNA can be detected in blood and lymph nodes; importantly, in this report, Bartonella was detected in the same proportion of clinically healthy dogs and dogs with lymphoma. Longitudinal studies should be conducted to determine the mode of transmission of Bartonella in dogs, whether lymphatic infection is persistent, or whether these bacteria may contribute to the development of lymphoma.

Canine acute leukaemia: 50 cases (1989-2014).

Acute leukaemia (AL) is a bone marrow malignancy of hematopoietic progenitors that historically is poorly responsive to treatment. With the widespread adoption of dose-intense chemotherapy, more human patients attain long-term survivals, but whether comparable progress has been made in canine AL is unknown. To investigate this question, medical records from three academic veterinary hospitals were reviewed. Fifty dogs met the criteria for AL, having excess circulating or marrow blasts, a major cytopenia(s), and no substantial lymphadenopathy. Thirty-six dogs received cytotoxic chemotherapy; 23 achieved a complete or partial response for a median of 56 days (range, 9-218). With failure or relapse, 14 dogs were rescued. Median survival with treatment was poor at 55 days (range, 1-300). Untreated (n = 6) and palliatively-treated (n = 8) dogs lived a median of 7.5 days. Most dogs developed chemoresistance within weeks of initiating treatment, and consequently, survival times for AL remain disappointingly short.

Sugar transporters in higher plants--a diversity of roles and complex regulation.

Sugar-transport proteins play a crucial role in the cell-to-cell and long-distance distribution of sugars throughout the plant. In the past decade, genes encoding sugar transporters (or carriers) have been identified, functionally expressed in heterologous systems, and studied with respect to their spatial and temporal expression. Higher plants possess two distinct families of sugar carriers: the disaccharide transporters that primarily catalyse sucrose transport and the monosaccharide transporters that mediate the transport of a variable range of monosaccharides. The tissue and cellular expression pattern of the respective genes indicates their specific and sometimes unique physiological tasks. Some play a purely nutritional role and supply sugars to cells for growth and development, whereas others are involved in generating osmotic gradients required to drive mass flow or movement. Intriguingly, some carriers might be involved in signalling. Various levels of control regulate these sugar transporters during plant development and when the normal environment is perturbed. This article focuses on members of the monosaccharide transporter and disaccharide transporter families, providing details about their structure, function and regulation. The tissue and cellular distribution of these sugar transporters suggests that they have interesting physiological roles.

High-specific-activity 111In-labeled anticarcinoembryonic antigen monoclonal antibody: improved method for the synthesis of diethylenetriaminepentaacetic acid conjugates.

A new method has been developed for conjugating diethylenetriaminepentaacetic acid (DTPA) to proteins using the N-hydroxysuccinimide active ester of DTPA. The DTPA-active ester was prepared using diisopropylcarbodiimide in a simple single step synthesis. DTPA-conjugated proteins were prepared by adding the DTPA-active ester reaction mixture to protein solutions (5 mg/ml) buffered at pH 7.0 and purified by Sephadex G-50 chromatography. A monoclonal antibody directed against carcinoembryonic antigen was reacted with four different amounts of the DTPA-active ester. Solid-phase enzyme immunoassay showed that the immunological activity of the antibody conjugate was not altered when the active ester: antibody molar ratio was 36:1 or 72:1; however, it decreased when the ratio was 180:1 or 360:1. The antibody heavy and light chains had slightly decreased electrophoretic mobilities when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a result consistent with the covalent attachment of DTPA to the protein. Sephadex G-200 chromatography showed that the native and conjugated antibodies were the same size. When the DTPA-conjugated antibody was incubated with 10, 50, and 100 microCi of 111In/micrograms of protein, specific activities of 9.8, 43.1, and 56.3 microCi/micrograms were obtained. Enzyme immunoassay and radioimmunoassay of the 111In-labeled antibody showed that it retained its full immunological activity. The high specific activity of the 111In-labeled antibody makes it suitable for imaging carcinoembryonic antigen-bearing tumors using low doses of antibody.

High-specific-activity 111In-labeled anticarcinoembryonic antigen monoclonal antibody: biodistribution and imaging in nude mice bearing human colon cancer xenografts.

Tumor imaging and biodistribution of an indium-labeled monoclonal antibody (MAB) to carcinoembryonic antigen (CEA) [anti-CEA MAB-diethylenetriaminepentaacetic acid (DTPA)-111In] have been investigated using LS174T human colon cancer xenografts in nude mice. Antibody specificity, dose, and specific activity were examined with respect to tumor uptake and quality of scintiscans at different times following injection. The CEA-bearing LS174T tumors were imaged specifically with anti-CEA MAB-DTPA-111In. Using 62.5 ng of indium-labeled MAB (50 microCi/micrograms) the ratio of activity in tissue expressed as a percentage of the total radioactive dose injected into the animal per gram tissue for tumor:blood increased from 0.66 +/- 0.02 (SE) at 1 h to 14.8 +/- 1.1 at 72 h. Scintiscan quality improved with the rise in tumor:blood ratio until 48 h. At longer intervals insufficient counts remained for imaging. The tumor:blood ratio and the scintiscan quality were not improved by increasing the MAB dose to 625 or 6250 ng but good images were obtained at longer times postinjection. By decreasing the 111In from 50 to 10 microCi/micrograms of MAB, the unbound 111In was decreased from 7 microCi/micrograms (14%) to 0.2 microCi/micrograms (2%). Even with the lower specific activity (9.8 microCi/micrograms) of the 10-microCi/micrograms preparation, scintiscan quality at the 62.5-ng dose was maintained. This anti-CEA MAB-DTPA-111In preparation was stable, retained immunological activity, did not require column chromatography to remove unbound 111In, was specific for a CEA-bearing tumor, and was effective for tumor imaging over a wide range of antibody doses (3 to 300 micrograms MAB/kg body weight). This anti-CEA MAB-DTPA-111In preparation is feasible and practical for imaging CEA-bearing tumors in humans.

Estimation of monoclonal antibody-associated 90Y activity needed to achieve certain tumor radiation doses in colorectal cancer patients.

In these measurements, we quantitated, via surgical samples, human primary tumor uptake of the anti-carcinoembryonic antigen monoclonal antibody T84.66. Uptake was measured in units of percentage of injected dose/kg with 111In as the radiolabel. All 11 colorectal lesions were nonnecrotic and were visualized upon scanning. Tumor volume was calculated using the three orthogonal dimensions as described by pathology. Uptake mean +/- SD was 6.55 +/- 3.55% injected dose/kg with a range of 1.2 to 10.4% injected dose/kg. Lesion mean volume was 36 cm3 with a range of 1.5 to 304 cm3. Using mean values, assuming no biological clearance and that the biodistribution of the monoclonal is independent of its radiolabel, the predicted human tumor 90Y beta dose was 0.12 Gy/mCi. Therefore a 10-Gy tumor dose would require 83 mCi of i.v. activity. Using least and highest uptake results, requisite activity values were 3-fold larger and smaller respectively. Thus, there was approximately an order of magnitude variation in the amount of 90Y predicted to achieve a given tumor dose in colorectal cancer patients. Murine and human uptake values were consistent if lesion mass and carcinoembryonic antigen content were taken into account.

Presurgical imaging with indium-labeled anti-carcinoembryonic antigen for colon cancer staging.

Over a 4-year period, 108 patients with known or suspected colorectal cancer were studied by radioimmunoconjugate scintigraphy prior to operative procedures. Study subjects received 0.2 to 40 mg i.v. of murine anti-carcinoembryonic antigen monoclonal antibody labeled with 2-5 mCi of 111In (Indacea). Resected tissues were analyzed for 111In and carcinoembryonic antigen content. Tumor, liver, and draining lymph nodes had over 10% injected dose/kg compared to less than 2.5% injected dose/kg for other normal tissues. Primary tumors that were successfully imaged were significantly larger and had higher 111In and carcinoembryonic antigen content. In 54 patients, primary tumors were visualized with a sensitivity of 78%. Hepatic metastases (58 patients) were visualized as negative filling defects (sensitivity, 45%). Extrahepatic (intraabdominal) metastases (25 patients) were visualized (sensitivity, 48%) as areas of increased uptake. Extraabdominal metastases were uncommon (10 patients; sensitivity, 80%). Of 56 patients with known or suspected hepatic metastases who presented with no evidence of extrahepatic disease by conventional tests (X-ray, computerized tomographic scan), 20 (36%) were documented to have extrahepatic metastases at exploratory surgery and 10 of these (50%) had the extrahepatic disease localized by the Indacea scan. The management of these 10 patients was, or could have been, modified by the scan findings and unnecessary surgery eliminated.