Transgenic avian-derived recombinant human interferon-alpha2b (AVI-005) in healthy subjects: an open-label, single-dose, controlled study.

BACKGROUND/AIMS: This study characterized the safety and pharmacological properties of AVI-005, a novel glycosylated recombinant human interferon-alpha2b produced from the egg whites of chickens transfected with human cDNA. METHODS: 18 healthy volunteers received single subcutaneous rising doses (0.5, 1.66 or 5 million international units, MIU) of AVI-005. A randomized parallel comparator group of 10 subjects received 5 MIU of unglycosylated IFN-alpha2b (Intron A). The pharmacokinetic parameters t1/2, tmax, Cmax, AUC0-24h, Vd, and clearance were compared between AVI-005 and unglycosylated IFN-alpa2b. RESULTS: At equipotent doses, AVI-005 had a larger AUC0-24h than the control interferon. Pharmacodynamic markers ofneopterin and beta2-microglobulin for the two treatments were similar. These markers were increased by AVI-005 in a dose-dependent manner. Pharmacodynamic responses to treatment with AVI-005 were shown by the change in mRNA expression for interferon inducible protein kinase and 2'5'-oligoadenylate synthetase. Adverse events in the two groups were qualitatively and quantitatively similar. CONCLUSION: AVI-005 demonstrates biological activity and pharmaco-kinetic properties in humans that support further development.

Quantitative measures of disease in broiler breeder chicks of different major histocompatibility complex genotypes after challenge with infectious bursal disease virus.

Criteria for evaluating genetic differences in resistance and susceptibility to infectious bursal disease (IBD) within a commercial broiler breeder line of chickens were compared. Line A broiler breeder chickens were challenged with graded doses of Animal and Plant Health Inspection Service (APHIS) strain IBD virus (IBDV) and evaluated at 2 time points, 3 days postinoculation (PI) and 10 days PI. Measures obtained at both time points included bursa to body weight, bursa histology, bursa lymphocyte count, and percentage of T cells in the bursa. Furthermore, viral load in the bursa was determined 3 days PI and anti-IBDV antibody titers, 10 days PI. A dose of 50 50% embryo infective dose caused IBD in about half the line A birds at the 10-day time point, and this dose was chosen for further studies. The data were analyzed for correlation among the various measures. Comparison of the 3-day- and 10-day-PI bursa lymphocyte counts indicated that birds challenged with low doses of virus suffered lymphocyte depletion at the 3-day time point, but many or all (depending on the dose) recovered by the 10-day time point. With a viral dose that caused bursal atrophy in about half the birds by 10 days PI, families segregating for 2 major histocompatibility complex (MHC) haplotypes were compared in terms of resistance to IBD. Results indicated that there was no difference among the 3 MHC genotypes in incidence of IBD by any of the disease measures.

Convergent and divergent points in catabolic pathways involved in utilization of fluoranthene, naphthalene, anthracene, and phenanthrene by Sphingomonas paucimobilis var. EPA505.

Catabolic pathways for utilization of naphthalene (NAP), anthracene (ANT), phenanthrene (PHE), and fluoranthene (FLA) by Sphingomonas paucimobilis EPA505 were identified. Accumulation of catabolic intermediates was investigated with three classes of Tn5 mutants with the following polycyclic aromatic hydrocarbon (PAH)-negative phenotypes; (class I NAP(-) PHE(-) FLA(-), class II NAP(-) PHE(-), and class III FLA(-)). Class I mutant 200pbhA had a Tn5 insertion within a meta ring fission dioxygenase (pbhA), and a ferredoxin subunit gene (pbhB) resided directly downstream. Mutant 200pbhA and other class I mutants lost the ability to catalyze the initial dihydroxylation step and did not transform NAP, ANT, PHE, or FLA. Class I mutant 401 accumulated salicylic acid, 2-hydroxy-3-naphthoic acid, 1-hydroxy-2-naphthoic acid, and hydroxyacenaphthoic acid during incubation with NAP, ANT, PHE, or FLA, respectively. Class II mutant 132pbhC contained the Tn5 insertion in an aldolase hydratase (pbhC) and accumulated what appeared to be meta ring fission products: trans-o-hydroxybenzylidene pyruvate, trans-o-hydroxynaphylidene pyruvate, and trans-o-hydroxynaphthyl-oxobutenoic acid when incubated with NAP, ANT, and PHE, respectively. When mutant 132pbhC was incubated with 1-hydroxy-2-naphthoic acid, it accumulated trans-o-hydroxybenzylidene pyruvate. Class III mutant 104ppdk had a Tn5 insertion in a pyruvate phosphate dikinase gene that affected expression of a FLA-specific gene and accumulated a proposed meta ring fission product; trans-o-hydroxyacenaphyl-oxobutenoic acid during incubation with FLA. Trans-o-hydroxyacenaphyl-oxobutenoic acid was degraded to acenaphthenone that accumulated with class III mutant 611. Acenaphthenone was oxidized via incorporation of one molecule of dioxygen by another oxygenase. 2,3-Dihydroxybenzoic acid was the final FLA-derived catabolic intermediate detected. Analysis of PAH utilization mutants revealed that there are convergent and divergent points involved in NAP, ANT, PHE, and FLA utilization by S. paucimobilis EPA505.

Sonographically guided directional vacuum-assisted breast biopsy using a handheld device.

OBJECTIVE: The goal of this study was to show that one can safely remove all sonographic evidence of masses in the breast less than or equal to 1.5 cm in greatest dimension using the 11-gauge handheld Mammotome, thereby reducing the possibility of a false-negative diagnosis and other shortcomings of the automated core biopsy device. SUBJECTS AND METHODS: Over a 12-week period (May 3--July 31, 2000), 124 sonographically guided breast biopsies were performed in 113 patients, using a new handheld directional vacuum-assisted biopsy device. All lesions that were less than or equal to 1.5 cm were biopsied using a handheld Mammotome; an attempt was made to continue the biopsy until no sonographic evidence of the lesion remained. RESULTS: Of these 124 lesions, 14 had infiltrating ductal carcinomas, four had infiltrating ductal carcinomas with associated ductal carcinoma in situ, one had infiltrating lobular carcinoma, one had ductal carcinoma in situ, three had atypical ductal hyperplasias, one had atypical lobular hyperplasia, and one had phyllodes tumor. Only one infiltrating ductal carcinoma was entirely removed histologically at Mammotome biopsy. There were no underestimates of disease. No cases of epithelial displacement were observed in any of the surgical excisions of malignancies. The remaining 99 lesions were benign. CONCLUSION: The handheld Mammotome diminishes the shortcomings of the automated core biopsy device. It reduces the possibility of false-negatives and underestimation of disease. It eliminates the need for multiple insertions and reduces the likelihood of epithelial displacement. As a result, we now use this device for all sonographically guided biopsies of breast masses smaller than 1.5 cm and recommend that others consider it for such use.

Breast biopsy avoidance: the value of normal mammograms and normal sonograms in the setting of a palpable lump.

PURPOSE: To review the authors' experience with patients who presented with breast lumps and had normal mammograms and normal sonograms. MATERIALS AND METHODS: The findings from 600 lumps in 486 women with no focal ultrasonographic (US) mass or mammographic finding in the area of clinical concern were retrospectively studied. Evaluated parameters included the individual reporting the lump, qualitative descriptors for the physical finding, mammographic density, US characteristics in the area of concern, whether there was a change in imaging and/or physical examination results, and whether there were diagnostic biopsy findings at follow-up. The study group included 540 lumps in 435 women who had a minimum mammographic and clinical follow-up of 2 years, as well as 60 additional lumps in 51 patients who underwent biopsy. RESULTS: No patient in the nonbiopsy group developed carcinoma at the initial site of concern during a mean mammographic and clinical follow-up period of 43 months, and all biopsy specimens were benign (negative predictive value, 100%). CONCLUSION: Results of this retrospective study suggest that breast biopsy may be avoided in women with palpable abnormalities when both US and mammography depict normal tissue at the lump site.

Stereotactic breast biopsy of nonpalpable lesions: determinants of ductal carcinoma in situ underestimation rates.

PURPOSE: To measure the effect of biopsy device, probe size, mammographic lesion type, lesion size, and number of samples obtained per lesion on the ductal carcinoma in situ (DCIS) underestimation rate. MATERIALS AND METHODS: Nonpalpable breast lesions at 16 institutions received a histologic diagnosis of DCIS after 14-gauge automated large-core biopsy in 373 lesions and after 14- or 11-gauge directional vacuum-assisted biopsy in 953 lesions. The presence of histopathologic invasive carcinoma was noted at subsequent surgical biopsy. RESULTS: By performing the chi(2) test, independent significant DCIS underestimation rates by biopsy device were 20.4% (76 of 373) of lesions diagnosed at large-core biopsy and 11.2% (107 of 953) of lesions diagnosed at vacuum-assisted biopsy (P <.001); by lesion type, 24.3% (35 of 144) of masses and 12.5% (148 of 1,182) of microcalcifications (P <.001); and by number of specimens per lesion, 17.5% (88 of 502) with 10 or fewer specimens and 11.5% (92 of 799) with greater than 10 (P <.02). DCIS underestimations increased with lesion size. CONCLUSION: DCIS underestimations were 1.9 times more frequent with masses than with calcifications, 1.8 times more frequent with large-core biopsy than with vacuum-assisted biopsy, and 1.5 times more frequent with 10 or fewer specimens per lesion than with more than 10 specimens per lesion.

Identification of the sentinel node in patients with breast cancer.

Sentinel node analysis represents a significant advance in the diagnosis and treatment of invasive breast cancer. The traditional crude method of full axillary dissection for assessing the status of the axillary nodes can now be discarded in favor of the much more elegant and modern approach of minimally invasive sentinel node analysis and its attendant elimination of the morbidity of traditional axillary node dissection. The many impediments to and pitfalls in the technique of sentinel node analysis, however, must be recognized and overcome for the procedure to be reliable and consistently successful. The use of ultrasound and a smaller particle size can help overcome many of these pitfalls. Because ultrasound identification of the axillary sentinel node in patients with invasive breast cancer is possible, it may allow for percutaneous excision of these nodes in the future (Fig. 8). Combining percutaneous excision and ablation of the primary breast carcinoma with percutaneous excision of the sentinel node allows for the nonsurgical treatment of small breast cancers in the future. The modern breast radiologist should be at the forefront of these advances.

Comparative value of 99mTc-sestamibi scintimammography and sonography in the diagnostic workup of breast masses.

OBJECTIVE: This study was conducted to assess the relative roles of 99mTc-sestamibi scintimammography and sonography in the evaluation of breast lesions that are indeterminate or suspicious on mammography or clinical examination. SUBJECTS AND METHODS: Twenty-five patients with 33 biopsy-proven breast lesions underwent both scintimammography and sonography. Lesions were categorized as benign or requiring biopsy on the basis of the absence or presence of a focus of increased activity on scintimammography and the shape, orientation, and echogenicity of the lesion on sonography. RESULTS: Sensitivity and specificity in detecting breast cancer were 92% and 95%, respectively, for scintimammography and 100% and 48%, respectively, for sonography. The higher specificity of scintimammography was statistically significant (p < 0.01). CONCLUSION: Although the overall accuracy of 99mTc-sestamibi scintimammography in the diagnosis of breast cancer was high, it has several disadvantages in comparison with sonography. Scintimammography has a slightly higher false-negative rate for breast cancer, is unable to reveal cysts, is more expensive, takes longer to perform, and involves ionizing radiation. For these reasons, scintimammography with 99mTc-sestamibi is unlikely to either replace sonography or be frequently used in addition to sonography.

Identification of four structural genes and two putative promoters necessary for utilization of naphthalene, phenanthrene, fluoranthene by Sphingomonas paucimobilis var. EPA505.

Sphingomonas paucimobilis var. EPA505 utilizes fluoranthene (FLA), naphthalene (NAP), and phenanthrene (PHE) as sole carbon sources for energy and growth. A genetic library of EPA505 was constructed using mini-Tn5 promoter reporter genes encoding for tetracycline resistance (tc(p-)) or luminescence (luxAB(p-)). Out of 2250 Tn5 mutants, ten were deficient in utilization of FLA, NAP, and/or PHE as sole carbon sources. Three classes of Tn5 mutants were defined: classI (nap(-)phe(-)fla(-)), classII (nap(-)phe(-)), and classIII (fla(-)). Four of five mutants in classI did not express dioxygenase function, whereas one classI mutant and all classII and classIII mutants retained dioxygenase activity. In Tn5 tc(p-) classI mutants 200 and 394 (dioxygenase negative) and classII mutant 132 (dioxygenase positive), promoter reporter was expressed when induced with FLA, NAP, PHE, other polycyclic aromatic hydrocarbons (PAHs), and several proposed PAH-derived catabolites. The Tn5 tc(p-) derived classIII mutant 104 was induced only with PAHs and not with PAH-derived catabolites. DNA sequence analysis of cloned regions of classI mutant 200 revealed that Tn5 inserted into a gene that shared (96%) DNA sequence homology with 2,3-dihydroxybiphenyl 1,2-dioxygenase that is designated pbhA. Nucleotide sequences downstream of pbhA shared (84%) homology to a Rieske-type ferredoxin subunit gene of a multicomponent dioxygenase designated pbhB. The Tn5 tc(p-) in classII mutant 132 occurred within sequences that shared (74%) homology with a trans-o-hydroxybenzylidene-pyruvate hydratase-aldolase gene (pbhC). Sequence analysis of the region proximal to this gene revealed a putative promoter that contained a binding site for a LysR transcriptional activator. In classIII mutant 104, the Tn5 tc(p-) resided within a region that shared 94% nucleotide homology to that of a pyruvate phosphate dikinase gene known to be involved in cellular uptake of glucose. The FLA-specific catabolic gene disrupted in mutant 104 was designated phbD. Functional and sequence analyses of promoter probe mutants allowed identification of four genes necessary for the utilization of PAHs that are controlled by at least two promoters that are affected by a wide range of aromatic compounds.

Performing a breast biopsy with a directional, vacuum-assisted biopsy instrument.

A recently developed method of minimally invasive breast biopsy involves use of a directional, vacuum-assisted instrument. Use of this instrument requires some changes in techniques and applications of breast biopsy, but it enables confident biopsy of breast lesions under both ultrasound (US) and stereotactic guidance. The device uses vacuum to pull tissue into the probe and to remove the specimen without withdrawing the probe each time. For stereotactic biopsy, to target the lesion, the probe is placed anterior or posterior to the lesion and stereotactic positioning views are obtained; for a US-guided procedure, the probe is advanced posterior to the lesion. Next, the direction that the probe aperture must be rotated to face the lesion is determined. Tissue samples are obtained at consecutive clock positions of 1 1/2-hour intervals to achieve contiguous sampling. At least 15 samples are obtained with an 11-gauge probe to acquire a minimum of 1,500 mg of tissue. If postbiopsy images reveal that the lesion has been removed, a percutaneous clip is placed to mark the biopsy site for follow-up examination and possible further treatment. Patients are examined the next day and given the biopsy results and treatment considerations, if needed; they are followed up approximately 1 week later to detect any complications (eg, discomfort, ecchymosis). By learning how to perform a directional, vacuum-assisted biopsy with either stereotactic or US guidance, the radiologist has an additional, valuable tool for bringing accurate breast biopsy to his or her community.

Atypical ductal hyperplasia diagnosed at stereotactic breast biopsy: improved reliability with 14-gauge, directional, vacuum-assisted biopsy.

PURPOSE: To compare histologic findings of atypical ductal hyperplasia (ADH) at 14-gauge, directional, vacuum-assisted breast biopsy (hereafter, vacuum-assisted biopsy) and at 14-gauge, automated, large-core breast biopsy (hereafter, large-core biopsy) with findings at histologic examination after surgical biopsy. MATERIALS AND METHODS: Nonpalpable breast lesions were diagnosed as ADH at histologic examination after vacuum-assisted biopsy in 88 lesions in seven institutions and after large-core biopsy in 55 previously reported lesions. Histologic findings at subsequent surgical biopsy were compared for the presence of carcinoma. RESULTS: On the basis of histologic findings of carcinoma at surgical biopsy, the diagnosis of ADH was not correct in 26 (48%) of 54 lesions sampled at large-core biopsy and in 13 (18%) of 74 lesions sampled at vacuum-assisted biopsy (Fisher exact test, P < .0004). More tissue specimens were obtained at vacuum-assisted biopsy (mean, 15.8 specimens) than at large-core biopsy (mean, 9.7 specimens). Individual specimens were twice as large at vacuum-assisted biopsy (mean, 34 mg) as at large-core biopsy (mean, 17 mg) (previously reported). CONCLUSION: ADH was diagnosed 2.7 times more reliably at vacuum-assisted biopsy than at large-core biopsy (with no increase in complications) with most of the improvement as a result of acquisition of more than 10 specimens per lesion, but carcinoma was sufficiently underestimated with both methods to necessitate surgical biopsy.

Stereotactic breast biopsy: improved tissue harvesting with the Mammotome.

The current study was performed to determine whether the Mammotome, a new breast biopsy instrument, is better at harvesting breast tissue percutaneously than an automated Tru-Cut (ATC) device. A total of 345 stereotactic breast biopsies were performed with the Mammotome. The Mammotome specimens were clinically evaluated on a five-point specimen scale that reflected the quality and quantity of the specimens and the rapidity of collection. In selected cases, specimen weights from both techniques were measured. In addition, by examining the lesion site post-biopsy, biopsies were categorized as incisional or excisional. Specimens obtained with the Mammotome were two times heavier than when obtained with the Biopty gun (34.3 mg vs. 17.2 mg, P < or = 0.0002). When aggregate Mammotome specimen weights were regressed against number of specimens submitted, average weight per specimen was 31.9 mg (P < or = 0.0001). When compared with the ATC device on the specimen scale, the Mammotome specimens were rated "Average" in 2.1 percent, "Good" in 13 percent, and "Very Good" in 84.9 percent. Also, 51.9 percent of the biopsies with the Mammotome were judged to be incisional; 48.1 percent, excisional. Three minor complications were encountered. The Mammotome more quickly harvests more breast tissue compared with ATC technology.

A practical approach to minimally invasive breast biopsy.

With the development of stereotactic or ultrasound-guided, large-core percutaneous breast biopsy and the evolution of mammotomy, radiologists are now able to render definitive diagnoses of breast lesions. To ensure success, however, there must be a commitment at the outset to put into place the required personnel and equipment. The radiologists involved must conscientiously adhere to standardized technique and be willing to assume clinical responsibility, including comprehensive follow-up methods. With these commitments, radiologists can substantially increase their contribution to the care of patients with a breast abnormality.

Sickness absence following a campaign of vaccination against influenza in the workplace.

This study was designed as a retrospective cohort study of those employees vaccinated against influenza vs. unvaccinated employees in a service company. The objective was to investigate whether vaccinating employees against influenza in an occupational setting was of any benefit. There were 2,557 persons entered in the study who were in continuous employment between 1 October 1990 and 31 March 1992 of which 23.5% (601) were vaccinated. The study was carried out at First Data Resources Limited in Basildon, Essex UK. The main outcome measure was self-reported influenza sickness lasting four or more days and reduction in sickness absence due to vaccination against influenza. The results were surprising. In the vaccinated members of staff, influenza illness was halved, Relative Risk = 0.46, 95% confidence limits (0.27 < RR < 0.76). The conclusions were that the study showed a significant decrease in sickness absence due to influenza illness, as a result of an active vaccination campaign carried out amongst otherwise healthy individuals in the occupational health environment. This is the first study of this nature in the UK to show statistically significant evidence of benefit from vaccinating healthy employees. It lends support to immunization against influenza in the workplace.

The evolution of minimally invasive breast biopsy: from FNA to percutaneous incisional and excisional biopsy.

Surgical biopsy of the breast has long been the most commonly accepted method of determining the na- ture of a clinical or mammographic abnormality. Because this method carries with it certain cost and morbidity drawbacks, physicians have investigated less invasive alternatives. Until recently, however, there has not been sufficient confidence in the minimally invasive techniques to supplant surgical breast biopsy. Fine needle aspiration (FNA) of the breast has been available for decades and, in some hands, per- formed reliably enough to avoid surgical biopsy in certain instances. For the most part, however, surgeons and other physicians have been reluctant to base definitive decision making upon the results of FNA.This is un- derstandable in that FNA carries significant insufficient tissue and false negative rates."l As a result, FNA frequently represented an additional test and attendant cost without obviating the need for surgical biopsy.

Needle biopsy techniques.

With the ability to perform good diagnostic mammography, breast ultrasound, ductography, cyst aspiration, abscess drainage, and stereotactic or ultrasound-guided percutaneous biopsy, the modern breast radiologist should play the central role in breast diagnosis. The definitive diagnoses afforded by percutaneous breast biopsy that obviate surgery entirely in benign lesions and streamline the therapeutic surgery for malignant lesions now can be obtained routinely. The future holds even more exciting challenges for the radiologist as percutaneous lumpectomy becomes a reality. Thus the breast radiologist, armed with the technology and techniques of the twenty-first century, truly stands on the threshold of a new era.

Solid breast nodules: use of sonography to distinguish between benign and malignant lesions.

PURPOSE: To determine whether sonography could help accurately distinguish benign solid breast nodules from indeterminate or malignant nodules and whether this distinction could be definite enough to obviate biopsy. MATERIALS AND METHODS: Seven hundred fifty sonographically solid breast nodules were prospectively classified as benign, indeterminate, or malignant. Benign nodules had no malignant characteristics and had either intense homogeneous hyperechogenicity or a thin echogenic pseudocapsule with an ellipsoid shape or fewer than four gentle lobulations. Sonographic classifications were compared with biopsy results. The sensitivity, specificity, and negative and positive predictive values of the classifications were calculated. RESULTS: Benign histologic features were found in 625 (83%) lesions; malignant histologic features, in 125 (17%). Of benign lesions, 424 had been prospectively classified as benign. Two lesions classified as benign were found to be malignant at biopsy. Thus, the classification scheme had a negative predictive value of 99.5%. Of 125 malignant lesions, 123 were correctly classified as indeterminate or malignant (98.4% sensitivity). CONCLUSION: Sonography can be used to accurately classify some solid lesions as benign, allowing imaging follow-up rather than biopsy.