Melatonin exerts direct inhibitory actions on ACTH responses in the human adrenal gland.

In nonhuman primates and rodents, melatonin acting directly on the adrenal gland, inhibits glucocorticoid response to ACTH. In these species, an intrinsic adrenal circadian clock is involved in ACTH-stimulated glucocorticoid production. We investigated whether these findings apply to the human adrenal gland by determining i) expression of clock genes in vivo and ii) direct effects of melatonin in ACTH-stimulated adrenal explants over a) expression of the clock genes PER1 (Period 1) mRNA and BMAL1 [Brain-Muscle (ARNT)-like] protein, ACTH-induced steroidogenic acute regulatory protein (StAR), and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and b) over cortisol and progesterone production. Adrenal tissue was obtained from 6 renal cancer patients undergoing unilateral nephrectomy-adrenalectomy. Expression of the clock genes PER1, PER2, CRY2 (Cryptochrome 2), CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1, was investigated by RT-PCR in a normal adrenal and in an adenoma. In independent experiments, explants from 4 normal adrenals were preincubated in culture medium (6 h) followed by 12 h in: medium alone; ACTH (100 nM); ACTH plus melatonin (100 nM); and melatonin alone. The explants' content of PER1 mRNA (real-time PCR) and StAR, 3ß-HSD, BMAL1 (immuno slot-blot), and their cortisol and progesterone production (RIA) were measured. The human adrenal gland expresses the clock genes PER1, PER2, CRY2, CLOCK, and BMAL1. ACTH increased PER1 mRNA, BMAL1, StAR, and 3ß-HSD protein levels, and cortisol and progesterone production. Melatonin inhibited these ACTH effects. Our study demonstrates, for the first time, direct inhibitory effects of melatonin upon several ACTH responses in the human adrenal gland.

Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users.

Administration of nevirapine to HIV-infected injection drug users who also receive methadone results in a significant reduction in methadone exposure after 7-10 days of therapy. Many patients require an increase in methadone dose to counteract this effect.

The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz.

AIMS: Methadone is predominantly metabolized by cytochrome P450 3A4 and the non nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is a recognized inducer of this enzyme. We evaluated the pharmacokinetics of methadone in the presence and absence of efavirenz when administered to HIV infected patients with a history of injection drug use (IDU). METHODS: Eleven patients on stable methadone maintenance therapy, due to commence antiretroviral therapy (ART), participated in this study. Steady state methadone kinetic profiles were obtained on two occasions 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 h post dosing. Following centrifugation, separated plasma was heated at 58 degrees C for 30 min to inactivate HIV and stored at -80 degrees C until methadone analysis by high performance liquid chromatography. RESULTS: When combined with efavirenz there was a marked decrease in the maximum plasma concentration (Cmax) of methadone from 689 (range 212-1568) to 358 (range 205-706) ng ml(-1), P = 0.007 : 95% confidence interval (CI) 112-549. The mean area under the methadone concentration curve 0-24 h (AUC(0,24 h)) was also significantly reduced from 12341 (range 3682-34147) to 5309 (range 2430-10349) ng ml(-1) h in the presence of efavirenz, P = 0.012 : 95% CI 1921-12143. Nine patients described symptoms of methadone withdrawal and received a dose increase. Although methadone AUC(0,24 h) was reduced by over 50% following efavirenz the mean increase in methadone dose required was 22% (range 15-30 mg). CONCLUSION: The inclusion of the NNRTI efavirenz in once daily ART for HIV patients with a history of IDU receiving methadone maintenance results in a significant reduction in methadone plasma concentrations mediated by enzyme induction. It is important to distinguish efavirenz neurological effects which were observed between days 1-5 of therapy from symptoms of methadone withdrawal which occurred from day 8 onwards. The dose of methadone was adjusted by increments of 10 mg to counteract the efavirenz inducing effect.

Biopsy of sentinel lymph nodes guided by lymphoscintigraphic mapping in patients with breast cancer.

OBJECTIVE: The purpose of this study was to determine the technical success rate of sentinel node biopsy with lymphoscintigraphy in women with breast cancer and the frequency with which sentinel node biopsy obviated axillary dissection. Factors affecting the success rate of sentinel node biopsy and lymphoscintigraphy were also evaluated. MATERIALS AND METHODS: Retrospective review revealed 119 women with breast cancer who underwent lymphoscintigraphy and sentinel node biopsy at our institution during the study period. A planned axillary dissection was performed in 13 of the first 16 patients; otherwise, axillary dissection was only performed if tumor was present in sentinel nodes or if the sentinel node biopsy was unsuccessful. RESULTS: Sentinel node biopsy was successful in 96% of patients, and sentinel node metastases were found in 20%. In 78% of patients, a negative sentinel node biopsy obviated axillary dissection. Prior excisional biopsy was not associated with a failed sentinel node biopsy (p = 0.750) but was associated with failed lymphoscintigraphy (p = 0.01). Successful lymphoscintigraphy was associated with successful sentinel node biopsy (p < 0.0001). No association was found between the histology or size of the tumor and a failed sentinel node biopsy (p = 0.46 and p = 0.1, respectively) or failed lymphoscintigraphy (p = 0.36 and p = 0.47, respectively). CONCLUSION: Sentinel node biopsy guided by lymphoscintigraphy, intraoperative gamma probe, and isosulfan blue dye is an effective alternative to axillary dissection in patients with breast cancer. Lymphoscintigraphy improved the success rate of sentinel node biopsy. Large tumor size or prior excisional biopsy should not prevent patients from having sentinel node biopsy.

Breast cancer in vivo: contrast enhancement with thermoacoustic CT at 434 MHz-feasibility study.

The authors performed thermoacoustic computed tomography (CT) with 434-MHz radio waves in five patients with documented breast cancer. Three of the patients underwent imaging before chemotherapy was initiated and two at the conclusion of their primary chemotherapy. In the former three patients, thermoacoustic CT demonstrated contrast enhancement in the region of the tumor. In the latter two patients, no contrast enhancement was seen, and pathologic examination after surgical resection of the area of original tumor confirmed complete remission of disease.

Benign versus malignant solid breast masses: US differentiation.

PURPOSE: To investigate the general applicability and interobserver variability of ultrasonographic (US) features in differentiating benign from malignant solid breast masses. MATERIALS AND METHODS: One hundred sixty-two consecutive solid masses with a tissue diagnosis were reviewed. Three radiologists reviewed the masses without knowledge of clinical history or histologic examination results. RESULTS: US features that most reliably characterize masses as benign were a round or oval shape (67 of 71 [94%] were benign), circumscribed margins (95 of 104 [91%] were benign), and a width-to-anteroposterior (AP) dimension ratio greater than 1.4 (82 of 92 [89%] were benign). Features that characterize masses as malignant included irregular shape (19 of 31 [61%] were malignant), microlobulated (four of six [67%] were malignant) or spiculated (two of three [67%] were malignant) margins, and width-to-AP dimension ratio of 1.4 or less (28 of 70 [40%] were malignant). If the three most reliable criteria had been strictly applied by each radiologist, the overall cancer biopsy yield would have increased (from 23% to 39%) by 16%. When US images and mammograms were available, the increase in biopsy yield contributed by US was not statistically significant (2%, P = .73). However, in independent reviews, one to three reviewers interpreted four carcinomas as benign at US. CONCLUSION: The data confirm that certain US features can help differentiate benign from malignant masses. However, practice and interpreter variability should be further explored before these criteria are generally applied to defer biopsy of solid masses.

Stereotactic biopsy of ductal carcinoma in situ of the breast using an 11-gauge vacuum-assisted device: persistent underestimation of disease.

OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of 14-gauge automated gun and 11-gauge directional vacuum-assisted biopsy techniques in the diagnosis of ductal carcinoma in situ of the breast. MATERIALS AND METHODS: We retrospectively reviewed 41 consecutive lesions that had been diagnosed as ductal carcinoma in situ using stereotactic needle biopsy. The first 21 lesions had been biopsied using a 14-gauge automated gun; the remaining 20 lesions, using an 11-gauge vacuum-assisted device. Surgical histopathologic results at lumpectomy were compared with the findings at needle biopsy and defined as either concordant, when only ductal carcinoma in situ (i.e., no evidence of invasive carcinoma) was evident at surgery, or discordant, when invasive carcinoma was found. One patient from the automated gun group was lost to follow-up and was not included in the analysis. RESULTS: Invasive carcinoma was found at surgery in seven (35%) of the 20 cases diagnosed using the automated gun compared with three (15%) of the 20 cases diagnosed using the vacuum-assisted device (p = .13). In all three of these discordant vacuum-assisted cases, only microinvasive disease was found at surgery. However, in only two of the seven discordant automated gun cases was only microinvasive disease found at surgery. CONCLUSION: The 11-gauge directional vacuum-assisted biopsy technique may improve the accuracy of ductal carcinoma in situ diagnosis. Underestimation of disease still occurs, however.

Advances in breast imaging.

Many exciting developments are occurring in breast imaging. Digital mammography holds the promise of telemammography and computer-aided diagnosis. Mammoscintigraphy may be helpful in identifying drug-resistant tumors before therapy. There is renewed interest in evaluating ultrasound as a potential adjunctive screening tool in women with radiographically dense breasts. Finally, contrast-enhanced magnetic resonance imaging may be used more extensively in the monitoring of tumor response to primary chemotherapy and in the preoperative workup of patients being considered for breast conservation therapy.

Fine-needle aspiration cytology of cystic hypersecretory ductal carcinoma in situ of the breast: a case report.

Cystic hypersecretory intraductal carcinoma is an unusual, cystic form of intraductal breast carcinoma affecting middle-aged women. Cytopathologists have rarely encountered this lesion, with only 2 other cases having been previously reported (Colandrea et al., Arch Pathol Lab Med 1988:112:560-563; Kim et al., Acta Cytol 1997;41:892-896). In our cases, the cytologic findings of both air-dried, Diff-Quick-stained and ethanol-fixed, Papanicolaou-stained smears are presented. The cytologic hallmarks of this entity include the presence of a few scattered epithelial cells with bland nuclear morphology in a background of extensive, amorphous, pink-staining material. Cytomorphologically, the differential diagnosis includes other entities containing pink-staining material such as colloid carcinoma, mucocele-like lesion of the breast, and benign fibrocystic change.

Marker clip placement following directional, vacuum-assisted breast biopsy.

The purpose of this study was to evaluate the accuracy of marker clip placement after 11-gauge directional, vacuum-assisted breast biopsies. During a 9-month period, 150 stereotactic breast biopsies were performed using a directional, vacuum-assisted device and an 11-gauge probe. In 114 cases, a marker clip was deployed at the biopsy site using the through-probe method. In 94 cases, stereotactic coordinates of the clip were obtained and were available for retrospective review. Comparing the coordinates of the lesion with those of the clip, placement errors were calculated. Overall, clip placement was within 5 mm of the lesion in 81 per cent of cases, within 5-10 mm of the lesion in 17 per cent of cases, and >10 mm from the lesion in 2 per cent of cases. Mean total placement error was 4.5 mm. The mean z axis error was 3.2 mm, compared with 0.88 and 2.0 mm for the x and y axes, respectively. Marker clip placement after vacuum-assisted biopsy is an accurate method of localizing the biopsy site should subsequent surgery be required.

Fixed-facility workplace screening mammography.

OBJECTIVE: Potential barriers to compliance with screening mammography guidelines include the cost and inconvenience involved with undergoing the procedure. Workplace screening with mobile mammography is one possible approach to the convenience barrier. However, fixed-facility workplace screening is a viable alternative for any company with a large workforce in one location. This paper describes our initial experience with one such fixed facility. MATERIALS AND METHODS: The facility was a cooperative venture by a large pharmaceutical company and an academic radiology department to provide convenient, no-cost (to the patient) screening mammography to employees, dependents, and retirees more than 40 years old. The pharmaceutical company built the facility within its corporate headquarters and the academic radiology department provided the equipment and personnel. The company was billed a fixed cost per examination. RESULTS: In the first 22 months of operation, 4210 (of 4559 scheduled) screening mammograms were obtained. The mean age of the population was 53 years old. Ninety percent of the screening mammograms were interpreted as negative or benign; 10% required additional workup. Of the screened population, 62 biopsies were recommended and 60 were performed. Of these, 42 were benign and 18 malignant. The cancer detection rate was 4.3 per 1000 (0.43%). At the time of diagnosis, six patients were stage 0, 10 patients were stage I, one patient was stage II, and one patient was stage III. Eleven of the 18 patients had minimal cancers. Of the patients who completed a satisfaction survey, 97% percent expressed a high degree of satisfaction with the screening process and stated they would use the facility in the future. CONCLUSION: A fixed facility for workplace screening mammography is a viable way to provide nearly barrier-free access to high-quality mammography. Patient acceptance is high.

Sonography of the breast.

Quality mammography remains the primary modality used to image the breast. Sonography currently is the most useful adjunctive technique to mammography, having roles in differentiating cystic from solid masses and in guiding interventional procedures. This article reviews these and other indications for breast ultrasound studies, including evaluation of palpable masses not visible in radiographically dense breasts, masses not completely evaluable with mammography, young patients especially susceptible to radiation damage, and abscesses. Ultrasound interpretation of cysts and solid masses are discussed, as are the relative disadvantages of ultrasound as a breast cancer screening tool.

Evaluation of the augmented breast.

Silicone gel implants and their complications constitute a public health problem. Millions of American women have these implants and many are concerned about their possible health effects. The history of breast augmentation as well as current concepts in imaging augmented patients are discussed in this article. Special attention is paid to the diagnosis of implant rupture by mammography, sonography, and MR imaging.

Comparison of mammography, sonography, and magnetic resonance imaging in the detection of silicone-gel breast implant rupture.

Silicone-gel breast implant rupture is difficult to diagnose preoperatively. A variety of radiological methods have been used for diagnosis. This study prospectively compares film-screen mammography, high-resolution sonography, and magnetic resonance imaging in the diagnosis of implant rupture using predetermined diagnostic criteria. Thirteen patients (24 implants) underwent film-screen mammography, sonography, and magnetic resonance imaging to evaluate the integrity of their implants. All patients subsequently underwent surgical removal of the implants. Preoperatively, the integrity of each implant was rated on a three-level classification system on the basis of one modality by a reviewer who was unaware of the results of the other two modalities. The three imaging modalities achieved the following sensitivities and specificities, respectively: mammography, 69% and 82%; sonography, 54% and 64%; MRI, 69% and 55%. Even though each modality addresses some of the limitations of the others, in this group of patients, there was no clearly superior imaging tool.

Cholesterol granuloma of the breast: a mimic of carcinoma.

Cholesterol granuloma of the breast is a rare condition that may be related to the common disorder mammary duct ectasia. Its importance is in its tendency to mimic carcinoma clinically and radiologically. The authors report a case in a 65-year-old asymptomatic woman.