Stereocontrolled Semisyntheses of Elliptone and 12aß-Hydroxyelliptone.

Operationally simple, stereocontrolled semisyntheses of the anticancer rotenoids elliptone and 12aß-hydroxyelliptone, isolated from Derris elliptica and Derris trifoliata, respectively, are described. Inspired by the work of Singhal, elliptone was prepared from rotenone via a dihydroxylation-oxidative cleavage, chemoselective Baeyer-Villiger oxidation, and acid-catalyzed elimination sequence. Elaboration of elliptone to 12aß-hydroxyelliptone was achieved via a diastereoselective chromium-mediated Étard-like hydroxylation. The semisynthesis of elliptone constitutes an improvement over previous methods in terms of safety, scalability, and yield, while the first synthesis of 12aß-hydroxyelliptone is also described.

Hepatic fascioliasis at a London hospital--the importance of recognising typical radiological features to avoid a delay in diagnosis.

Hepatic fascioliasis is a zoonosis caused by the trematode Fasciola hepatica, which can cause hepatobiliary disease in humans via the ingestion of contaminated water or aquatic vegetables. Reported cases of human infection with F. hepatica arise in regions where cattle are raised, with particular abundance in South America and the Middle East. The typical radiological appearances associated with fascioliasis are well reported and are likely to be more easily recognisable by radiologists in these areas of high prevalence. However, in Western countries where the disease is seldom found, there may be a delay in diagnosis and treatment owing to unfamiliarity with the radiological appearances, in addition to the non-specific clinical features on presentation. Here we describe a case of a 22-year-old Bangladeshi woman whose only clinical feature was right upper quadrant pain. Abnormal imaging of her abdomen on admission began a process of investigations to seek the correct diagnosis.

Radial artery aneurysm resulting from repetitive occupational injury: Tailor's thumb.

INTRODUCTION: True radial artery aneurysms are very rare and a cause is rarely identified. CASE REPORT: An unusual case of a true radial artery aneurysm in a tailor of fifty years; presenting with a growing, tender lump at the base of his thumb. DISCUSSION: Radial artery aneurysms are classically pseudoaneurysms from iatrogenic traumatic injury - arterial cannulation. This is the first case in the literature to demonstrate a true aneurysm secondary to repetitive occupational injury.

fMRI-adaptation reveals dissociable neural representations of identity and expression in face perception.

The distributed model of face processing proposes an anatomical dissociation between brain regions that encode invariant aspects of faces, such as identity, and those that encode changeable aspects of faces, such as expression. We tested for a neuroanatomical dissociation for identity and expression in face perception using a functional MRI (fMRI) adaptation paradigm. Repeating identity across face pairs led to reduced fMRI signal in fusiform cortex and posterior superior temporal sulcus (STS), whereas repeating emotional expression across pairs led to reduced signal in a more anterior region of STS. These results provide neuroanatomical evidence for the distributed model of face processing and highlight a dissociation within right STS between a caudal segment coding identity and a more rostral region coding emotional expression.

Common and distinct neural responses during direct and incidental processing of multiple facial emotions.

Whether common or distinct neural systems underpin perception of different emotions and the degree to which these systems are automatically engaged during emotional perception are unresolved. We performed an event-related fMRI experiment in which subjects viewed morphed emotional faces displaying low or high intensities of disgust, fear, happiness, or sadness under two task conditions. The amygdala and fusiform cortex responded to high-intensity expressions of all emotions, independent of task. Right superior temporal sulcus showed an additive effect of the emotion-directed task and high-intensity emotion. Ventromedial prefrontal and somatosensory cortices, regions implicated in providing representations of somatic states, showed enhanced activity during explicit emotional judgments. We failed to find predicted differences between emotions. The results suggest that amygdala contributes to task-independent perceptual processing of a range of emotions. We interpret ventromedial prefrontal and somatosensory cortex activations as evidence that these regions contribute to explicit emotion processing through linking emotion perception with representations of somatic states previously engendered by emotions.

Automatic and intentional brain responses during evaluation of trustworthiness of faces.

Successful social interaction partly depends on appraisal of others from their facial appearance. A critical aspect of this appraisal relates to whether we consider others to be trustworthy. We determined the neural basis for such trustworthiness judgments using event-related functional magnetic resonance imaging. Subjects viewed faces and assessed either trustworthiness or age. In a parametric factorial design, trustworthiness ratings were correlated with BOLD signal change to reveal task-independent increased activity in bilateral amygdala and right insula in response to faces judged untrustworthy. Right superior temporal sulcus (STS) showed enhanced signal change during explicit trustworthiness judgments alone. The findings extend a proposed model of social cognition by highlighting a functional dissociation between automatic engagement of amygdala versus intentional engagement of STS in social judgment.

Altered expression and localization of PKC eta in human breast tumors.

Protein kinase C (PKC) eta is a PKC isoform whose upregulation is associated with differentiation in many epithelial tissues, including the rat mammary gland. The purpose of this study was to examine whether PKC eta is altered, in expression or localization, in human breast cancer. Paraffin sections of 49 in situ breast lesions, 29 invasive breast tumors, and nine normal breast biopsies were examined for PKC eta expression by immunohistochemistry. Adjacent regions of normal epithelium, and in situ lesions that were present adjacent to invasive lesions were also analyzed. In normal epithelium, regardless of the presence of adjacent in situ or invasive lesions, PKC eta was present in the cytoplasm of the luminal epithelium, and increased in areas of normal lobular development, similar to normal rat mammary gland. PKC eta staining intensity was homogeneous in normal lobules, but heterogeneous in in situ and invasive lesions, being focally increased in cells with aberrant nuclear morphology. In situ lesions were similar to adjacent normal epithelium in average staining intensity, regardless of whether invasion was also present. However, the invasive lesions themselves were significantly decreased in staining intensity compared to adjacent in situ lesions. In addition, 75% of invasive breast cancer lesions showed decreased staining relative to adjacent normal epithelium, compared to 37% of in situ lesions. The invasive tumors which possessed high PKC eta staining were associated with positive lymph node status. These results demonstrate that quantitative and qualitative alterations in PKC eta occur in human breast cancers.

Accuracy of sentinel node biopsy in predicting nodal status in patients with breast carcinoma.

BACKGROUND AND OBJECTIVES: While sentinel lymph node biopsy is considered by many to have replaced axillary node dissection in the management of breast cancer, concerns remain regarding false-negative results. METHODS: To investigate the accuracy of sentinel node biopsy, we reexamined all sentinel and nonsentinel nodes with multilevel sectioning and immunohistochemical staining in 42 consecutive cases of breast cancer in which sentinel node biopsy was performed and followed by axillary dissection. RESULTS: By routine hematoxylin and eosin (H&E) staining, 34% of patients were found to be node positive, with no cases of false-negative sentinel node biopsy. Reevaluation of 775 negative sentinel and nonsentinel nodes with an additional two levels and immunohistochemistry identified three "node-negative" patients who had micrometastases in the sentinel node, increasing detection in 8% of cases. More important, is the fact however, that there were no cases where additional sections and immunohistochemistry identified metastases in nonsentinel nodes that had bypassed the sentinel node. The accuracy of the sentinel node in predicting the nodal status was 100%. CONCLUSIONS: Cytokeratin immunohistochemistry will identify more patients with nodal micrometastases; however, it was unable to identify any cases where micrometastases were present in nonsentinel nodes when the sentinel node was negative. The status of the sentinel node accurately identifies the status of the axillary basin.

Clinical presentation and treatment of non-Hodgkin's lymphoma of the thyroid gland.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) of the thyroid is a rare malignancy. The traditional approach to curative treatment of localized (stages I and II) NHL of the thyroid gland is surgical resection. The recent success of multimodality chemoradiotherapy suggests that surgery should be reserved for providing a tissue diagnosis or relief from acute airway obstruction. It is questionable whether this has made an impact on treatment approaches. METHODS: Retrospective chart review was conducted for all cases of localized NHL of the thyroid gland treated at Roswell Park Cancer Institute between January 1970 and January 1999. RESULTS: Ten patients (8 women, 2 men) with a mean age of 56.8 years were identified. Nine patients (90%) presented with a neck mass; seven patients (70%) had a history of Hashimoto's disease. Nine patients (90%) had extensive investigations to rule out extrathyroidal disease. All patients were treated with either a total thyroidectomy (eight patients) or a thyroid lobectomy (two patients). Nine (90%) were initially treated outside of Roswell Park Cancer Institute and referred secondarily for consideration of further therapy. Adjuvant therapy consisting of cyclophosphamide-based chemoradiotherapy was administered to nine patients. Overall survival was 80% at a mean follow-up of 8.6 years with a disease-specific survival rate of 100%. CONCLUSIONS: A review of the literature suggests that fine needle aspiration (FNA) with flow cytometry and immunohistochemistry can be used to accurately diagnose NHL of the thyroid gland. Open biopsy should be reserved for cases where this technique is not available or where the diagnosis can not be confirmed by FNA alone. Extrathyroidal NHL should be ruled out by chest x-ray, CT scan of the abdomen, and bone marrow biopsy. Further review suggests that the most efficacious therapy is systemic chemotherapy in combination with radiation for local control. Debulking surgery should be used only to provide relief from acute airway obstruction.

Intraoperative pathologic evaluation of a breast cancer sentinel lymph node biopsy as a determinant for synchronous axillary lymph node dissection.

BACKGROUND: Intraoperative pathologic evaluation of a breast cancer sentinel lymph node (SLN) biopsy permits synchronous axillary lymph node dissection (ALND), but frozen section is time consuming and potentially inaccurate. This study evaluated intraoperative gross examination and touch prep analysis (TPA) of a breast cancer SLN biopsy as determinants for synchronous ALND. METHODS: Intraoperative gross examination/TPA were performed on the SLN of consecutive breast cancer patients from 1997 to 2000. Patients with an intraoperative "positive" SLN underwent synchronous ALND. Intraoperative results were compared with the final pathology. RESULTS: Thirty-seven of 150 patients had a positive SLN on final pathology. Intraoperative gross examination/TPA identified 54% (20 of 37) of these patients. All intraoperative "positive" patients underwent synchronous ALND. Of 17 "false-negative" findings, 53% (9 of 17) had micrometastatic disease. There were no "false-positive" results. Overall sensitivity and specificity were 54% and 100%, respectively. CONCLUSIONS: Gross examination/TPA are simple, rapid techniques for the intraoperative evaluation of a breast cancer SLN. As there were no false-positive results, the rationale behind SLN biopsy was preserved. These techniques permitted synchronous ALND in over half of all patients with a positive SLN. This represents a potential benefit to the patient by eliminating a second hospitalization for delayed ALND.

Downregulation of gelsolin correlates with the progression to breast carcinoma.

The actin cytoskeleton underlies several normal cellular functions and is deranged during carcinogenesis. Gelsolin, a multifunctional actin-binding protein, is downregulated in several types of tumors and its abnormal expression is one of the most common defects noted in invasive breast carcinoma (ICA). This study utilizes immunohistochemistry to examine the expression of gelsolin in 95 ICA, 59 ductal carcinoma in situ (DCIS) and 36 benign lesions, including 17 atypical ductal hyperplasia (ADH). Cytoplasmic staining was scored as positive, reduced or negative. Gelsolin expression was then correlated with patient's age, tumor size, histologic grade and lymph node status. All unremarkable breast biopsies, 88% of ADH, 44% of DCIS and 28% of ICA were positive for gelsolin. This represents a significant difference among the groups (p = < 0.0001) and the trend towards reduced gelsolin with the progression to ICA is significantly linear (p = < 0.0001). For invasive carcinoma, patients older than 44 years were significantly more likely to have decreased expression of gelsolin than patients 44 years old and younger (p = 0.007). Bivariate analysis showed no correlation of gelsolin expression with lymph node status (p = 0.62), tumor size (p = 0.10), histologic grade (p = 0.42), estrogen receptor status (p = 1.0) or other clinicopathologic parameters. In clinical follow-up, there were 18 breast tumor related deaths within a median follow-up time of 4.2 years. Survival analysis indicated that the level of gelsolin expression may be associated with survival (p = 0.06). In summary, the frequency of gelsolin deficiency increases significantly with progression from ADH to DCIS to ICA. Additionally, gelsolin expression may be an independent marker of prognosis.

Breast cancer risk factors and HER2 over-expression in tumors.

Few epidemiologic studies have investigated the potential role of HER2 in the etiology of breast cancer. We conducted a case-case study of 156 women with incident, invasive ductal carcinoma. Multivariate unconditional logistic regression was used to estimate the odds ratios for a HER2 positive tumor in relation to known and putative risk factors of breast cancer. HER2 status was detected by immunohistochemistry on archival tissue. HER2 positive breast cancers tended to be larger and were less likely to express estrogen receptors, and the incidence rate was higher in patients less than 40 years old. We observed an association between a self-reported history of benign breast disease and the occurrence of HER2 positive breast cancer (OR, 2.1;95% CI, 1.1-4.1). We did not detect associations between HER2 over-expression and family history of breast cancer, parity, late age at first birth, ever having breast fed an infant, or oral contraceptive use. Our findings merit consideration in light of recent evidence of HER2 amplification or over-expression in benign breast disease. Should the link to breast cancer be established, HER2 positive benign breast disease could potentially serve as an early marker for preventive intervention.

Flow cytometric DNA analysis of specimen mammography-guided fine-needle aspirates of ductal carcinoma in situ.

Flow cytometric studies of screening mammography detected ductal carcinoma in situ (DCIS) are limited by the lack of fresh cell samples. We have performed flow cytometric DNA analyses of specimen mammography-guided fine-needle aspirates of 50 consecutive DCIS lesions detected by screening mammography. The comedo histologic subtype had an aneuploidy rate of 39% (9 of 23); noncomedo subtypes had an aneuploidy rate of 19% (5 of 27), p=ns. Noncomedo subtypes were more likely to have low (less than 2.2%) S-phase percentages, 59% (16 of 27) as compared to comedo, 9% (2 of 23), p<0.05. High and intermediate nuclear grade DCIS lesions had an insignificantly greater rate of aneuploidy, 35% (9 of 26) and 33% (4 of 12) respectively, as compared to low nuclear grade lesions, 8% (1 of 12), p=ns. Low and intermediate nuclear grade DCIS lesions had low S-phase percentage rates of 67% and 50% respectively, as compared to the high nuclear grade lesions low S-phase percentage rate, 15%, p=ns. Aneuploidy and lesser rates of low S-phase percentages were significantly associated with necrosis and apoptosis. Our data suggest that flow cytometric DNA analysis of mammographic lesion-specific, fresh cell samples obtained by fine-needle aspiration under specimen mammographic guidance can assess mammography-detected DCIS lesions when gross fresh tissue procurement is not possible.

Down-regulation of gelsolin expression in human breast ductal carcinoma in situ with and without invasion.

Expression of gelsolin, an actin filament regulatory protein, in human breast ductal carcinoma in situ (DCIS) was analyzed by immunohistochemistry using a monoclonal antibody. Formalin-fixed paraffin-embedded tissues from 59 pure DCIS specimens and 33 DCIS specimens with associated invasive components were evaluated for gelsolin reactivity and compared to eight normal breast cases and 76 invasive breast cancers. The proportion of cases exhibiting negative/low expression of gelsolin in the epithelium was as follows -- normal, 0%; pure DCIS, 56%; DCIS associated with invasion, 58% in the DCIS component and 66% in the invasive component; invasive carcinoma, 70%. These data demonstrate that down-regulation of gelsolin expression in breast epithelium frequently parallels progression to malignancy. Testing gelsolin expression (normal vs. negative/low levels) in the DCIS lesions for associations with patient age or any of the following histopathologic parameters revealed no significant (95% probability level) correlations -- tumor size; pathologic (Van Nuys system) grade; nuclear grade; necrosis; presence of histologic calcifications; presence or type of adjacent benign lesions; architectural histologic pattern; and mammographic extent. Gelsolin loss was more commonly associated with mammographic soft tissue lesions as compared to calcified lesions (P = 0.009). A positive trend of borderline significance (P = 0.06) found in the DCIS with invasion group was a correlation between down-regulated gelsolin expression in the DCIS component and size (< versus > or = 15 mm) of the invasive tumor. In conclusion, reduced gelsolin protein is detectable in at least half of breast lesions which have progressed to DCIS. The trend between increasing gelsolin loss and malignant progression from normal epithelium to DCIS to invasive breast cancer (P < 0.0001) suggests additional investigation is needed to determine the potential of altered gelsolin expression as a marker for prognosis and for therapeutic interventions in breast cancer.

Angiogenesis and dynamic MR imaging gadolinium enhancement of malignant and benign breast lesions.

PURPOSE: To determine whether dynamic magnetic resonance (MR) imaging enhancement parameters are associated with vessel density of malignant and benign breast lesions. MATERIALS AND METHODS: Forty-five patients with 48 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging followed by excisional biopsy and Factor VIII staining and vessel density measurement in the lesions. RESULTS: The vessel densities were not significantly different in 25 malignant breast lesions as compared to 23 benign breast lesions. Among all 48 lesions, greater MR enhancement showed an association with increased vessel density. Seventy-four percent of all lesions with MRI enhancement amplitude greater or equal to three times post-precontrast ratio had vessel densities greater than the median of 172 as compared to 34% of lesions with enhancement amplitude less than three times, p = 0.02. The rate and washout of MR enhancement showed no significant association with vessel density. CONCLUSION: Although there is an overall significant association between greater MRI enhancement amplitude and vessel density, MRI gadolinium enhancement of breast lesions is not an accurate predictor of vessel density.

Cathepsin D and dynamic magnetic resonance imaging gadolinium enhancement in malignant and benign breast lesions.

Our purpose was to determine whether the expression of cathepsin D, a proteolytic enzyme implicated in basement membrane degradation, is associated with dynamic magnetic resonance imaging (MRI) enhancement of breast lesions. Forty-five patients with 48 breast lesions underwent gadolinium-enhanced spoiled gradient recalled echo MRI followed by excisional biopsy and cathepsin D staining and semiquantitative measurement in the lesions. There was no significant difference in cathepsin D staining of 25 malignant and 23 benign breast lesions. A significant association was seen between high cathepsin D staining and positive axillary lymph nodes in invasive carcinomas. Nine of nine (100%) node-positive carcinomas had high cathepsin D, as compared to three of seven (43%) node-negative carcinomas (P = 0.02). No significant associations were observed between cathepsin D staining and MRI enhancement amplitude, rate, or washout. Cathepsin D has no effect upon MRI gadolinium enhancement of malignant and benign breast lesions but is associated with positive axillary lymph nodes in invasive carcinomas.

Widespread loss of gelsolin in breast cancers of humans, mice, and rats.

Down-regulation of gelsolin, an actin-binding protein, is frequently found in several types of transformed cells and tumors. The present study demonstrates that gelsolin protein and RNA were absent or markedly reduced in human breast cancer cell lines relative to "normal" mortal human mammary epithelial cells and benign, immortalized cell lines. Moreover, actin filaments were usually attenuated coincident with the reduction in gelsolin. Gelsolin was also missing or greatly decreased in 70% of 30 human sporadic, invasive breast carcinomas examined by immunocytochemistry and in 100% of virally induced mouse and chemically induced rat mammary carcinomas evaluated by Northern analysis. Southern analysis revealed no major mutations in the gelsolin gene of human breast cancer cells. Our results show that partial or total loss of gelsolin expression is common to the majority of breast cancers of diverse etiologies in three animal species and point to gelsolin as a candidate suppressor of breast cancer.

Invasive breast carcinoma: analysis of dynamic magnetic resonance imaging enhancement features and cell proliferative activity determined by DNA S-phase percentage.

BACKGROUND: There is little information regarding associations between magnetic resonance imaging (MRI) enhancement and biologic parameters of breast carcinoma. A prospective study was undertaken to correlate MRI dynamic contrast enhancement features with cell proliferative activity, as determined by DNA S-phase percentage. METHODS: Seventeen patients with invasive breast cancer underwent MRI at 1.5 tesla using a dynamic gadolinium-enhanced spoiled gradient recall echo technique. DNA analysis of samples of the excised lesions was then performed using flow cytometry. RESULTS: Invasive carcinomas with high DNA S-phase percentages (> or = 6.9%, the median value in this study), a measure of increased cell proliferation, were associated with a peripheral MRI enhancement pattern in 4 of 6 (67%) lesions compared with 0 of 11 carcinomas with lower DNA S-phase percentages (< or = 6.9%) (P = 0.006). There was no significant association between a high DNA S-phase percentage and greater MRI enhancement amplitude, rate, or washout. There was no significant association between aneuploid DNA content and any MRI enhancement feature. CONCLUSIONS: Increased cell proliferation in invasive breast carcinoma, as determined by high DNA S-phase percentage, is significantly associated with a peripheral MRI enhancement pattern but unrelated to greater MRI enhancement amplitude, rate, or washout.

Suspect breast lesions: findings at dynamic gadolinium-enhanced MR imaging correlated with mammographic and pathologic features.

PURPOSE: To prospectively correlate dynamic contrast enhancement at magnetic resonance (MR) imaging with mammographic and pathologic features of suspect breast lesions. MATERIALS AND METHODS: Forty-nine patients with 51 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging at 1.5 T, as well as excisional biopsy or cyst aspiration. RESULTS: Twenty-two of 22 (100%) invasive carcinomas 8 mm or more in diameter, including three (12%) not evident on dense mammograms, enhanced 2.0 or more times the unenhanced intensity. One of three predominantly ductal carcinomas in situ and 10 of 26 (38%) benign lesions enhanced 2.0 or more times. Time-intensity curves were not statistically significantly different among enhancing carcinomas, fibroadenomas, or other benign lesions and showed no statistically significant correlations with pathologic size, nodal status, or hormone receptor status of invasive carcinomas. CONCLUSION: MR imaging enhancement of 2.0 or more times had high sensitivity (100%) for invasive carcinomas 8 mm or more in diameter, with moderate specificity (65%). Time-intensity curves showed no significant difference between enhancement of benign and malignant lesions.

Calcium oxalate is associated with benign breast tissue. Can we avoid biopsy?

Breast biopsies are commonly performed for abnormal, usually clustered, calcifications detected by mammography. Calcium phosphate is the predominant form of calcium seen in breast tissue and is frequently associated with malignancy. Calcium oxalate, which can also be present in breast tissue, has been exclusively associated with benign lesions. Thus, if mammography could distinguish calcium phosphate from calcium oxalate, biopsy could be avoided in some patients. Pathologic findings and corresponding mammograms of 55 patients who underwent biopsy for abnormal calcifications were reviewed. The authors evaluated such pathologic features as type of calcification, anatomic location, and association with fibrocystic changes or carcinoma. Mammographically, calcifications were categorized by size, distribution, and morphology, and each was assigned a density rating of low, medium, or high. Of the 55 cases, 41 contained calcium phosphate only, 8 contained calcium oxalate only, and 6 contained both. If only calcium oxalate was present, the calcium was always associated with benign epithelium. Of 47 cases, calcium phosphate was associated with benign breast disease in 28 and with carcinoma in 19. Five of six cases with both calcium phosphate and calcium oxalate contained carcinoma; calcium phosphate was seen in the carcinoma area in all five. Radiologically, calcium phosphate was typically medium to high density, whereas calcium oxalate was characterized as amorphous, low to medium density. Other low-density calcifications were almost always benign, unless pleomorphic in shape. Although further work is necessary to confirm these findings, it appears that, radiologically, low-density, amorphous, calcifications, even if clustered, are associated with benign breast disease, and may represent calcium oxalate. Patients with such calcifications may be managed conservatively.