Meta-analysis of sentinel node imprint cytology in breast cancer

BACKGROUND: Intraoperative diagnosis of breast cancer metastases in axillary sentinel nodes is desirable to avoid a second operation for lymphadenectomy. Imprint or touch-preparation cytology is a popular technique that has high specificity and a wide range of sensitivity. METHODS: A systematic search of electronic databases was performed. Included articles were assessed for methodological and reporting quality. Random-effects model pooled estimates of sensitivity and specificity were calculated. Single-variable and multivariable meta-regression analyses were performed for predictors of sensitivity. RESULTS: Thirty-one studies were included; all were of good methodological quality but reporting quality varied. Pooled sensitivity of imprint cytology was 63 (95 per cent confidence interval (c.i.) 57 to 69) per cent and specificity was 99 (95 per cent c.i. 98 to 99) per cent. Pooled sensitivity for macrometastases was 81 per cent and that for micrometastases 22 per cent. Mean or median primary tumour size (P = 0.004), the prevalence of metastases (P = 0.103) and the proportion of micrometastases (P = 0.022) were significant risk factors in single-variable meta-regression analysis. Only the proportion of micrometastases remained significant in multivariable analysis. Frozen sectioning had better sensitivity than imprint cytology in three of four direct comparisons. CONCLUSION: Imprint cytology is simple and rapid, and has good sensitivity for macrometastases. The significance of poor sensitivity for micrometastases will be determined by trials investigating their natural history.     

Dexamethasone inhibits maturation and alters function of monocyte-derived dendritic cells from cord blood

Critically ill infants are treated with dexamethasone (Dx) and other glucocorticoids to reduce inflammation and to promote lung and cardiac function. The neonatal immune system is immature, so neonatal dendritic cells (DCs) might be especially sensitive to glucocorticoid-mediated immunosuppression. To test this, we compared Dx treatment of monocyte-derived DCs from cord (CB) and adult blood (AB). Dx decreased CD1a levels on both AB and CB DCs. CB-treated cells also exhibited decreased expression of CD83 and increased expression of CD14, alterations not observed in AB DCs. Characteristic immature endocytic activity was sustained and enhanced in Dx-treated CB DCs, whereas AB DCs matured normally. Maintenance of endocytosis corresponded with CD14 expression. Dx markedly increased CB DC IL-10, a T cell helper 2 (Th2)-preferential cytokine, while reducing IL-12, a counterbalancing Th1 cytokine. AB DCs were also affected, but increases in IL-10 and decreases in IL-12 were more modest. Dx treatment also inhibited DC-induced T cell proliferation, but CB DCs were inhibited more. In short, neonatal DCs seemed to be especially sensitive to the immunosuppressive effects of Dx as indicated by altered phenotype, endocytic function, ability to stimulate T cells, and cytokine shift favoring Th2. These alterations in DC function are consistent with an increased risk for certain infections and atopic diseases.     

Comparison of type 1 and type 2 cytokine production by mononuclear cells cultured with streptococcus mutans and selected other caries bacteria

A feature of pulpal immune responses is the predominance of type 1 cytokine mRNA under shallow caries and a mixed (type 1/type 2) profile under deep caries. These results prompted an examination of the cytokine profiles induced by bacteria in shallow caries (Streptococcus mutans and Actinomyces viscosus) and deep caries (Lactobacillus casei, Pseudoramibacter alactolyticus, and Prevotella intermedia). All isolates induced interferon-gamma and interleukin-10, whereas interleukin-4 and interleukin-2 titers were low to undetectable. S. mutans was the most potent and persistent interferon-gamma inducer. Differences in interleukin-10 were apparent at low doses but were less dramatic, with L. casei the dominant producer. S. mutans induced substantially more interferon-gamma than interleukin-10 over all doses and time points, suggesting strong type 1 polarization. P. alactolyticus induced significantly more interleukin-10 than interferon-gamma at higher concentrations, suggesting polarization toward type 2. A similar amount of interferon-gamma and interleukin-10 induced by L. casei, A. viscosus, and P. intermedia reflected a mixed profile. A better understanding of pulpal immune response to caries bacteria may enable us to develop an immune system-based pulp therapy in the future.     

Patient perception of comorbid conditions after acoustic neuroma management: survey results from the acoustic neuroma association

OBJECTIVES/HYPOTHESIS: Based on survey results of the Acoustic Neuroma Association, the patient ratings of the most difficult aspects of acoustic neuroma management were reported and a review of the literature was made regarding comorbid conditions associated with acoustic neuroma treatment and their impact on patient quality of life. STUDY DESIGN: Cohort study of 1940 patients who were members of the Acoustic Neuroma Association. METHODS: A detailed questionnaire was mailed to 2372 members of the Acoustic Neuroma Association to identify preoperative and postoperative symptoms, complications, and long-term effects on physical and psychosocial function. For 1940 respondents (81.8%) who reported the "most difficult aspect of the AN [acoustic neuroma] experience," the responses were analyzed by tumor size, surgical approach, and patient age and sex. Statistical analysis was performed using SPSS software. RESULTS: Respondents reported that the most difficult aspect of the acoustic neuroma experience was hearing loss (25.8%), followed by facial weakness (17.9%), eye problems (10.8%), and headache (10.5%). In order of frequency, men reported hearing loss, balance problems, perioperative surgical experience, and eye and facial weakness, and women reported hearing loss, facial weakness, eye problems, and headache. Facial weakness was a morbidity more often reported for men and women who had large tumors, who were young, or who had undergone the retrosigmoid approach. Balance dysfunction was significant in patients older than 75 years of age. In patients with small tumors, headaches and balance problems were frequently reported. CONCLUSION: In the large cohort study of patients with acoustic neuroma, perceptions regarding the impact of treatment illustrated why it is incumbent on physicians to understand the sentiments of patients with acoustic neuroma when counseling them and recommending optimal management strategies.     

Intradural aneurysm arising from the posterior genu of the cavernous carotid artery mimicking a posterior communicating aneurysm: case report

OBJECTIVE AND IMPORTANCE: We present a rare case of an intradural aneurysm that arose from the posterior genu of the cavernous carotid artery and was diagnosed via angiography as originating from the internal carotid artery (ICA) at the level of the posterior communicating artery. Our review of the English-language literature found no other case of an intradural aneurysm that originated at the posterior genu of the cavernous ICA. CLINICAL PRESENTATION: A 65-year-old woman presented with increasingly severe left retro-orbital headaches. Her family history included aneurysmal subarachnoid hemorrhage. Angiography revealed an 11-mm aneurysm, which was interpreted as arising from the left ICA at the level of the posterior communicating artery. INTERVENTION: During a left pterional craniotomy, an aneurysm was identified underneath the oculomotor nerve; its neck seemed to arise from the posterior communicating artery segment. Despite clipping of the aneurysm attachment to the ICA and trapping of the posterior communicating segment, the aneurysm continued to fill. Further dissection revealed that the aneurysm's neck originated from the cavernous ICA. Placement of fenestrated clips around the oculomotor nerve successfully occluded the intradural portion of the aneurysm, as documented by an intraoperative angiogram. CONCLUSION: We discuss this unique case to draw attention to the importance of the interpretation and adequacy of preoperative angiography, and we review pertinent vascular anatomy.     

Cyclic ketone inhibitors of the cysteine protease cathepsin K

Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure--activity studies on a series of acyclic ketone-based inhibitors of cathepsin K have led to the design and identification of two series of cyclic ketone inhibitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consistent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred. This C-3 stereochemical preference is in contrast to the X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer. The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of the enzyme in two alternate directions. Epimerization issues associated with the labile alpha-amino ketone diastereomeric center contained within these inhibitor classes has proven to limit their utility despite promising pharmacokinetics displayed in both series of compounds.     

Glutathione S-transferases in nitrogen mustard-resistant and -sensitive cell lines

Tumor cell resistance to alkylating agents was studied by examining Walker 256 rat mammary carcinoma cells differentially sensitive to nitrogen mustards. A resistant subpopulation (WR) was selected by exposure to chlorambucil. WR cells showed approximately a 15-fold resistance to the cytotoxic effects of nitrogen mustards and elevated glutathione S-transferase (GST) activity when compared to the sensitive parent cell line (WS). To extend these findings, the GSTs from WR and WS were purified by affinity chromatography on S-hexylglutathione coupled to epoxy-activated agarose. Substrate specificity experiments using purified GSTs demonstrated different profiles of enzyme activity for WR and WS and suggested differential isoenzyme expression in these two cell lines. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis revealed that the major GST present in both WR and WS was a 26,000-Da subunit that was immunologically distinct from the rat liver GSTs. This GST subunit cross-reacted with antibodies against anionic human placental GST. In addition, three GST forms common to rat liver (29,500, 28,500 and 27,500 molecular weight) were also identified. Overexpression of the 29,500-Da protein was observed in WR cells. These data suggest that differential expression of GST subunits may contribute to the nitrogen mustard-resistant phenotype.     

Identification of a glutathione S-transferase associated with microsomes of tumor cells resistant to nitrogen mustards

Walker 256 rat mammary carcinoma cells resistant to chlorambucil (WR) exhibited an approximate 4-fold increase in glutathione S-transferase (GST) activity using 1-chloro-2,4-dinitrobenzene as compared to the sensitive parent cell line (WS). WR cells maintained without biannual exposure to chlorambucil (WRr) reverted to the sensitive phenotype and possessed GST levels equivalent to WS. Mitochondria, microsomes and cytosol were isolated from WS, WR and WRr cell lines and analyzed for their GST composition. GST activity in each subcellular compartment of resistant cells was increased over the sensitive cells. Antibodies raised against total rat liver cytosolic GST crossreacted in resistant cells with two microsomal proteins (25.7 kD and 29 kD). The 29 kD protein was not detected in microsomal fractions from either WS or WRr and this protein was found to be dissimilar from cytosolic GST subunits in its isoelectric point (pI 6.7) and migration on two-dimensional polyacrylamide gels. In addition, the 29 kD microsome-associated GST from WR cells was immunologically distinct from a 14 kD GST subunit previously identified in rat liver microsomes. These data implicate the induction of a specific microsomal GST subunit in WR cells following drug selection and suggest its potential involvement in the establishment of cellular resistance to chlorambucil.