Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling.

PURPOSE: To develop a genome-based classification scheme for clear-cell sarcoma (CCS), also known as melanoma of soft parts (MSP), which would have implications for diagnosis and treatment. This tumor displays characteristic features of soft tissue sarcoma (STS), including deep soft tissue primary location and a characteristic translocation, t(12;22)(q13;q12), involving EWS and ATF1 genes. CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression, and a propensity for regional lymph node metastases. MATERIALS AND METHODS: RNA samples from 21 cell lines and 60 pathologically confirmed cases of STS, melanoma, and CCS/MSP were examined using the U95A GeneChip (Affymetrix, Santa Clara, CA). Hierarchical cluster analysis, principal component analysis, and support vector machine (SVM) analysis exploited genomic correlations within the data to classify CCS/MSP. RESULTS: Unsupervised analyses demonstrated a clear distinction between STS and melanoma and, furthermore, showed that CCS/MSP cluster with the melanomas as a distinct group. A supervised SVM learning approach further validated this finding and provided a user-independent approach to diagnosis. Genes of interest that discriminate CCS/MSP included those encoding melanocyte differentiation antigens, MITF, SOX10, ERBB3, and FGFR1. CONCLUSION: Gene expression profiles support the classification of CCS/MSP as a distinct genomic subtype of melanoma. Analysis of these gene profiles using the SVM may be an important diagnostic tool. Genomic analysis identified potential targets for the development of therapeutic strategies in the treatment of this disease.     

Quantitative tumor apoptosis imaging using technetium-99m-HYNIC annexin V single photon emission computed tomography.

PURPOSE: Radiolabeled annexin V may allow for repetitive and selective in vivo identification of apoptotic cell death without the need for invasive biopsy. This study reports on the relationship between quantitative technetium-99m- (99mTc-) 6-hydrazinonicotinic (HYNIC) radiolabeled annexin V tumor uptake, and the number of tumor apoptotic cells derived from histologic analysis. PATIENTS AND METHODS: Twenty patients (18 men, two women) suspected of primary (n = 19) or recurrent (n = 1) head and neck carcinoma were included. All patients underwent a spiral computed tomography (CT) scan, 99mTc-HYNIC annexin V tomography, and subsequent surgical resection of the suspected primary or recurrent tumor. Quantitative 99mTc-HYNIC annexin V uptake in tumor lesions divided by the tumor volume, derived from CT, was related to the number of apoptotic cells per tumor high-power field derived from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assays performed on sectioned tumor slices. RESULTS: Diagnosis was primary head and neck tumor in 18 patients, lymph node involvement of a cancer of unknown primary origin in one patient, and the absence of recurrence in one patient. Mean percentage absolute tumor uptake of the injected dose per cubic centimeter tumor volume derived from tomographic images was 0.0003% (standard deviation [SD], 0.0004%) at 1 hour postinjection (PI) and 0.0001% (SD, 0.0000%) at 5 to 6 hours PI (P =.012). Quantitative 99mTc-HYNIC annexin V tumor uptake correlated well with the number of apoptotic cells if only tumor samples with no or minimal amounts of necrosis were considered. CONCLUSION: In the absence of necrosis, absolute 99mTc-HYNIC annexin V tumor uptake values correlate well with the number of apoptotic cells derived from TUNEL assays.     

Markers of coagulation and angiogenesis in cancer-associated venous thromboembolism.

PURPOSE: We sought to determine whether venous thromboembolism in cancer patients is associated with aberrant plasma levels of hemostatic and angiogenic factors. PATIENTS AND METHODS: Peripheral blood was collected before anticoagulant therapy from cancer patients with acute deep venous thrombosis (DVT; DVT + cancer group, n = 32), those without DVT (cancer control group, n = 36), and patients with acute DVT but no cancer (DVT control group, n = 58). Plasma assays of activation and inhibition of coagulation and fibrinolysis, as well as angiogenesis activation, were then performed. RESULTS: Median levels of thrombin-antithrombin complex, prothrombin fragments 1 + 2, and von Willebrand factor antigen were significantly greater in the DVT + cancer group than in the cancer control and DVT control groups (17.8 ng/mL v 4.6 ng/mL and 9.8 ng/mL, P =.0001 and P =.003, respectively; 3.65 nmol/L v 1.60 nmol/L and 2.71 nmol/L, P <.0001 and P =.011, respectively; and 4.04 U/mL v 2.26 U/mL and 2.06 U/mL, P <.0001, respectively). Median levels of tissue-type plasminogen activator were also significantly higher, while protein C activity was lower in the DVT + cancer group than in the DVT control group (14.6 ng/mL v 9.50 ng/mL, respectively, P =.0005; 0.89 U/mL v 1.11 U/mL, respectively, P =.0008). CONCLUSION: These data not only support prior observations of coagulation activation in patients with malignancy, but also provide new evidence for enhanced coagulation activation in the setting of acute venous thromboembolism in cancer. Future prospective studies are warranted to determine whether these and other potential markers of hypercoagulability may help to identify cancer patients at highest risk for venous thromboembolism.     

A prospective study of the correlation between genital pathogens and morbidity following diathermy loop excision of the transformation zone.

A prospective study of 48 women was carried out to estimate the incidence of common genital pathogens in women referred to colposcopy clinic requiring diathermy loop excision and to compare patient morbidity in the subgroups with and without genital pathogens. Of the 43 women included in the analysis, genital pathogens were present in 24 cases (56%) and absent in 19 (44%) of the 24 positive cases, 19 (79%) women had pathogen(s) on the cervical swab, 24 (100%) had pathogen(s) on the high vaginal swab and 15 (63%) had both a positive cervical and high vaginal swab (HVS). The most frequently isolated groups of organisms were mixed anaerobes, alone (four HVS and four cervical) or in combination with Gardnerella vaginalis (four HVS and three cervical) or coliforms (two HVS and two cervical). The mean duration of bleeding and vaginal discharge in the two study groups was not statistically significant (t value 1.97, P 0.05; and t value 0.48, P 0.5, respectively). However, the mean duration of bleeding graded by the patient as being moderate to severe was significantly different in the two groups (t value 3.18 P 0.01). Fifty-six per cent of the women in the study had confirmed genital pathogens, predominantly anaerobes, and the prolonged moderate-to-severe bleeding in this group suggests a potential role for prophylactic bacteriocides, although the study size was unable to implicate a single pathogen.     

Do Multiple Measurements Employing Different Ultrasonic Techniques Improve the Accuracy of Amniotic Fluid Volume Assessment?

Summary: This investigation was undertaken to determine if the accuracy of the ultrasound assessment of abnormal amniotic fluid volume (oligohydramnios or poly-hydramnios) is improved by employing multiple sonographic amniotic fluid measurements. Four ultrasound techniques consisting of the subjective assessment (ultrasonic visualization without measurement), largest vertical pocket, amniotic fluid index and 2-diameter pocket technique were performed followed by amniocentesis and dye-dilution confirmation of amniotic fluid volume in 66 singleton pregnancies. The ultrasound accuracy to detect abnormal amniotic fluid volume ranged from 61% with the largest vertical pocket to 70% with the 2-diameter pocket procedure used separately. Receiver operator characteristic curves demonstrated that combining the 4 ultrasonic measurements did not improve the accuracy of identifying amniotic fluid volumes.     

Patient satisfaction with health care providers in South Africa: the influences of race and socioeconomic status.

OBJECTIVE: The first democratic government elected in South Africa in 1994 inherited huge inequalities in health status and health provision across all sections of the population. This study set out to assess, 4 years later, the influence of race and socioeconomic status (SES) on perceived quality of care from health care providers. DESIGN: A 1998 countrywide survey of 3820 households assessed many aspects of health care delivery, including levels of satisfaction with health care providers among different segments of South African society. RESULTS: Fifty-one percent (n = 1953) of the respondents had attended a primary care facility in the year preceding the interview and were retained in the analysis. Both race and SES were significant predictors of levels of satisfaction with the services of the health care provider, after adjusting for gender, age, and type of facility visited. White and high SES respondents were about 1.5 times more likely to report excellent service compared with Black and low SES respondents, respectively. CONCLUSION: In South Africa, race and SES are not synonymous and can no longer be considered reliable proxy indicators of one another. Each has distinct and significant but different degrees of association with client satisfaction. Any assessment of equity-driven health policy in South Africa should consider the impacts of both race and SES on client satisfaction as one of the indicators of success.     

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer.

We evaluated somatic genetic alterations in the kinase domain of the EGFR gene in the tumors of 219 non-small cell lung cancer patients of primarily Caucasian and African American origins. We identified 26 patients (12%) whose tumors had a mutation in the EGFR gene, and 11 (5%) patients carried novel genomic variations consistent with germ-line polymorphisms. All but one mutation were identified in Caucasian patients affected with adenocarcinoma. EGFR mutations were more frequent in women and in nonsmokers, but a significant portion of the affected patients were men (12 of 26) and current or past smokers accounted for half of the patients affected (13 of 26). Screening subjects with EGFR mutations may identify patients whose tumors could respond to targeted therapy using tyrosine kinase inhibitors.     

Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol).

PURPOSE: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophor-ethanol (Taxol). EXPERIMENTAL DESIGN: ABI-007 and Taxol were given i.v. to Harlan Sprague-Dawley male rats to determine pharmacokinetic and drug disposition. Paclitaxel pharmacokinetic properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m(2), 30 minutes; n = 14) or Taxol (175 mg/m(2), 3 hours; n = 13), with cycles repeated every 3 weeks. RESULTS: The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans [21.13 versus 14.76 L/h/m(2) (P = 0.048) and 663.8 versus 433.4 L/m(2) (P = 0.040), respectively]. CONCLUSIONS: Paclitaxel formulated as ABI-007 differs from paclitaxel formulated as Taxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness.     

黄芪总黄酮抗肝损伤作用初探

目的研究黄芪总黄酮(total navonoids 0f Astragalus,TFA)对扑热息痛所致小鼠肝损伤的预防功效。方法观察不同剂量(0、100、300、400、500 ms/kg)扑热息痛对c57BL/6J小鼠肝脏的损伤作用,比较经1天或5天(每天2次)的TFA预处理后对扑热息痛(400 mg/kg)所致肝损伤的防护作用。结果扑热息痛对小鼠肝损伤作用具有明显的量效关系。不同剂量的TFA对扑热息痛诱导小鼠肝损伤有不同程度的防护作用,其作用强度与药物浓度成正比；TFA可增加血清中SOD活性(P＜0．05)；高剂量的TFA(100mg/kg)具有降低肝组织中脂质过氧化物质的作用；此外,在相同TFA剂量下,5天组对扑热息痛诱导小鼠肝损伤的预防作用优于1天组。结论提示TFA可预防扑热息痛诱导的肝损伤,其预防作用与其使用时间有密切关系。     

A preliminary FMRI study of sustained attention in euthymic, unmedicated bipolar disorder.

The symptoms of bipolar disorder suggest dysfunction of anterior limbic networks that modulate emotional behavior and that reciprocally interact with dorsal attentional systems. Bipolar patients maintain a constant vulnerability to mood episodes even during euthymia, when symptoms are minimal. Consequently, we predicted that, compared with healthy subjects, bipolar patients would exhibit abnormal activation of regions of the anterior limbic network with corresponding abnormal activation of other cortical areas involved in attentional processing. In all, 10 unmedicated euthymic bipolar patients and 10 group-matched healthy subjects were studied with fMRI while performing the Continuous Performance Task-Identical Pairs version (CPT-IP). fMRI scans were obtained on a 3.0 T Bruker system using an echo planar imaging (EPI) pulse sequence, while subjects performed the CPT-IP and a control condition to contrast group differences in regional brain activation. The euthymic bipolar and healthy subjects performed similarly on the CPT-IP, yet showed significantly different patterns of brain activation. Specifically, bipolar patients exhibited increased activation of limbic, paralimbic, and ventrolateral prefrontal areas, as well as visual associational cortices. Healthy subjects exhibited relatively increased activation in fusiform gyrus and medial prefrontal cortex. In conclusion, these differences suggest that bipolar patients exhibit overactivation of anterior limbic areas with corresponding abnormal activation in visual associational cortical areas, permitting successful performance of an attentional task. Since the differences occurred in euthymia, they may represent trait, rather than state, abnormalities of brain function in bipolar disorder.