Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: common mechanisms and possible targets for intervention.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including kidneys, skin, joints, blood and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to the activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in patients with SLE compared to age- and gender-matched controls, and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T-cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies.

Lupus-prone New Zealand Black/New Zealand White F1 mice display endothelial dysfunction and abnormal phenotype and function of endothelial progenitor cells.

Patients with systemic lupus erythematosus (SLE) have an impairment in phenotype and function of endothelial progenitor cells (EPCs) which is mediated by interferon alpha (IFN-alpha). We assessed whether murine lupus models also exhibit vasculogenesis abnormalities and their potential association with endothelial dysfunction. Phenotype and function of EPCs and type I IFN gene signatures in EPC compartments were assessed in female New Zealand Black/New Zealand White F(1) (NZB/W), B6.MRL-Fas(lpr)/J (B6/lpr) and control mice. Thoracic aorta endothelial and smooth muscle function were measured in response to acetylcholine or sodium nitropruside, respectively. NZB/W mice displayed reduced numbers, increased apoptosis and impaired function of EPCs. These abnormalities correlated with significant decreases in endothelium-dependent vasomotor responses and with increased type I IFN signatures in EPC compartments. In contrast, B6/lpr mice showed improvement in endothelium-dependent and endothelial-independent responses, no abnormalities in EPC phenotype or function and downregulation of type I IFN signatures in EPC compartments. These results indicate that NZB/W mice represent a good model to study the mechanisms leading to endothelial dysfunction and abnormal vasculogenesis in lupus. These results further support the hypothesis that type I IFNs may play an important role in premature vascular damage and, potentially, atherosclerosis development in SLE.

Effects of prasterone (dehydroepiandrosterone) on markers of cardiovascular risk and bone turnover in premenopausal women with systemic lupus erythematosus: a pilot study.

DHEA (dehydroepiandrosterone) is a weak androgen with proposed efficacy in the treatment of mild to moderate lupus, and possible beneficial effects on cardiovascular risk and bone mineral density. We hypothesized that treatment with 200 mg a day of Prasterone (DHEA) would improve pre-clinical measures of atherosclerosis: flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), and circulating apoptotic endothelial cells (CD 146(AnnV +)), as well markers of bone metabolism. Thirteen premenopausal female patients with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)

Technical comment on "Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis".

Reassessment of citrullinome cargo in neutrophil extracellular traps confirms the presence of citrullinated peptides.

Specimen Collection for Translational Studies in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by painful nodules, sinus tracts, and scars occurring predominantly in intertriginous regions. The prevalence of HS is currently 0.053-4%, with a predominance in African-American women and has been linked to low socioeconomic status. The majority of the reported literature is  retrospective, population based, epidemiologic studies. In this regard, there is a need to establish a repository of biospecimens, which represent appropriate gender and racial demographics amongst HS patients. These efforts will diminish knowledge gaps in understanding the disease pathophysiology. Hence, we sought to outline a step-by-step protocol detailing how we established our HS biobank to facilitate the formation of other HS tissue banks. Equipping researchers with carefully detailed processes for collection of HS specimens would accelerate the accumulation of well-organized human biological material. Over time, the scientific community will have access to a broad range of HS tissue biospecimens, ultimately leading to more rigorous basic and translational research. Moreover, an improved understanding of the pathophysiology is necessary for the discovery of novel therapies for this debilitating disease. We aim to provide high impact translational research methodology for cutaneous biology research and foster multidisciplinary collaboration and advancement of our understanding of cutaneous diseases.

Impaired translational response and increased protein kinase PKR expression in T cells from lupus patients.

Activation of peripheral blood T cells results in a rapid and substantial rise in translation rates and proliferation, but proliferation in response to mitogen stimulation is impaired in systemic lupus erythematosus (SLE). We have investigated translation rates and initiation factor activities in T cells from SLE patients in response to activating signals. Activation by PMA plus ionomycin strongly increased protein synthesis in control T cells but not in T cells from SLE patients. The rate of protein synthesis is known to be strongly dependent on the activity of two eukaryotic translation initiation factors, eIF4E and eIF2alpha. We show that following stimulation, eIF4E expression and phosphorylation increased equivalently in control and SLE T cells. Expression of eIF4E interacting proteins - eIF4G, an inducer, and 4E-BP1 and 4E-BP2, two specific repressors of eIF4E function - and the phosphorylation level of 4E-BP1, were all identical in control and SLE T cells. In contrast, the protein kinase PKR, which is responsible for the phosphorylation and consequent inhibition of eIF2alpha activity, was specifically overexpressed in activated SLE T cells, correlating with an increase in eIF2alpha phosphorylation. Therefore, high expression of PKR and subsequent eIF2alpha phosphorylation is likely responsible, at least in part, for impaired translational and proliferative responses to mitogens in T cells from SLE patients.

Frequent novel DNA copy number increase in squamous cell head and neck tumors.

We have undertaken a study of DNA copy number changes in head and neck squamous cell carcinomas to identify novel DNA copy number changes and to determine the significance of previous findings of cytogenetic alterations in cultured cells. Comparative genomic hybridization was performed on genomic DNA extracted from ten tumors. A novel copy number gain on chromosome 3q26-27 and a loss of chromosome 3p were found at high frequency (> or = 50% of tumors). Many other novel chromosomal copy number changes were identified but occurred at a lower frequency. In addition, our data confirm that DNA copy number changes that frequently occur in cultured cells, such as loss of chromosome 3p, also occur in tumors. Frequently altered loci may encode oncogenes or tumor suppressor genes involved in head and neck squamous cell carcinoma tumorigenesis.

Enlargement of cerebral third ventricle in psychotic patients with delayed response to neuroleptics.

Enlargement of the cerebral third ventricle appears to be a replicable finding in groups of patients with psychotic illnesses, and there is evidence for an association of third ventricle enlargement with poorer response to treatment. Third ventricle area and width were measured from computed tomography (CT) scans in 24 mood-incongruent psychotic patients and 14 controls age and gender matched to schizophrenic patients. Patients were treated with a fixed dose of haloperidol and classified as rapid responders (55% symptom reduction on New Haven Schizophrenic Index (NHSI) within 4.5 +/- 1.3 days) or delayed responders (55% symptom reduction on NHSI within 18.6 +/- 10.5 days). The significant enlargement of third ventricle area was isolated among the 12 delayed neuroleptic responders (19.3 +/- 9.0 mm2) compared with the 14 controls (11.7 +/- 4.8 mm2, p = 0.01), and 12 other mood-incongruent psychotics. Third ventricle width also showed a trend towards larger width in the delayed responders. There was a clear positive correlation between ventricular size and patient's age exclusively in the delayed responders (r = 0.78); a comparable relationship between ventricular size and age was not present in controls, or in the other psychotics. This finding is consistent with an age-related progressive degenerative process in the central nervous system (CNS) isolated to the neuroleptic-delayed responsive psychotics.

Psychiatrists' beliefs about gender-appropriate behavior.

Psychiatrists' beliefs regarding gender-appropriate behavior may influence their treatment of patients. Psychiatrists of both sexes (men: N = 76; women: N = 57) were asked to characterize optimal mental health for hypothetical female and male patients on the Bem Sex Role Inventory. The subjects' ratings for men and women were similar with two exceptions: more of the female psychiatrists rated masculine traits as optimal for female patients, and more male psychiatrists chose traits characteristic of Bem's undifferentiated category (low levels of both masculine and feminine traits) as optimal for both male and female patients. The results indicate significant changes in psychiatrists' attitudes toward gender in the past 20 years.

Prognostic factors in adult soft-tissue sarcomas of the head and neck.

PURPOSE: The main objectives of this study were (a) to review the treatment results of primary head and neck soft-tissue sarcoma at our institution, (b) to identify important prognostic factors in local control and survival, and (c) to assess the efficacy of salvage therapy. METHODS AND MATERIALS: Sixty-five patients were treated at the University of California, San Francisco, between 1961 and 1993. Seventeen patients (27%) had low-grade, 10 (15%) had intermediate-grade, and 38 (58%) had high-grade sarcomas. Tumors were > 5 cm in 35 patients. Local management consisted of surgery alone in 14 patients (22%), surgery and radiotherapy in 40 (61%), and radiotherapy alone in 11 (17%) patients. The median follow-up was 64 months. RESULTS: The 5-year actuarial local control rate of the entire group was 66%. Tumor size and grade were important predictors for local control on multivariate analysis. The actuarial local control rate at 5 years was 92% for T1 vs. 40% for T2 primaries (p = 0.004), and 80% for Grade 1-2 vs. 48% for Grade 3 tumors (p = 0.01). None of the patients treated with radiotherapy alone with a dose of 50-65 Gy were controlled locally. Combined radiotherapy and surgery appeared to yield superior local control compared to surgery alone (77% vs. 59%); however, the difference was not statistically significant. The 5-year actuarial overall and cause-specific survivals were 56% and 60%, respectively. Unfavorable prognostic factors for cause-specific survival on multivariate analysis were age > 55 (p = 0.009), high tumor grade (p = 0.0002), inadequate surgery (p = 0.008), and positive surgical margins (p = 0.0009). In patients who underwent salvage therapy for treatment failure, the 5-year actuarial survival after salvage treatment was 26%. CONCLUSION: Tumor size and grade were important predictors for local control. Age, grade, adequacy of surgery, and status of surgical margins were significant prognostic factors for survival. There was a trend of improved local control with combined surgery and radiotherapy compared to either modality alone for high-risk patients. Radiotherapy alone with doses < or = 65 Gy was insufficient for control of gross disease. Aggressive salvage therapy was worthwhile in patients whose disease was uncontrolled after the initial treatment.

Lymph node metastasis in maxillary sinus carcinoma.

PURPOSE: To evaluate the incidence and prognostic significance of lymph node metastasis in maxillary sinus carcinoma. METHODS AND MATERIALS: We reviewed the records of 97 patients treated for maxillary sinus carcinoma with radiotherapy at Stanford University and at the University of California, San Francisco between 1959 and 1996. Fifty-eight patients had squamous cell carcinoma (SCC), 4 had adenocarcinoma (ADE), 16 had undifferentiated carcinoma (UC), and 19 had adenoid cystic carcinoma (AC). Eight patients had T2, 36 had T3, and 53 had T4 tumors according to the 1997 AJCC staging system. Eleven patients had nodal involvement at diagnosis: 9 with SCC, 1 with UC, and 1 with AC. The most common sites of nodal involvement were ipsilateral level 1 and 2 lymph nodes. Thirty-six patients were treated with definitive radiotherapy alone, and 61 received a combination of surgical and radiation treatment. Thirty-six patients had neck irradiation, 25 of whom received elective neck irradiation (ENI) for N0 necks. The median follow-up for alive patients was 78 months. RESULTS: The median survival for all patients was 22 months (range: 2.4-356 months). The 5- and 10-year actuarial survivals were 34% and 31%, respectively. Ten patients relapsed in the neck, with a 5-year actuarial risk of nodal relapse of 12%. The 5-year risk of neck relapse was 14% for SCC, 25% for ADE, and 7% for both UC and ACC. The overall risk of nodal involvement at either diagnosis or on follow-up was 28% for SCC, 25% for ADE, 12% for UC, and 10% for AC. All patients with nodal involvement had T3-4, and none had T2 tumors. ENI effectively prevented nodal relapse in patients with SCC and N0 neck; the 5-year actuarial risk of nodal relapse was 20% for patients without ENI and 0% for those with elective neck therapy. There was no correlation between neck relapse and primary tumor control or tumor extension into areas containing a rich lymphatic network. The most common sites of nodal relapse were in the ipsilateral level 1-2 nodal regions (11/13). Patients with nodal relapse had a significantly higher risk of distant metastasis on both univariate (p = 0.02) and multivariate analysis (hazard ratio = 4.5, p = 0.006). The 5-year actuarial risk of distant relapse was 29% for patients with neck control versus 81% for patients with neck failure. There was also a trend for decreased survival with nodal relapse. The 5-year actuarial survival was 37% for patients with neck control and 0% for patients with neck relapse. CONCLUSION: The overall incidence of lymph node involvement at diagnosis in patients with maxillary sinus carcinoma was 9%. Following treatment, the 5-year risk of nodal relapse was 12%. SCC histology was associated with a high incidence of initial nodal involvement and nodal relapse. None of the patients presenting with SCC histology and N0 necks had nodal relapse after elective neck irradiation. Patients who had nodal relapse had a higher risk of distant metastasis and poorer survival. Therefore, our present policy is to consider elective neck irradiation in patients with T3-4 SCC of the maxillary sinus.

Leflunomide Aventis Pharma.

Hoechst Marion Roussel (HMR; now Aventis Pharma) launched leflunomide (HWA-486), an immunomodulator and a disease-modifying antirheumatic drug (DMARD), for the treatment of rheumatoid arthritis (RA) in the US in late 1998 [310118]. By August 2000, the compound had been launched extensively across all of Latin America and in all major European countries [380046]. The compound is also under preclinical investigationfor the prevention of transplant rejection [279727], [304402]. In 1998, HMR filed for approvalfor RA in Europe [279727]. In September 1998, the FDA approved leflunomide for the treatment of active RA in adults and it was launched shortly thereafter [298204], [299258], [310118]. In September 1999, the EU Commission accepted the view of the Committee for Proprietary Medicinal Products, published in May 1999 [326040], [337534], and gave approval for the use of leflunomide in RA in adults [339128]. Lehman Brothers has reported that EU launch was delayed by rare side effects including pancytopenia [354434]. In August 1998, the Arthritis Advisory Committee unanimously recommended that leflunomide be contraindicatedfor pregnancy, and that a pregnancy registry should be established to monitor possible teratogenic effects of the drug [296187]. Kyorin had a licence to develop leflunomide in Japan. Product approval was scheduled for 1998 [159079], but no development has been reported since 1994. Preclinical studies in an animal model of experimental allergic encephalomyelitis (EAE) have shown leflunomide to be a powerful immunosuppressant which may have potential in diseases such as multiple sclerosis [187881]. Leflunomide is rapidly processed in vivo to its active metabolite, A-771726 (RS-61980) [202941], [253615]. In 1996, leflunomide was designated as one of HMR's nine top-priority products, serving an unmet medical need and addressing a potential market in excess of US $500 million per year [221118].

Cimetidine-induced alterations in desipramine plasma concentrations.

Concurrent administration of cimetidine for 4 days to eight patients taking maintenance doses of desipramine led to significant elevations of desipramine (P less than 0.001) and its hydroxylated metabolite 2-hydroxydesipramine (P less than 0.001). The mean increase in desipramine plasma levels was 51% and that for 2-hydroxydesipramine was 46%. The present results suggest that tricyclic antidepressant plasma level monitoring might be indicated for certain patients taking concurrent cimetidine and desipramine.

Fine-needle aspiration biopsy in the management of solid breast tumors.

Fine-needle aspiration biopsy (FNA) is a cost-effective and clinically reliable tool in the management of palpable solid breast lesions. Review of 369 FNA biopsy specimens revealed an accuracy of 92%. The sensitivity was 78% and the specificity was 100%. There were no false-positive results. Positive predictive value was 100%, and negative predictive value was 78%. A positive FNA biopsy result, which confirms a clinical (physical examination and mammography) impression of carcinoma, can be the basis for planning and performing a definitive procedure. Despite the absence of false-positive results, we have not proceeded with a definitive surgical procedure if an FNA biopsy result disagreed with our clinical impression. Fine-needle aspiration biopsy may be used to reassure and support both the patient's and the surgeon's decision not to perform a biopsy of "subsuspicious lesions." A negative FNA biopsy result does not exonerate the clinically suspicious lesion.

Microsurgical reconstruction of the midface.

OBJECTIVE: To establish a treatment algorithm for reconstructing complex midfacial defects. DESIGN: Retrospective case series. SETTING: University-based teaching hospital. PATIENTS: Thirty-one consecutive patients were treated from 1991 through 1995. The 18 males and 13 females were aged 15 to 90 years (mean age, 58 years). The cause of the defect included neoplasm (n = 27) and trauma (n = 4). Reconstruction consisted of 1 of 4 free flaps: rectus abdominis, radial forearm, fibula, or latissimus dorsi. Aesthetic and functional results were determined by patient questionnaires and physical examinations. MAIN OUTCOME MEASURES: Length of stay, postoperative morbidity and mortality, degree of aesthetic and functional restoration, and detection of tumor recurrence. RESULTS: Twenty-seven (87%) of the 31 patients underwent reconstruction with a single major procedure. All of the flaps survived. Postoperative hospital stays averaged 14 days. Late tumor recurrence occurred in 7 (23%) of the 31 patients and was promptly detected. Aesthetic and functional results were rated good or excellent in 77% (24/31) and 87% (27/31) of patients, respectively. Of the 20 patients who underwent alveolar ridge resection, 16 (80%) received dental rehabilitation, 44% of whom received osseointegrated implants into either a bone flap or remaining native bone. Osseointegrated implants were inset during the initial reconstruction 57% (4/7 patients) of the time. CONCLUSIONS: For complex midfacial defects, free-flap transfer can be performed with a high degree of success, restoring both appearance and function in most patients. The only instance in which bone is necessary to reconstruct the midface involves those areas in which osseointegrated implants are needed, ie, alveolar ridge (dental implant) and/or orbit (ocular prosthesis). In such cases, the fibula osteocutaneous free flap is the flap of choice. Otherwise, soft-tissue flaps are selected based on wound size.

Systemic toxicity following administration of sirolimus (formerly rapamycin) for psoriasis: association of capillary leak syndrome with apoptosis of lesional lymphocytes.

BACKGROUND: Sirolimus (formerly rapamycin) is an immunosuppressive agent that interferes with T-cell activation. After 2 individuals with psoriasis developed a capillary leak syndrome following treatment with oral sirolimus lesional skin cells and activated peripheral blood cells were analyzed for induction of apoptosis. OBSERVATIONS: A keratome skin specimen from 1 patient with sirolimus-induced capillary leak syndrome had a 2.3-fold increase in percentage of apoptotic cells (to 48%) compared with an unaffected sirolimus-treated patient with psoriasis (21%). Activated peripheral blood T cells from patients with psoriasis tended to exhibit greater spontaneous or dexamethasone-induced apoptosis than did normal T cells, particularly in the presence of sirolimus. CONCLUSIONS: Severe adverse effects of sirolimus include fever, anemia, and capillary leak syndrome. These symptoms may be the result of drug-induced apoptosis of lesional leukocytes, especially activated T lymphocytes, and possibly release of inflammatory mediators. Because patients with severe psoriasis may develop capillary leak from various systemic therapies, clinical monitoring is advisable for patients with inflammatory diseases who are treated with immune modulators.

Recurrence of clival chordoma along the surgical pathway.

Chordomas are locally aggressive malignant tumors of notochordal origin whose metastatic potential is increasingly recognized. Surgical pathway recurrence has been noted only rarely in the literature. We present three patients with clival chordomas whose sole or initial recurrence was along the pathway of prior surgical access. A characteristic mass found along the pathway of prior surgical access for resection of a chordoma should suggest recurrent chordoma.

MR imaging in two cases of subacute denervation change in the muscles of facial expression.

SUMMARY: Denervation changes in muscle following damage to cranial and peripheral nerves can be observed on both CT and MR imaging studies. These findings are well described for cranial nerves (CN) V, X, XI, and XII. The CT findings of denervation atrophy due to CN VII dysfunction have been reported. We describe the MR imaging findings in two patients with perineural spread of tumor along CN VII. Both patients showed T2 prolongation and postcontrast enhancement in muscles of facial expression, suggestive of subacute denervation changes.

Clinical utility of positron emission tomography with 18F-fluorodeoxyglucose in detecting residual/recurrent squamous cell carcinoma of the head and neck.

PURPOSE: The use of positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) to detect residual/recurrent squamous cell carcinoma of the head and neck has been tested only in small groups of patients. Our purpose, therefore, was to evaluate the ability of this technique to detect the presence of tumor at both primary and nodal sites in a large cohort of patients. METHODS: All patients referred for PET scanning over a 2.5-year period with a question of residual or recurrent squamous cell carcinoma of the head and neck were identified. Thirty-five of 44 patients had sufficient follow-up to be meaningful to our analysis (range, 6-33 months). PET scans were interpreted visually with knowledge of the clinical history and correlative anatomic imaging findings. Detection of disease involving primary and nodal sites was assessed independently. Additionally, because each patient had been referred in an attempt to resolve a specific clinical problem, the usefulness of PET in accurately addressing these questions was assessed. RESULTS: At the primary site, sensitivity and specificity for residual/recurrent disease were 100% and 64%, respectively; for nodal disease, sensitivity and specificity were 93% and 77%, respectively. In helping to resolve the clinical question being asked, the positive predictive value of the test result was 65% and the negative predictive value was 91%. CONCLUSION: The high sensitivity and negative predictive value of PET scanning in our cohort of patients suggest an important role for this technique in the care of patients with suspected residual/recurrent head and neck carcinoma. The lower figures obtained for specificity and positive predictive value reflect the fact that increased FDG uptake may be due to either tumor or inflammation.

The transsphenoethmoid approach to the sphenoid sinus and clivus.

Surgical access to the sphenoid sinus and clivus for the resection of benign and malignant disease is difficult and is often associated with significant morbidity. The transsphenoethmoid approach, an extension of a familiar otolaryngological procedure, with or without a limited medial maxillectomy, allows access to this region with little morbidity and excellent cosmetic results. Since 1988, the transsphenoethmoid approach has been used in 15 patients at our institution for resection of primary and recurrent chordomas, chondrosarcomas, pituitary macroadenomas, repair of cerebrospinal fluid leaks, and drainage of petroclival cysts. In most instances, an ipsilateral approach is most satisfactory. When necessary, a contralateral transsphenoethmoid approach is used when the tumor is posterolateral to the internal carotid artery and as far lateral as the abducens nerve.