Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype.

Familial aggregations of testicular germ cell tumor (FTGCT) have been well described, suggesting the existence of a hereditary TGCT subset. Approximately 1.4% of newly diagnosed TGCT patients report a positive family history of TGCT. Sons and siblings of TGCT patients have four- to sixfold and eight- to tenfold increases in TGCT risk respectively. Segregation analyses suggest an autosomal recessive mode of inheritance. Linkage analyses have identified several genomic regions of modest interest, although no high-penetrance cancer susceptibility gene has been mapped yet. These data suggest that the combined effects of multiple common alleles, each conferring modest risk, might underlie familial testicular cancer. Families display a mild phenotype: the most common number of affected families is 2. Age at diagnosis is 2-3 years younger for familial versus sporadic cases. The ratio of familial seminoma to nonseminoma is 1.0. FTGCT is more likely to be bilateral than sporadic TGCT. This syndrome is cancer site specific. Testicular microlithiasis is a newly recognized FTGCT component. Candidate gene-association studies have implicated the Y chromosome gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT risk. Two genomewide association studies of predominantly sporadic but also familial cases of TGCT have implicated the KIT-ligand, SPRY4, and BAK1 genes as TGCT risk modifiers. All five loci are involved in normal testicular development and/or male infertility. These genetic data provide a novel insight into the genetic basis of FTGCT, and an invaluable guide to future TGCT research.

Magnetic resonance imaging and transvaginal ultrasound for determining fibroid burden: implications for research and clinical care.

OBJECTIVES: To compare magnetic resonance and ultrasound imaging for uterine fibroid measurement. STUDY DESIGN: Eighteen women undergoing hysterectomy for symptomatic fibroids underwent preoperative pelvic ultrasound and magnetic resonance imaging. Resected fibroids were correlated with the images. Weighted kappa agreement statistics and Spearman correlations for patient characteristics were calculated. RESULTS: Magnetic resonance imaging identified 121 of 151 pathologically confirmed fibroids, yielding 91% positive predictive value (95% confidence interval [CI], 85-95) and 80% sensitivity (95% CI, 73-86). Positive predictive value and sensitivity for ultrasound were 97% (95% CI, 89-100) and 40% (95% CI, 32-48), respectively. Mean diameter-equivalent discrepancies between imaging and pathologic measurements were 0.51 +/- 0.68 cm for magnetic resonance imaging and 0.76 +/- 0.88 cm for ultrasound. kappa statistics comparing imaging to pathology showed better agreement for magnetic resonance than ultrasound (kappa = 0.60 vs 0.36). The number of fibroids detected by magnetic resonance imaging predicted measurement errors (r = 0.76; P = .0002). CONCLUSION: Superior sensitivity and minimal measurement discrepancies suggest magnetic resonance imaging may be preferentially used for fibroid assessment in clinical research.

Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity.

PURPOSE: Sorafenib inhibits Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab is a monoclonal antibody targeted against VEGF. We hypothesized that the complementary inhibition of VEGF signaling would have synergistic therapeutic effects. PATIENTS AND METHODS: Patients had advanced solid tumors, Eastern Cooperative Oncology Group performance status of 0 to 1, and good end-organ function. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level [DL] 1) or 10 mg/kg (DL2) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD). RESULTS: Thirty-nine patients were treated. DL1 was the MTD and administered in cohort 2 (N = 27). Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization >or= 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/d at a median of four cycles (range, one to 12 cycles). CONCLUSION: Combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.

OBJECTIVE: To evaluate whether 3-month administration of CDB-2914, a selective progesterone receptor modulator, reduces leiomyoma size and symptoms. METHODS: Premenopausal women with symptomatic uterine leiomyomata were randomly assigned to CDB-2914 at 10 mg (T1) or 20 mg (T2) daily or to placebo (PLC) for 3 cycles or 90-102 days if no menses occurred. The primary outcome was leiomyoma volume change determined by magnetic resonance imaging at study entry and within 2 weeks of hysterectomy. Secondary outcomes included the proportion of amenorrhea, change in hemoglobin and hematocrit, ovulation inhibition, and quality-of-life assessment. RESULTS: Twenty-two patients were allocated, and 18 completed the trial. Age and body mass index were similar among groups. Leiomyoma volume was significantly reduced with CDB-2914 administration (PLC 6%; CDB-2914 -29%; P=.01), decreasing 36% and 21% in the T1 and T2 groups, respectively. During treatment, hemoglobin was unchanged, and the median estradiol was greater than 50 pg/mL in all groups. CDB-2914 eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles: CDB-2914, 20%; PLC, 83%; P=.001). CDB-2914 improved the concern scores of the uterine leiomyoma symptom quality-of-life subscale (P=.04). One CDB-2914 woman developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. CONCLUSION: Compared with PLC, CDB-2914 significantly reduced leiomyoma volume after three cycles, or 90-102 days. CDB-2914 treatment resulted in improvements in the concern subscale of the Uterine Fibroid Symptom Quality of Life assessment. In this small study, CDB-2914 was well-tolerated without serious adverse events. Thus, there may be a role for CDB-2914 in the treatment of leiomyomata. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,www.clinicaltrials.gov, NCT00290251 LEVEL OF EVIDENCE: I.

Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity.

We describe the clinical features of 28 patients with juvenile dermatomyositis (JDM) and 1 patient with adult-onset dermatomyositis (DM), all of whom developed lipodystrophy (LD) that could be categorized into 1 of 3 phenotypes, generalized, partial, or focal, based on the pattern of fat loss distribution. LD onset was often delayed, beginning a median of 4.6 years after diagnosis of DM. Calcinosis, muscle atrophy, joint contractures, and facial rash were DM disease features found to be associated with LD. Panniculitis was associated with focal lipoatrophy while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more associated with generalized LD. Specific LD features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with LD, in a gradient of frequency and severity among the 3 sub-phenotypes. Metabolic studies frequently revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial LD. Regional fat loss from the thighs, with relative sparing of fat loss from the medial thighs, was more frequent in generalized than in partial LD and absent from DM patients without LD. Cytokine polymorphisms, the C3 nephritic factor, insulin receptor antibodies, and lamin mutations did not appear to play a pathogenic role in the development of LD in our patients. LD is an under-recognized sequela of JDM, and certain DM patients with a severe, prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for the development of this complication. High-risk JDM patients should be screened for metabolic abnormalities, which are common in generalized and partial LD and result in much of the LD-associated morbidity. Further study is warranted to investigate the pathogenesis of acquired LD in patients with DM.

Adiponectin and leptin in African Americans.

OBJECTIVE: African Americans (AAs) have less visceral and more subcutaneous fat than whites, thus the relationship of adiponectin and leptin to body fat and insulin sensitivity in AA may be different from that in whites. METHODS AND PROCEDURES: Sixty-nine non-diabetic AA (37 men and 32 women), aged 33 +/- 1 year participated. The percent fat was determined by dual-energy X-ray absorptiometry, abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume by computerized tomography (CT), and insulin sensitivity by homeostasis model assessment (HOMA). RESULTS: VAT was greater in men (1,619 +/- 177 cm(3) vs. 1,022 +/- 149 cm(3); P = 0.01); women had a higher percentage of body fat (34.1 +/- 1.4 vs. 24.0 +/- 1.2; P < 0.0001), adiponectin (15.8 +/- 1.2 microg/ml vs. 10.4 +/- 0.8 microg/ml; P = 0.0004) and leptin (23.2 +/- 15.8 ng/ml vs. 9.2 +/- 7.2 ng/ml; P < 0.0001). SAT and HOMA did not differ because of the sex. Adiponectin negatively correlated with VAT (r = -0.41, P < 0.05) in men, and with VAT (r = -0.55, P < 0.01), and SAT (r = -0.35, P < 0.05) in women. Adiponectin negatively correlated with HOMA in men (r = -0.38, P < 0.05) and women (r = -0.44, P < 0.05). In multiple regression, sex (P = 0.02), HOMA (P = 0.03) and VAT (P = 0.003) were significant predictors of adiponectin (adj R (2) = 0.38, P < 0.0001). Leptin positively correlated with VAT, SAT, percent fat and HOMA in men (r = 0.79, r = 0.86, r = 0.89, and r = 0.53; P < 0.001) and women (r = 0.62, r = 0.75, r = 0.83, and r = 0.55; P < 0.01). In multiple regression VAT (P = 0.04), percent body fat (P < 0.0001) and sex (P = 0.01), but not HOMA were significant predictors of serum leptin (adj R (2)= 0.82, P < 0.0001). DISCUSSION: The relationship of adiponectin and leptin to body fat content and distribution in AA is dependent on sex. Although VAT and insulin sensitivity are significant determinants of adiponectin, VAT and percent body fat determine leptin.

Lack of reliability of CA125 response criteria with anti-VEGF molecularly targeted therapy.

BACKGROUND: CA125 is an accepted indicator of epithelial ovarian cancer (EOC) response and is used to monitor patients treated with cytotoxic chemotherapy. It is uncertain how CA125 is affected by molecularly targeted drugs. In this pilot study, the authors analyzed the utility of CA125 to predict disease behavior in patients who were receiving sorafenib, a Raf-kinase/VEGFR2 inhibitor, and bevacizumab, an anti-VEGF monoclonal antibody. METHODS: Fifteen of 42 patients had recurrent EOC. Patients received sorafenib 200 mg orally twice daily or D1-5 of 7 and bevacizumab 5 mg/kg to 10 mg/kg intravenously every 2 weeks for 28-day cycles. Computed tomography (CT) scans were performed every 2 cycles for restaging, and CA125 was measured monthly. CA125 concentrations were retrospectively analyzed as a function of clinical behavior. RESULTS: Fourteen of 15 patients had abnormal CA125 concentrations at study entry (median 1056 U/mL; range, 67 U/mL to 9813 U/mL). Seven (47%) patients had partial response by imaging criteria. Five of these 7 patients had partial response by CA125 criteria (71% sensitivity). Eight (53%) patients would have had partial responses if CA125 criteria were used; only 5 were confirmed by CT (63 % specificity). Imaging and CA125 criteria combined yielded a higher total response rate of 10 of 15 (67%). Three patients with objective partial response by imaging lasting >20, >22, and >24 cycles would have terminated treatment prematurely if CA125 had been used. CONCLUSIONS: CA125 changes may not correspond to imaging response criteria for EOC patients who are receiving sorafenib and bevacizumab. Caution is recommended when using CA125 as a response criterion of molecularly targeted agents until prospective studies validate CA125 changes with objective imaging response results.

Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers.

PURPOSE: To determine the toxicities, maximum tolerated dose (MTD) and pharmacokinetics of the recombinant immunotoxin SS1P (anti-mesothelin dsFv-PE38) in patients with mesothelin-expressing cancers. EXPERIMENTAL DESIGN: SS1P given as a 30-min i.v. infusion every other day (QOD) for six or three doses was administered to 34 patients with advanced mesothelioma (n = 20), ovarian (n = 12), and pancreatic (n = 2) cancer. RESULTS: The initial cohort of 17 patients received SS1P QOD x 6 doses and the MTD was 18 microg/kg/dose. Dose-limiting toxicities (DLT) included grade 3 uticaria (one patient) and grade 3 vascular leak syndrome (two patients). To allow further SS1P dose escalation, 17 patients were treated on the QOD x 3 schedule and the MTD was 45 microg/kg/dose. The DLT was grade 3 pleuritis and was seen in two of two patients treated at a dose of 60 microg/kg and in one of nine patients treated at a dose of 45 microg/kg. At the MTD of 45 microg/kg, the mean C(max) of SS1P was 483 ng/mL and half-life was 466 min. Of the 33 evaluable patients treated, 4 had minor responses, 19 had stable disease (including 2 with resolution of ascites), and 10 had progressive disease. CONCLUSIONS: SS1P is well tolerated with pleuritis as the DLT at the highest dose level. Evidence of clinical activity was noted in a group of heavily pretreated patients. Phase II clinical trials of SS1P are being planned for malignant mesothelioma and other mesothelin-expressing malignancies.

Gynecologic and hormonal effects of raloxifene in premenopausal women.

OBJECTIVE: To assess the effects of raloxifene on the ovaries, uterus, and serum hormone levels in premenopausal women. DESIGN: Prospective study comparing pretreatment findings with findings for those on treatment. SETTING: Government research hospital. PATIENT(S): Thirty women 35 to 47 years of age who were at high risk of breast cancer and had regular, ovulatory menstrual cycles. INTERVENTION(S): Raloxifene (60 mg) and calcium (1,200 mg) daily for 2 years. MAIN OUTCOME MEASURE(S): Sonographic evidence of ovarian stimulation (>or=2 corpora lutea, or follicular cysts of >2 cm, or single follicular cyst of >3 cm). Changes in endometrial thickness, fibroid size, hormone levels, and menstrual-cycle length. RESULT(S): Fifteen subjects developed some cycles with asymptomatic ovarian stimulation, and 9 developed benign endometrial polyps, compared with 2 subjects and 1 subject pretreatment, respectively. Uterine fibroid size was unchanged during raloxifene use in 16 subjects with fibroids. On treatment, E(2) levels increased significantly only during the follicular phase, with peak E(2) levels significantly higher in cycles showing ovarian stimulation compared with those without. Sex hormone-binding globulin increased, but levels of LH, FSH, P, DHEAS, and T did not. Endometrial thickness and cycle length were unchanged. CONCLUSION(S): Premenopausal subjects receiving raloxifene showed sonographic and hormonal evidence of ovarian stimulation. Endometrial thickness, cycle length, and fibroid size were unchanged. Benign asymptomatic endometrial polyps developed in some.

A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer: a phase II clinical study with proteomic profiling.

BACKGROUND: c-Kit and platelet-derived growth factor receptor (PDGFR) are potential molecular targets in epithelial ovarian cancer (EOC). Imatinib inhibits the kinase domain and subsequent downstream signaling of these receptor tyrosine kinases. The objective of this study was to investigate biochemical and biologic effects of imatinib on EOC. METHODS: Patients with recurrent EOC who had received no more than 4 prior regimens and who had good end-organ function were eligible. Imatinib was administered orally at a dose of 400 mg twice daily in continuous, 28-day cycles with reassessment imaging studies obtained every other cycle. Tumor core biopsies were obtained prior to and at 4 weeks into therapy; microdissected tumor and stroma were subjected to protein lysate array analysis. Blood samples were obtained monthly for cytokine measurements. RESULTS: Twenty-three patients were enrolled, including 16 patients who received imatinib 600 mg daily because of gastrointestinal (GI) toxicity and fluid accumulation at the starting dose. The median time to disease progression was 2 months (range, 2-14 months). Common grade 3 toxicities included edema/ascites/pleural effusions in 11 patients (48%), GI complaints in 8 patients (35%), fatigue in 3 patients (13%), and grade 2 and 3 cytopenias in 10 patients and 3 patients (43% and 13%), respectively. Increased circulating levels of interleukin 6 were associated with grade >/=2 fluid collection (P = .02). A statistically significant trend was observed between pretreatment phosphorylated-kit levels in microdissected tumor and stroma and GI toxicity (P < .01), between tumor levels of epidermal growth factor receptor (EGFR) and PDGFR with grade of fatigue (P

The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis.

UNLABELLED: A pilot study of a 48-week course of pioglitazone demonstrated significant improvements in the biochemical and histological features of nonalcoholic steatohepatitis (NASH). The aim of the study was to assess the effects of stopping pioglitazone. Twenty-one patients with NASH were treated with pioglitazone (30 mg/day) for 48 weeks and underwent baseline and end-of-treatment evaluation including liver biopsy. Thirteen patients were followed for at least 48 weeks after stopping therapy and 9 underwent repeat liver biopsy. Statistical comparisons were made to evaluate whether discontinuation of pioglitazone resulted in a reversal of improvements seen on therapy. Stopping pioglitazone was associated with subsequent elevation in serum alanine aminotransferase levels (from 34 +/- 13 to 70 +/- 39 IU/l), decrease in adiponectin (from 9.7 +/- 9.1 to 5.1 +/- 4.5 microg/ml), worsening insulin sensitivity (HOMA Index: from 2.9 +/- 1.8 to 5.5 +/- 5.4), and increase in total hepatic fat (from 30% +/- 32% to 71% +/- 33%) despite no change in average body weight compared to the end of treatment. Repeat liver biopsy in 9 patients revealed significant worsening of parenchymal inflammation (from 1.2 +/- 0.7 to 2.9 +/- 1.1) and steatosis (from 0.9 +/- 0.6 to 2.1 +/- 1.3) but no change in fibrosis (from 1.1 +/- 1.2 to 1.2 +/- 1.3). NASH was again present on liver biopsy in 7 patients. CONCLUSION: These findings suggest that long-term therapy with pioglitazone may be necessary to maintain improvements in disease activity in patients with NASH, although weight gain during treatment may ultimately limit its beneficial effects.

Struma ovarii coincident with Hashimoto's thyroiditis: an unusual cause of hyperthyroidism.

OBJECTIVE: To report the identification of struma ovarii in a patient with a history of struma ovarii and new hyperthyroidism. DESIGN: Case report. SETTING: Academic research hospital. PATIENT(S): A woman with hyperthyroidism who has struma ovarii coincident with Hashimoto's thyroiditis. INTERVENTION(S): Laparoscopic salpingo-oophorectomy. MAIN OUTCOME MEASURE(S): Measurement of thyroid hormone parameters before and after surgery. RESULT(S): After removal of the second struma ovarii, hyperthyroidism resolved. CONCLUSION(S): In a patient with two different causes of abnormal thyroid function, it is important to seek an encompassing clinical scenario.

Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis.

OBJECTIVE: To evaluate whether persistence of pelvic pain after excision of endometriosis was associated with adenomyosis as defined by a thickened uterine junctional zone (JZ) on magnetic resonance (MR) imaging. DESIGN: Prospective clinical trial. SETTING: Government research hospital. PATIENT(S): Fifty-three women with chronic pelvic pain. INTERVENTION(S): Preoperative MR imaging to measure uterine JZ thickness, surgical excision, and pathologic diagnosis of endometriosis. Those with biopsy-proven endometriosis were randomized to raloxifene or placebo. Visual analog scale (VAS) was used to rate dysmenorrhea and nonmenstrual pain severity before surgery and 3 months later. MAIN OUTCOME MEASURE(S): Comparison of JZ thickness and pain severity before and 3 months after surgery in women with endometriosis controlling for medical treatment. RESULT(S): Forty of the 53 patients had biopsy-proven endometriosis, and 6 of these 40 women with endometriosis had a thickened JZ. Overall, dysmenorrhea at 3 months was positively correlated with preoperative JZ thickness (r = 0.47, P=.01). Dysmenorrhea pain severity showed no significant decrease in those patients whose JZ measured >or=11 mm compared with those with JZ <8 mm (P<.0001; VAS decreased 4.3 +/- 0.6), or >or=8 and <11 mm (P<.02; VAS decreased 4.8 +/- 1.3). Nonmenstrual pain severity was correlated with JZ thickness (r = 0.51, P=.004) at 3 months with a significant decrease in nonmenstrual pain only in women with a JZ <8 mm (VAS decreased 4.0 +/- 0.7, P<.0001). The association between dysmenorrhea and nonmenstrual pain reduction and thinner JZ remained after controlling for medical treatment. CONCLUSION(S): Following surgical excision of endometriosis, chronic pelvic pain was significantly more likely to persist with JZ thickness >11mm on preoperative MR imaging. This suggests that myometrial JZ abnormalities or adenomyosis may contribute to chronic pelvic pain in women with endometriosis.

Pilot study investigating the age-related decline in ovarian function of regularly menstruating normal women.

OBJECTIVE: To use a pilot study to investigate markers of the age-related decline in ovarian function of regularly menstruating normal women. DESIGN: Prospective. SETTING: Tertiary research center. PATIENT(S): Healthy volunteers (n = 42) aged 18 to 50 years who had regular ovulatory menstrual cycles and a prior pregnancy. INTERVENTION(S): A single 300-IU dose of human recombinant FSH on day 3 of the menstrual cycle. MAIN OUTCOME MEASURE(S): Antral follicle count by transvaginal ultrasound and basal and FSH-stimulated serum markers. RESULT(S): Age correlated most strongly with FSH-stimulated inhibin B (r = -0.660), followed by antral follicle count (r = -0.578), basal FSH (r = 0.509), basal Müllerian inhibiting substance (MIS; r = -0.468), and basal inhibin B (r = -0.358). Total antral follicle count correlated most strongly with basal MIS level (r = 0.642). CONCLUSION(S): Of the parameters tested, FSH-stimulated serum inhibin B level had the strongest correlation with age. Basal serum MIS level had the strongest correlation with total antral follicle count. We confirm a previous report that in normal women, the antral follicle count as determined by transvaginal ultrasound examination correlates better with age than do basal FSH and basal inhibin B levels.

Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure.

OBJECTIVE: To assess the association between serum adrenal cortex autoantibodies and histologically confirmed autoimmune lymphocytic oophoritis. DESIGN: Controlled, prospective. SETTING: Tertiary research center. PATIENT(S): Two hundred sixty-six women with 46,XX spontaneous premature ovarian failure. INTERVENTION(S): Ovarian biopsy in 10 women. MAIN OUTCOME MEASURE(S): Serum adrenal cortex autoantibodies assessed by indirect immunofluorescence and autoimmune oophoritis assessed by immunohistochemical lymphocyte markers. RESULT(S): We obtained a histologic diagnosis of autoimmune oophoritis in four women who tested positive for adrenal cortex autoantibodies and excluded this diagnosis in ovarian biopsies from six women who tested negative for adrenal cortex autoantibodies (4/4 vs. 0/6). Women with histologically confirmed autoimmune oophoritis had a greater total ovarian volume as assessed by transvaginal sonography (11.4 +/- 5.6 mL vs. 1.5 +/- 0.4 mL) (mean +/- SEM). They were also more likely to have subclinical adrenal insufficiency and clinical signs of androgen deficiency (3/4 vs. 0/6). Overall, 10/266 women tested positive for adrenal cortex autoantibodies (3.8%, 95% confidence interval: 1.8%-6.5%). CONCLUSION(S): In women who present with 46,XX spontaneous premature ovarian failure as their primary concern there is a clear association between serum adrenal cortex autoantibodies and the presence of histologically confirmed autoimmune oophoritis.

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy.

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206-->226 mg/dL, P = .002), glucose (220-->144 mg/dL, P = .02), insulin (46.4-->24.8 muIU/mL, P = .004), ALT (54-->24 U/L, P = .02), AST (47-->22 U/L, P = .046), liver volume (3209-->2391 cm(3), P = .007), and liver fat content (31-->11%, P = .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH.

Both subcutaneous and visceral adipose tissue correlate highly with insulin resistance in african americans.

OBJECTIVE: The contribution of visceral adipose tissue (VAT) to insulin resistance is well-established; however, the role of subcutaneous abdominal adipose tissue (SAT) in insulin resistance remains controversial. Sex may determine which of these two components of abdominal obesity is more strongly related to insulin resistance and its consequences. The aim of this study was to determine whether both VAT and SAT contribute to insulin resistance in African Americans and to examine the effects of sex on this relationship. RESEARCH METHODS AND PROCEDURES: This was a cross-sectional study of 78 nondiabetic African-American volunteers (44 men, 35 women; age 33.8 +/- 7.3 years; BMI 30.9 +/- 7.4 kg/m2). VAT and SAT volumes were measured using serial computerized tomography slices from the dome of the diaphragm to the iliac crest. The insulin sensitivity index (SI) was determined from the minimal model using data obtained from the frequently sampled intravenous glucose tolerance test. RESULTS: In men, both VAT and SAT were negatively correlated with SI (r for both correlations = -0.57; p < 0.01). In women, the correlation coefficient between VAT and SI was -0.50 (p < 0.01) and between SAT and SI was -0.67 (p < 0.01). In women, the correlation coefficient for SI with SAT was significantly greater than the correlation coefficient with VAT (p = 0.02). DISCUSSION: Both SAT and VAT are strongly correlated with insulin resistance in African Americans. For African-American women, SAT may have a greater effect than VAT on insulin resistance.

Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy.

Leptin, an adipocyte hormone, when replaced in patients with lipodystrophy, improves insulin resistance, hyperglycemia, dyslipidemia, and hepatic steatosis. Changes in body composition accompany this metabolic improvement. We studied 14 patients (3 men and 11 women); 12 of who had generalized lipodystrophy (7 congenital, 5 acquired), and 2 patients had partial lipodystrophy. Body composition and related parameters were evaluated at baseline and after 4 and 12 months of leptin therapy. Baseline body mass index (BMI) was 21.7 +/- 0.8 kg/m(2), the percent body fat was 9.5% +/- 1.6%, and the serum leptin level was 1.7 +/- 0.3 ng/mL. On treatment, serum leptin levels increased by 10-fold. All patients reported a decrease in appetite on therapy. After 4 months, both daily caloric intake and resting energy expenditure (REE) decreased. The liver volume decreased (baseline = 3,055 +/- 281 cm(3); 4 months = 2,433 +/- 243 cm(3), P =.006). Dual energy x-ray absorptiometry (DEXA) demonstrated significant decreases in fat mass (5.4 +/- 0.8 kg to 5.0 +/- 0.8 kg; P =.003) and lean body mass (51.2 +/- 3.2 kg to 48.3 +/- 3.4 kg; P =.003) at 4 months on therapy. There was no impact of leptin therapy on bone mineral content, mineral density, and metabolism. Changes in body composition occurred during the first 4 months of leptin therapy, but then stabilized and were sustained thereafter.

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsy-proven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study.