Metastatic melanoma to the ovary in pregnancy: A case report.

Metastatic melanoma to the ovary is an uncommon presentation. We report a case of metastatic melanoma to the ovary that presented as a growing left adnexal mass during pregnancy and was thought to be benign by imaging and frozen section pathology. Here we discuss the challenges in radiologic and pathologic diagnosis, as well as considerations for the mother and newborn.

Transversus abdominis plane block in robotic gynecologic oncology: a randomized, placebo-controlled trial.

OBJECTIVE: Although robotic surgery decreases pain compared to laparotomy, postoperative pain can be a concern near the site of a larger assistant trocar site. The aim of this study was to determine the efficacy of transversus abdominis plane (TAP) block on 24-hour postoperative opiate use after robotic surgery for gynecologic cancer. METHODS: Sixty-four subjects with gynecologic malignancies who were scheduled to undergo robotic surgery were enrolled into the study. They were randomized to receive a unilateral TAP block to the side of the assistant port via ultrasound guidance. The block was comprised of 30 cc of 0.25% bupivacaine with 3 mcg/mL epinephrine or saline. Opiate use was measured and converted into IV morphine equivalents. Patient-reported pain was measured using the Brief Pain Inventory (BPI) and Visual Analog Scale (VAS). RESULTS: The treatment group used a mean of 64.9 mg morphine in the first 24h compared to 69.3mg for controls (primary outcome, p=0.52). After age-adjustment, the treatment group used a mean of 11.1mg morphine less than controls (p=0.09). Postoperative pain scores assessed by the BPI (6.44 vs. 6.97, p=0.37) and the VAS (3.12 vs. 3.61, p=0.30) were equivalent. Block placement was uncomplicated in 98.4% of participants with mean BMI of 35.3 kg/m(2). Linear regression revealed an approximate 8.1mg decrease in morphine equivalents used per additional decade of life (p=0.0008). There was a positive correlation between the amount of opiates and BMI with an additional 8.8 mg of morphine per 10 kg/m(2) increase in BMI (p=0.0012). CONCLUSIONS: TAP block is safe and feasible in this patient population with a large proportion of morbid obesity. Preoperative TAP block does not significantly decrease opiate use. However; based on these data, a clinically useful nomogram has been created to aid clinicians in postoperative opiate-dosing for patients based on age and BMI.

BRCA2 alteration is important in clear cell carcinoma of the ovary.

BRCA2 has been shown to play a significant role in hereditary ovarian carcinoma. Several cases of clear cell carcinoma (CCC) of the ovary containing BRCA2 mutations have been identified. We hypothesize that sequence variants of the BRCA2 gene are common in CCC of the ovary. Multiple methods were utilized to detect BRCA2 genetic alterations in a cohort of 13 ovarian CCC. These included an LOH analysis for copy number, real-time and methylation-specific polymerase chain reaction (PCR) to probe for BRCA2 promoter methylation, in addition to protein truncation testing (PTT) gel screening for nonsense BRCA2 mutations, and finally direct gene sequencing to either confirm the nonsense mutations or to detect candidate missense mutations in the remaining tumor samples. Whenever a sequence variation was detected in a tumor sample, the corresponding region was sequenced from a blood sample to determine germline status. Seven BRCA2 sequence variations were identified in 6 of the 13 CCC (46%); three tumors contained an alteration in BRCA2 copy number. Only one subject carried a germline sequence variation that might alter BRCA2 function despite the fact that a family history of breast, ovarian or colon cancer was common in this population. The 5-year disease-specific survival probability for patients with a BRCA2 alteration is 87.5%, compared to only 40% for those patients without a BRCA2 alteration (p = 0.39). Alterations in BRCA2 gene sequence, copy number, or expression are extremely common in CCC and may contribute to a paradoxical better clinical outcome.

E-cadherin is a novel transcriptional target of the KLF6 tumor suppressor.

The tumor suppressor KLF6 is a member of the Krüppel-like family of transcription factors, which has been implicated in the pathogenesis of several human carcinomas. Uncovering the transcriptional targets relevant for its tumorigenic properties, including cellular proliferation and invasion, will be essential to understanding possible mechanisms by which KLF6 and its antagonistic splice form, KLF6-SV1, regulate this development. To begin defining possible metastatic-related pathways, we analysed the effect of KLF6 dysregulation on a recognized suppressor of cellular invasion, E-cadherin. Targeted KLF6 reduction in an ovarian cancer cell line, SKOV-3, resulted in a 50% reduction of E-cadherin expression (P<0.01) and conversely, KLF6-SV1 silencing upregulated E-cadherin approximately fivefold (P<0.0001). These changes resulted from KLF6 directly transactivating the E-cadherin promoter as demonstrated by luciferase promoter assay and chromatin immunoprecipitation (ChIP). KLF6-mediated changes in E-cadherin levels were accompanied by downstream changes in both the subcellular localization of beta-catenin and c-myc expression levels. Moreover, and consistent with these experimental findings, patient-derived epithelial ovarian tumors with low KLF6 and high KLF6-SV1 expression ratios had significantly decreased E-cadherin expression (P<0.0001). These combined findings highlight the E-cadherin pathway as a novel and functionally important mediator by which changes in KLF6 and KLF6-SV1 can directly alter ovarian tumor invasion and metastasis.

Heat shock protein 27 in the placentas of women with and without severe preeclampsia.

BACKGROUND: Although not fully understood, heat shock proteins (HSP) are well known stress response proteins. The purpose of this analysis was to determine whether staining for HSP27 was different between placentas from pregnancies complicated by severe pre-eclampsia with intrauterine growth restriction (IUGR) as compared to controls. METHODS: Sterile placental tissue was collected from ten women whose pregnancies were complicated by severe preeclampsia with IUGR and from ten women with uncomplicated by severe pre-eclampsia with IUGR and from ten women with uncomplicated term pregnancies. The tissue was then stained for HSP27. RESULTS: The median age of the patients was 27 years (mean 27, range 17-37). The median estimated gestational age at delivery was 38 weeks (mean 37, range 29-41). Overall 12 of 20 placentas stained positively for HSP27 (nuclear and/or cytoplasmic). Eight of ten placentas from women with pre-eclampsia and IUGR stained positively for HSP27 (p = 0.046). CONCLUSION: HSP27 staining of the placenta is twice as common in patients with severe preeclampsia as compared to patients with normal term gestations. These preliminary results warrant the inauguration of a similar but larger study to examine the significance of these findings.

The role of p53 mutation in BRCA1-associated ovarian cancer.

Ovarian cancer remains the most deadly gynecologic malignancy, resulting in an estimated 23,300 new cases and 13,900 deaths in the United States in the year 2002. The discovery of the BRCA1 gene in 1994 has proven to be of great interest to the study of hereditary ovarian cancer. BRCA1 gene mutation confers a 16-42% lifetime risk of the development of ovarian cancer in those affected. Although BRCA1 functions as a tumor suppressor gene, conflicting studies have shown that BRCA1 dysfunction alone may not be sufficient for tumorigenesis. p53 is a tumor suppressor gene found to be dysfunctional in nearly 50% of all human cancers and in up to 80% of ovarian malignancies. The p53 protein product plays a crucial role in DNA surveillance and repair at the Gap 1-synthesis (G1-S) cell cycle checkpoint. Studies exhibiting the interaction of BRCA1 and p53 and the role of this interaction in DNA damage response led many investigators to suggest that p53 gene mutation is required for BRCA1-associated tumor development. This review explores the evidence for BRCA1 and p53 interplay, and outlines the crucial role p53 may play in BRCA1-related ovarian cancer.

Human immunodeficiency virus type 1 protease genotype predicts immune and viral responses to combination therapy with protease inhibitors (PIs) in PI-naive patients.

Protease genotype, as a variable in outcome to combination therapy for human immunodeficiency virus (HIV) type 1 infection, was evaluated among protease inhibitor-naive children and adolescents who had received extensive treatment with reverse-transcriptase inhibitors. After 24 weeks of combination therapy, 35% had viral and immune success (VSIS patients), 19% had viral and immune failure (VFIF patients), and 46% had viral failure but marked improvement in CD4 T cells (VFIS patients). Disease stage was the only pretherapy clinical variable associated with outcome (P=.02). Although reverse-transcriptase genotype was unrelated to outcome, pretherapy protease genotype was related significantly to therapy response (P=.005). Odds for immune or viral failure were 17.7 to 1 and 2.5 to 1, respectively, for protease genotype as a single variable. Protease genotype combined with disease stage and CD4 cell percentage predicted correct therapy response for 81% of patients (100% of VFIF, 78% of VSIS, and 75% of VFIS patiens). Naturally occurring amino acid polymorphisms in protease provide sensitive biomarkers for treatment response among inhibitor-naive patients with advanced HIV disease.

Proton magnetic resonance spectroscopy of human basal ganglia: response to cocaine administration.

BACKGROUND: Proton magnetic resonance spectroscopy was used to determine the effects of intravenous cocaine or placebo administration on human basal ganglia water and metabolite resonances. METHODS: Long echo time, proton magnetic resonance spectra of water and intracellular metabolites were continuously acquired from an 8-cm(3) voxel centered on the left caudate and putamen nuclei before, during, and after the intravenous administration of cocaine or a placebo in a double-blind manner. RESULTS: Cocaine, at both 0.2 and 0.4 mg/kg, did not alter the peak area for water. Cocaine at 0.2 mg/kg induced small and reversible increases in choline-containing compounds and N-acetylaspartate peak areas. Cocaine at 0.4 mg/kg induced larger and more sustained increases in choline-containing compounds and N-acetylaspartate peak areas. No changes in either water or metabolite resonances were noted following placebo administration. CONCLUSIONS: These increases in choline-containing compounds and N-acetylaspartate peak areas may reflect increases in metabolite T2 relaxation times secondary to osmotic stress and/or increased phospholipid signaling within the basal ganglia following cocaine administration. This is the first report of acute, drug-induced changes in the intensity of human brain proton magnetic resonance spectroscopy resonance areas.

Cerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenance.

This study evaluated cerebral phosphorus metabolites in opiate-dependent polydrug abusers in methadone maintenance therapy (MMT) and determined whether metabolite profiles differed based on treatment duration. Phosphorus magnetic resonance spectroscopy (31P-MRS) data were acquired with the ISIS volume localization method from a 50-mm thick axial brain slice through the orbitofrontal and occipital cortices. Study subjects included 15 MMT subjects, seven having undergone treatment for an average of 39 +/- 23 weeks (mean +/- S.D.) and eight having undergone treatment for 137 +/- 53 weeks, as well as an age matched comparison group (n = 16). The methadone dose administered on the study day averaged 70.5 +/- 17.1 mg and was statistically equivalent in short- and long-term subgroups. MMT subjects (n = 15) differed from control subjects in percent phosphocreatine (%PCr) levels (-13%), and in both phosphomonoester (%PME, +13%) and phosphodiester (%PDE, +10%) levels, which likely reflect abnormalities in energy and phospholipid metabolism, respectively. There were no sex effects or group by sex interaction effects on these measures. In short-term MMT treatment subjects, abnormal %PCr (-18%), %PME (+20%) and %PDE (+17%) levels were found compared with control subjects. The only metabolite abnormality detected in long-term MMT subjects was decreased %PCr (-9%), in spite of continued illicit drug abuse. From these data, we conclude that polydrug abusers in MMT have 31P-MRS results consistent with abnormal brain metabolism and phospholipid balance. The nearly normal metabolite profile in long-term MMT subjects suggests that prolonged MMT may be associated with improved neurochemistry.

Effects of myo-inositol ingestion on human brain myo-inositol levels: a proton magnetic resonance spectroscopic imaging study.

BACKGROUND: Cerebrospinal fluid levels of myo-Inositol (m-Ino) are reported to be decreased in patients with affective disorder, and dietary supplements of m-Ino have been shown to reduce the symptoms of major depression. Myo-Inositol transport across the blood-brain barrier is mediated by a low capacity, saturable system. This study tests whether dietary m-Ino increases brain m-Ino or changes brain metabolism of m-Ino, possibly explaining the ability of this compound to alter mood. METHODS: Using proton magnetic resonance spectroscopic imaging, we measured m-Ino levels in occipital gray and parietal white matter of seventeen healthy subjects. Magnetic resonance spectroscopic imaging was performed twice at baseline as well as at day 4 and day 8 while subjects ingested 6 g of m-Ino twice a day. RESULTS: Following 4 days of m-Ino, m-Ino/Cr was 20% higher than baseline levels in occipital gray matter (p < 0.04) and 8% higher in parietal white matter (p = ns). By day 8, m-Ino/Cr ratios had returned to baseline values. CONCLUSIONS: Brain m-Ino levels initially increase during m-Ino administration and subsequently return to baseline levels. The time-limited increases observed for brain m-Ino may reflect homeostatic mechanisms, possibly associated with the role of m-Ino as a cerebral osmolyte, or with changes in brain phosphoinositide metabolism.

Donor polymorphism of tumor necrosis factor gene: relationship with variable severity of hepatitis C recurrence after liver transplantation.

BACKGROUND: Hepatitis C-related liver failure is the leading indication for liver transplantation worldwide. Although histologic recurrence is identified in the majority of patients, the spectrum of allograft injury is wide. To date, most studies have focused on the contribution of immunosuppression and viral factors. We hypothesized that the allograft plays a significant role in determining timing and severity of hepatitis C virus (HCV) recurrence. The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly variable severity of HCV recurrence. METHODS: Thirty-one HCV-seropositive liver transplant recipients with long-term follow-up were studied. Genomic DNA was extracted from archived donor spleens which corresponded to each patient. We performed polymerase chain reaction amplification, followed by sequencing for two promoter TNF-alpha variants (at positions -238 and -308), and restriction fragment length analysis for four polymorphic loci within the TNF-beta gene (NcoI, TNFc, aa13, and aa26). RESULTS: The relative prevalence of polymorphisms corresponded to distributions previously reported in normal control populations. Twenty-two of 31 (71%) patients received a donor liver homozygous for the wild type allele (TNF1) at the -308 TNF-alpha promoter region. The interval to histologic recurrence was significantly shorter and severity of HCV allograft hepatitis was significantly greater in patients with one or two TNF308.2 alleles. At last follow-up biopsy, 5 of 9 (56%) patients with a TNF308.2 donor liver had evidence of severe histological activity index as compared to 2 of 22 (9%) of patients receiving a donor liver homozygous for the TNF1 allele (P = 0.01). There was no correlation between rejection rates and the presence of any TNF-alpha or TNF-beta alleles. TNF-beta polymorphisms within the donor liver did not correlate with severity of HCV recurrence. CONCLUSIONS: The donor TNF-alpha promoter genotype may influence the inflammatory response to HCV reinfection of the graft and contribute to accelerated graft injury. If the association between this genetic marker (TNF308.2) and disease progression is confirmed, it could improve our understanding of HCV pathogenesis and influence donor selection and patient management.

Cocaine administration induces human splenic constriction and altered hematologic parameters.

Cocaine is a potent vasoconstrictor that has been shown to alter hemoglobin, hematocrit, and red blood cell counts in both animals and humans. The present study evaluated whether cocaine administration induces splenic constriction in men and whether spleen-volume changes temporally correlate with altered hematologic parameters. Spleen volume was assessed at baseline and after cocaine administration (0.4 mg/kg) by using magnetic resonance imaging. A group of five healthy men, aged 31 +/- 2 (SE) yr and reporting occasional cocaine use (13 +/- 5 lifetime exposures), participated. Cocaine reduced spleen volume by 20 +/- 4% (P < 0.03) 10 min after drug administration. Spleen volume returned to normal (101 +/- 3% baseline) within 35 min after cocaine administration, indicating that the reduction is a transient phenomenon. In subjects administered cocaine from whom blood samples were obtained (n = 3), cocaine increased hemoglobin levels, hematocrit, and red blood cell count to 104.5 +/- 0.9, 105.6 +/- 1.2, and 106.5 +/- 1.0% of baseline levels, respectively (P < 0.03), but it did not alter white blood cell and platelet counts. Placebo administration (n = 5) did not alter hematologic parameters. These results suggest that cocaine induces splenic constriction in humans, and this may contribute to temporally concordant hematologic parameter changes. These events may help to preserve or increase tissue oxygenation in periods of high oxygen demand and/or increased vascular resistance.

Cocaine decreases relative cerebral blood volume in humans: a dynamic susceptibility contrast magnetic resonance imaging study.

Cocaine has substantial effects on cerebral hemodynamics which may partly underlie both its euphorigenic and toxic effects. Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) was used to determine whether a dose-effect relationship could be detected between cocaine administration and cerebral blood volume reduction in human brain. Twenty-three healthy and neurologically normal adult males with a history of recreational cocaine use (3-40 lifetime exposures) participated. Subjects underwent DSC-MRI measurements of relative cerebral blood volume (rCBV) at baseline and 10 min after i.v. double-blind placebo or cocaine (0.2 or 0.4 mg/kg) administration. Placebo administration resulted in superimposable rCBV curves with post-placebo CBV averaging 104+/-4% (mean+/-SE) of baseline, indicating no CBV change. Both cocaine doses induced CBV decreases which were statistically equivalent and post-cocaine CBV averaged 77+/-4% of baseline (P < 0.002), when measured 10 min following drug administration. These data suggest that DSC-MRI can detect cocaine-induced CBV reductions indicative of vasoconstriction, and that it may be useful for evaluating treatments designed to reduce the cerebrovascular effects of cocaine.

Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography.

CONTEXT: Clinical observations and case reports suggest that there are important cerebrovascular complications of cocaine use, but no studies have documented a direct link. OBJECTIVE: To determine whether low-dose cocaine administration induces cerebral vasoconstriction in healthy cocaine users. DESIGN: Randomized controlled trial. SUBJECTS: Twenty-four healthy and neurologically normal men (mean age, 29 years) reporting median cocaine use of 8 lifetime exposures (range, 3 to >40). INTERVENTION: Double-blind intravenous administration of cocaine (0.4 or 0.2 mg/kg) or placebo, with cerebral magnetic resonance angiography performed at baseline and 20 minutes following infusion. MAIN OUTCOME MEASURE: Cocaine-induced angiographic change indicative of vasoconstriction, as independently and concordantly rated by 2 reviewers blind to treatment condition. RESULTS: Cocaine-induced cerebral vasoconstriction in a dose-related fashion (P=.03), with angiograms indicative of vasoconstriction found in 5 of 8 and 3 of 9 subjects receiving 0.4- and 0.2-mg/kg cocaine, respectively, compared with 1 of 7 subjects administered placebo. Outcome stratification by frequency of self-reported lifetime cocaine use (3-10 times, 11-40 times, or >40 times) revealed a statistically stronger dose-related effect (P<.001), suggesting that greater lifetime cocaine use was associated with a greater likelihood of vasoconstriction. CONCLUSIONS: Cocaine administration induced dose-related cerebral vasoconstriction on magnetic resonance angiograms. These changes occurred at low cocaine doses and in the absence of other risk factors, including polydrug abuse, hypertension, or cerebrovascular disease. Outcome stratification by prior cocaine use statistically strengthened the relationship between cocaine administration and vasoconstriction, suggesting that cocaine may have a cumulative residual effect in promoting cerebrovascular dysfunction.

Non-gynecologic laparoscopy in second and third trimester pregnancy: obstetric implications.

PURPOSE: To review the effect of non-gynecologic laparoscopic procedures performed during the second and third trimesters of pregnancy on pregnancy outcome. MATERIALS AND METHODS: A review of the patient log for the antenatal obstetrical unit was used to identify the patients in this series from January 1, 1997 to December 31, 1997. Medical records were then analyzed to identify estimated gestational age at surgery and delivery, type of delivery, use of tocolysis, and complications from surgery. RESULTS: Nine patients were identified as having non-gynecologic laparoscopic surgery (without conversion to laparotomy) during the second or third trimester of pregnancy. The median estimated gestational age at surgery was 25 weeks (mean 24 weeks). The most common procedure performed was laparoscopic cholecystectomy (6 patients). Five patients received tocolysis after the initial procedure. All patients delivered at greater than or equal to 37 weeks estimated gestational age (median 38 weeks). No infants were admitted to the neonatal intensive care unit. CONCLUSIONS: Laparoscopic procedures appear safe in second and third trimester pregnancy. In this study, laparoscopic cholecystectomies were performed as late as 34 weeks estimated gestational age without any adverse effects on pregnancy outcome.

Evaluation of a new immunodiagnostic assay for Helicobacter pylori antibody detection: correlation with histopathological and microbiological results.

Infection with Helicobacter pylori has been associated with the pathogenesis of chronic active gastritis and gastric and duodenal ulcer disease. Detection of immunoglobulin G antibodies to H. pylori offers a simple alternative to direct detection of the organism in biopsied tissue by culture or histopathological methods. A rapid flow-through membrane-based enzyme immunoassay for the detection of human immunoglobulin G antibodies to H. pylori has been developed and evaluated. Clinical evaluations were performed with 256 patient serum samples obtained from four clinical sites. Biopsy samples were obtained by endoscopic procedures at the same time as the serum samples, and were histopathologically and microbiologically categorized for the presence or absence of H. pylori. Sensitivity and specificity for this rapid enzyme immunoassay were 92 and 88%, respectively, compared directly with endoscopy results. After discordant results were resolved by a quantitative microwell enzyme-linked immunosorbent assay, the resulting sensitivity and specificity were 94 and > 99%, respectively. These results indicate that this rapid enzyme immunoassay is a useful technique to determine H. pylori infection status and is a viable alternative to invasive endoscopic procedures.

1.5 tesla magnetic resonance imaging of acute spinal trauma.

Fifty patients with spinal injury above L2 were studied with MRI; forty-two had initial and followup studies permitting correlation of MRI abnormalities with neurologic improvement. Two discrete patterns of MRI abnormality were identified, presumably representing cord hemorrhage and edema respectively. A third pattern appeared to represent a mixed type of injury. The correlation between the MRI patterns of cord injury and neurologic recovery was excellent. The ability of MRI to demonstrate and characterize acute cord injury appears to exceed that of other diagnostic techniques.

Diagnosis of oral herpes simplex virus infections: practical aspects of viral culture.

Viral culture is a valuable aid in the diagnosis of herpes simplex virus infections of the oral cavity, but it is underutilized by members of the dental profession. This article outlines indications for culture, practical aspects of collection and transportation of specimens, reasons for false-negative and false-positive test results, and cost.