Feasibility of collecting tumor samples of breast cancer patients diagnosed up to 50 years ago in the Child Health and Development Studies.

Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels.

This study investigated the relationship of children's autism symptoms with their toxic metal body burden and red blood cell (RBC) glutathione levels. In children ages 3-8 years, the severity of autism was assessed using four tools: ADOS, PDD-BI, ATEC, and SAS. Toxic metal body burden was assessed by measuring urinary excretion of toxic metals, both before and after oral dimercaptosuccinic acid (DMSA). Multiple positive correlations were found between the severity of autism and the urinary excretion of toxic metals. Variations in the severity of autism measurements could be explained, in part, by regression analyses of urinary excretion of toxic metals before and after DMSA and the level of RBC glutathione (adjusted R(2) of 0.22-0.45, P < .005 in all cases). This study demonstrates a significant positive association between the severity of autism and the relative body burden of toxic metals.

Characterization and quantitation of NF-kappaB nuclear translocation induced by interleukin-1 and tumor necrosis factor-alpha. Development and use of a high capacity fluorescence cytometric system.

A new quantitative cytometric technique, termed the ArrayScanTM, is described and used to measure NF-kappaB nuclear translocation induced by interleukin (IL)-1 and tumor necrosis factor-alpha (TNFalpha). The amount of p65 staining is measured in both the nuclei defined by Hoechst 33342 labeling and in the surrounding cytoplasmic area within a preselected number of cells/well in 96-well plates. Using this technique in synchronously activated human chondrocytes or HeLa cells, NF-kappaB was found to move to the nucleus with a half-time of 7-8 min for HeLa and 12-13 min for chondrocytes, a rate in each case about 4-5 min slower than that of Ikappa Balpha degradation. IL-1 receptor antagonist and anti-TypeI IL-1 receptor antiserum on the one hand and anti-TNFalpha and monoclonal anti-TNF receptor 1 antibodies on the other hand could be shown to respectively inhibit IL-1 and TNFalpha stimulation in both cell types. In contrast, a polyclonal anti-TNF receptor 1 antiserum exhibited both a 50% agonism and a 50% antagonism to a TNFalpha stimulation in a dose-dependent fashion, indicating that subtle functional responses to complex agonist and antagonist stimuli could be measured. The effects of different proteasome inhibitors to prevent Ikappa Balpha degradation and subsequent NF-kappaB translocation could also be discriminated; Leu-Leu-Leu aldehyde was only a partial inhibitor with an IC50 of 2 microM, while clastolactacystin beta-lactone was a complete inhibitor with an IC50 of 10 microM. The nonselective kinase inhibitor K252a completely inhibited both IL-1 and TNFalpha stimulation in both cell types with an IC50 of 0.4 microM. This concentration, determined after a 20-min stimulation, was shown to be comparable with that obtained for inhibition of IL-6 production induced by a 100-fold lower IL-1 and TNFalpha concentration measured after 17 h of stimulation. These results suggest that the ArrayScanTM technology provides a rapid, sensitive, quantitative technique for measuring early events in the signal transduction of NF-kappaB.

Evaluation of the solid hepatic mass.

With the expanding use of abdominal imaging studies, evaluation of solid hepatic masses has become a common clinical challenge. In this review, the clinicopathologic characteristics of the most common causes of solid hepatic masses have been discussed. As the case scenarios demonstrate, the appropriate selection of imaging techniques and proper management of an individual patient depend on the clinical context. Often, complementary radiologic studies are necessary to narrow the differential diagnosis. Percutaneous biopsy or surgery is frequently required to confirm the diagnosis and to exclude malignancy definitively. The evaluation and management of solid hepatic masses is a cooperative venture that requires a multidisciplinary approach.

Post-transfusion acquired malaria complicating orthotopic liver transplantation.

Early infectious complications within the first 3 months of orthotopic liver transplantation are common and are associated with significant morbidity and mortality. Here we report the first case of transfusion-acquired malaria in an orthotopic liver transplantation recipient. The patient was found to have Plasmodium ovale malaria during evaluation of a severe febrile illness. The infection was traced to a platelet transfusion and responded to treatment with chloroquine. Risk factors associated with the development of malaria infection are identifiable and should be reviewed from the recipient and donor when possible. Routes of infection in the liver transplant patient would include blood products, the organ itself, and resurgence of latent infection. Theoretically, immunosuppression may have an impact on the disease process. Clinicians caring for these patients need to have a high index of suspicion in order to diagnose and treat malaria effectively in the post-transplant setting. Although rare, malaria should be added to the list of pathogens that can infect organ transplant recipients.

Nuclear imaging of solid hepatic masses.

This review has focused on the unique role of radionuclide scintigraphy in characterization of hepatic mass lesions. Radionuclide scintigraphy, unlike most other imaging modalities, is based on specific physiological and biochemical properties of each pathological entity that affects the liver. Hepatic scintigraphy, with its widespread availability, noninvasive nature, and relatively low cost is a powerful adjunct to other imaging techniques in the investigation of hepatic mass lesions. We have reviewed clinical presentation and characteristic findings of most hepatic lesions and have described reported findings with all available imaging modalities with particular emphasis on hepatic scintigraphy (Table 1) as well as a suggested algorithm for workup of solid hepatic masses (Fig 6). Additionally, the role of newer, more specialized techniques including PET scanning, 123I-labeled VIP, and 111In-labeled DTPA-D-Phe-octreotide scanning are reviewed. Hepatic nuclear scintigraphy continues to play an important role in the management of patients with solid hepatic masses.

Fatal Vibrio parahemolyticus septicemia in a patient with cirrhosis. A case report and review of the literature.

Vibrio parahemolyticus has been well documented to cause outbreaks of infectious diarrhea, usually related to poor food handling; only rarely has it been reported to cause fetal septicemia. In contrast, Vibrio vulnificus is a well-known cause of septicemia, especially in patients with cirrhosis. A 31-year-old woman with cirrhosis who developed fatal V. parahemolyticus sepsis after ingesting raw seafood is described. We review the clinical syndromes associated with sepsis caused by these two organisms. Leg pain and bullous skin lesions may be a clue to the diagnosis. Febrile patients with cirrhosis should be questioned regarding recent seafood ingestion, and appropriate antibiotics chosen if this history is obtained. Physicians should inform patients at risk to avoid raw seafood in an attempt to prevent this potentially lethal syndrome.

Fast three-dimensional time-of-flight MR angiography of the intra-cranial vasculature.

Magnetic resonance angiography is most commonly performed with the three-dimensional (3D) time-of-flight (TOF) technique. As currently practiced, this requires long image acquisition times (5-10 minutes). The authors show that the acquisition time of 3D TOF images can be reduced to less than 1 minute by using a very short TR (< 10 msec). Under normal flow conditions, the major vessels of the circle of Willis were consistently well demonstrated on these fast 3D TOF images. Signal saturation was observed in studies of patients with abnormal blood flow. In those cases, it was demonstrated that serial acquisition of fast 3D TOF data during and after contrast agent administration could be used to overcome the saturation effects. Time-resolved fast 3D TOF imaging during and after contrast agent administration can also provide qualitative assessment of flow and may depict other features that cannot be observed in TOF studies with long imaging times.

Transjugular intrahepatic portosystemic shunting: decreased survival for patients with high APACHE II scores.

OBJECTIVES: To determine which clinical characteristics are associated with decreased survival after transjugular intrahepatic portosystemic shunting (TIPS). METHODS: Forty-nine consecutive patients were treated with TIPS; 46 of them had refractory variceal bleeding. Univariate statistics and logistic regression analyses were used to determine the relationship between clinical, biochemical, and hemodynamic variables and 30-day) survival. RESULTS: Shunt insertion was successful in 48 (98.0%) of 49 cases. Median portal-systemic gradient was reduced from 22.5 (range 9-36) [median (5th-95th percentile)] to 12 (range 4-20) mm Hg. Thirty (61.2%) of 49 patients survived more than 30 days; four patients died more than 30 days after TIPS in mean follow-up of 8.4 months. Significant differences (p < 0.05) were found between those who survived more than 30 days and those who did not, with respect to preprocedural prothrombin time, bilirubin, albumin, alanine aminotransferase, and treatment with vasopressin and nitrates, balloon tamponade, or mechanical ventilation. Whereas there were no significant differences between the pre- and post-TIPS portal vein pressures and portal-systemic gradients in survivors and non-survivors, the pre- and post-TIPS hepatic vein pressures were significantly lower in survivors. Survival was inversely proportional to Child-Pugh class (p < 0.01) and to APACHE II score (p < 0.01). The single determinant most closely associated with decreased survival in the month after TIPS was the APACHE II score, a score of 18 stratifying patients into those at low and high risk of mortality [odds ratio 21.7 (CI 3.6-131.7)]. Only 1 (7.7%) of 13 patients with Child-Pugh C cirrhosis and an APACHE II score exceeding 18 survived more than 30 days. CONCLUSIONS: Patients with advanced cirrhosis, especially those with high pre-TIPS APACHE II scores, are at high risk for reduced survival after TIPS, despite adequate portal decompression.

Ursodiol for hepatobiliary disorders.

PURPOSE: To explain the rationale supporting the use of ursodiol (ursodeoxycholic acid) for the treatment of patients with cholesterol gallstones and chronic liver diseases and to describe the results obtained in clinical trials. DATA SOURCES: Personal databases of the authors and MEDLINE were used to identify relevant English-language articles. STUDY SELECTION: Randomized controlled trials evaluating ursodiol for the treatment of patients with cholesterol gallstones and chronic liver diseases were emphasized. DATA SYNTHESIS: Ursodiol is at least as effective as chenodiol (chenodeoxycholic acid) for the dissolution of cholesterol gallstones and is associated with fewer adverse effects. Ursodiol desaturates bile, solubilizing cholesterol from the stone surface. The diameter of the largest stone is the most important determinant of successful dissolution. Dissolution with ursodiol is effective for approximately 30% to 50% of stones smaller than 20 mm in diameter, with the best results for small, buoyant stones. A meta-analysis of randomized trials with ursodiol found that the dissolution rate was 37% for patients treated with ursodiol at doses of more than 7 mg/kg per day or of more than 500 mg/d for at least 6 months. Maintenance therapy is effective for prevention of gallstone recurrence. Ursodiol also improves biochemical markers of cholestasis and inflammation when used to treat cholestatic liver diseases. By displacing potentially hepatotoxic bile salts, it appears to interrupt the cycle of cholestatic injury. It may also exert hepatoprotective membrane-stabilizing or immunomodulatory effects (or both). Improvements in laboratory variables are limited to the treatment period, with relapses after withdrawal of therapy. Pruritus may be markedly relieved in individual patients treated with ursodiol. CONCLUSIONS: Ursodiol is a safe and effective therapy for the treatment of patients with cholesterol gallstones. Although treatment with ursodiol leads to improvement in biochemical markers for cholestatic liver diseases, whether it alters the natural history of these disorders is the subject of ongoing trials.

Intestinal varices: treatment with the transjugular intrahepatic portosystemic shunt.

PURPOSE: To perform a retrospective evaluation of transjugular intrahepatic portosystemic shunt (TIPS) placement for treatment of intestinal varices. MATERIALS AND METHODS: TIPS were placed in nine patients (six women and three men, aged 36-85 years [mean, 64 years]) with small- (n = 6) and large- (n = 3) intestinal varices. Six patients were actively bleeding at the time of shunt placement. One patient with colon cancer underwent prophylactic TIPS placement for variceal decompression before colectomy. RESULTS: The mean preprocedure portosystemic gradient of 26.8 mm Hg +/- 5.1 was reduced to 8.8 mm Hg +/- 2.9. Bleeding was controlled in all but one case, in which supplemental variceal embolization was required. Two patients died within 5 days of TIPS placement of preexisting multisystem failure. Three patients died of unrelated causes at 2, 6, and 7 months. The remaining patients were alive an average of 15 months after TIPS placement. There was no recurrent bleeding in any case. CONCLUSION: TIPS placement is an effective method of decompressing intestinal varices.

Chronic hepatitis C. Advances in diagnostic testing and therapy.

The methods for diagnosing hepatitis C virus infection have been evolving since the first-generation enzyme-linked immunosorbent assay antibody test was devised in 1989. In addition to assaying for serum antibodies against viral proteins, serum and liver tissue can be tested for viral RNA, evidence of ongoing viral replication. The improving ability to diagnose hepatitis C has furthered the understanding of the natural history of this infection. Acute hepatitis C results in chronic elevations of serum transaminase levels following nearly one half of cases. Cirrhosis complicates approximately 20% of chronic infections. Long-standing chronic hepatitis C may play a role in the pathogenesis of hepatocellular carcinoma. Sustained normalization of serum transaminase levels, often accompanied by a decrease in or disappearance of viral RNA, occurs in approximately 25% of patients with chronic hepatitis C who are treated with a 6-month course of recombinant interferon alfa. This treatment can occasionally be complicated by hematologic, endocrinologic, and psychiatric adverse effects but is usually fairly well tolerated. Whether interferon therapy will diminish the risk of cirrhosis or carcinoma is not yet known. This article reviews the diagnosis of chronic hepatitis C infection as well as the mechanisms of action, efficacy, and adverse effects associated with interferon alfa therapy.

Recurrent bleeding from anorectal varices: successful treatment with a transjugular intrahepatic portosystemic shunt.

Anorectal varices are portal-systemic collaterals commonly found in patients with portal hypertension. Although these varices rarely bleed, when bleeding does occur it may be massive and life threatening. Anorectal varices may be mistaken for hemorrhoids and there is no agreed upon method for their definitive diagnosis. Additionally, there is no standard therapy for bleeding anorectal varices, and when techniques designed for the control of hemorrhoidal bleeding are employed the results can be disastrous. We report here the first use of a transjugular intrahepatic portosystemic shunt (TIPS) for the permanent control of bleeding anorectal varices. Magnetic resonance imaging/magnetic resonance venography (MRI/V) was used as a non-invasive method for the identification of anorectal varices and to confirm the successful decompression of these varices with TIPS placement. MRI/V and TIPS may provide significant advances in the diagnosis and treatment of rectal variceal bleeding.

Hepatic arterial injury after transjugular intrahepatic portosystemic shunt placement: report of two cases.

Transjugular intrahepatic portosystemic shunts (TIPS) were placed in two patients for treatment of variceal hemorrhage and refractory ascites. In both patients, branches of the right hepatic artery were inadvertently punctured during portal vein localization. In one case, right hepatic artery occlusion resulted in irreversible liver failure. In the other case, intraperitoneal bleeding resulted from the arterial injury. Embolization could not be performed due to celiac axis occlusion. Four days after surgical repair, the patient died of multiorgan failure. Hepatic arterial injuries are a serious complication of TIPS creation. Aggressive efforts to recanalize occlusions and superselective embolization of extravasation are recommended.

Scintigraphic evaluation of liver masses: cavernous hepatic hemangioma.

Hepatic cavernous hemangioma must be included in the differential diagnosis of any hepatic solid mass. It is the second most common neoplasm of the liver, following intrahepatic metastases. With the exception of giant or symptomatic HCH, it does not require specific intervention. The ability to diagnose HCH radiologically (Table 2) has significant clinical importance. When confronted with clinical data and a preliminary radiologic study suggestive of HCH, serial planar blood-pool scintigraphy (with SPECT if the lesion is < 3-4 cm) should probably be the initial diagnostic examination. In comparison to MRI, it is safer, less expensive and easier for some patients to tolerate. For small, deep seated lesions or those adjacent to the heart or large vessels, MRI is the preferred test. Dynamic CT is probably most useful in patients with normal renal function in whom optimal imaging of the extrahepatic abdomen is desired. If the etiology of an incidental hepatic mass suspected to be an HCH is still not evident after these studies, angiography or biopsy are the remaining options. As described, angiography is sensitive and relatively specific for HCH. Although percutaneous biopsy may be associated with increased risk of bleeding, fine-needle biopsy has been shown to be safe for hemangiomas. However, fine-needle biopsy is more useful for confirming a suspected malignancy than for actually diagnosing hemangioma.

Primary aortoduodenal fistula: a unique presentation of a pseudoaneurysm associated with cystic medial necrosis.

A 42-yr-old man who exsanguinated from an acute upper gastrointestinal bleed was found to have a primary aortoduodenal fistula on postmortem examination. The fistula arose in an aortic pseudoaneurysm associated with cystic medial necrosis. Although there was no suggestion of Marfan's syndrome on physical examination, there was cystic medial necrosis of not only the involved aorta, but also other systemic arteries. Primary aortoduodenal fistula is a rare cause of acute upper gastrointestinal bleeding and is usually associated with atherosclerotic disease of the aorta. This is the first report of a pseudoaneurysm associated with cystic medial necrosis presenting as an aortoduodenal fistula.