Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma.

OBJECTIVE: Oral mitotane (o,p'-DDD) is a cornerstone of medical treatment for adrenocortical carcinoma (ACC). AIM: Serum mitotane concentrations >14  mg/l are targeted for improved efficacy but not achieved in about half of patients. Here we aimed at a better understanding of intestinal absorption and lipoprotein association of mitotane and metabolites o,p'-dichlorodiphenylacetic acid (o,p'-DDA) and o,p'-dichlorodiphenyldichloroethane (o,p'-DDE). DESIGN: Lipoproteins were isolated by ultracentrifugation from the chyle of a 29-year-old patient and serum from additional 14 ACC patients treated with mitotane. HPLC was applied for quantification of mitotane and metabolites. We assessed NCI-H295 cell viability, cortisol production, and expression of endoplasmic reticulum (ER) stress marker genes to study the functional consequences of mitotane binding to lipoproteins. RESULTS: Chyle of the index patient contained 197  mg/ml mitotane, 53  mg/ml o,p'-DDA, and 51  mg/l o,p'-DDE. Of the total mitotane in serum, lipoprotein fractions contained 21.7±21.4% (VLDL), 1.9±0.8% (IDL), 8.9±5.5% (LDL1), 18.9±9.6% (LDL2), 10.1±4.0% (LDL3), and 26.3±13.0% (HDL2). Only 12.3±5.5% were in the lipoprotein-depleted fraction. DISCUSSION: Mitotane content of lipoproteins directly correlated with their triglyceride and cholesterol content. O,p'-DDE was similarly distributed, but 87.9±4.2% of o,p'-DDA found in the HDL2 and lipoprotein-depleted fractions. Binding of mitotane to human lipoproteins blunted its anti-proliferative and anti-hormonal effects on NCI-H295 cells and reduced ER stress marker gene expression. CONCLUSION: Mitotane absorption involves chylomicron binding. High concentrations of o,p'-DDA and o,p'-DDE in chyle suggest intestinal mitotane metabolism. In serum, the majority of mitotane is bound to lipoproteins. In vitro, lipoprotein binding inhibits activity of mitotane suggesting that lipoprotein-free mitotane is the therapeutically active fraction.

Right-Crossed, Fused Renal Ectopia L-Shaped Kidney Type with Urinary Chyluria.

Crossed fused renal ectopia combined with chyluria is extremely rare. Here we report the case of a patient who was admitted to our institution since milky urine and was finally found to have an L-shaped fused kidney and renal pelvis fistula. The patient was cured by renal pelvic instillation sclerotherapy.

Chylothorax diagnosis: can the clinical chemistry laboratory do more?

BACKGROUND: Chylothorax is a rare anatomical disruption of the thoracic duct associated with a significant degree of morbidity and mortality. Diagnosis usually relies upon lipid analysis and visual inspection of the pleural fluid. However, this may be subject to incorrect interpretation. The aim of this study was to compare pleural fluid lipid analysis and visual inspection against lipoprotein electrophoresis. METHODS: Nine pleural effusion samples suspected of being chylothorax were analysed. A combination of fluid lipid analysis and visual inspection was compared with lipoprotein electrophoresis for the detection of chylothorax. RESULTS: There was 89% concordance between the two methods. Using lipoprotein electrophoresis as gold standard, calculated sensitivity, specificity, negative predictive value and positive predictive value for lipid analysis/visual inspection were 83%, 100%, 100% and 75%, respectively. CONCLUSION: Examination of pleural effusion samples by lipoprotein electrophoresis may provide important additional information in the diagnosis of chylothorax.

Post-traumatic chylous knee effusion.

Chylous joint effusion is a rare condition in which synovial fluids containing large amounts of lipids take on a milky appearance as a result. We report on a 19-year-old male patient with posttraumatic chylous knee effusion. Several days after striking his knee against the ground because of a traffic accident, his left knee showed obvious swelling. Aspiration of his knee was performed, yielding 70ml of purulent-appearing fluid. To distinguish this condition from purulent or tuberculosis arthritis, arthroscopic biopsy and debridement were performed. Arthroscopic examination visualized distinctive yellow-white soft lesions covering much of the joint capsule, resembling a cobweb. Tissue cultures for bacteria were negative. Pathologically, we identified clusters of xanthoma cells with fibrin exudation due to disruption of the synovium and intra-articular fat pad necrosis. Centrifuging the aspiration fluid yielded a thick creamy lipid layer as the supernatant. A fresh drop preparation showed that the specimen contained innumerable fat globules, which stained red with oil red O stain. The patient was able to walk without difficulty or further swelling of his knee at the end of the second postoperative week. Posttraumatic chylous effusion is self-limited. Purulent arthritis or tuberculosis arthritis, however, should still be the presumptive diagnosis in such cases. Arthroscopic irrigation and debridement should be considered for these traumatic cases to confirm diagnosis and to speed up recovery.

[Performance evaluation of affinity column mediated immunometric assay for tacrolimus].

BACKGROUND: Therapeutic drug monitoring (TDM) of tacrolimus is essential because of narrow therapeutic range and poor correlation of dose to blood concentration. Affinity Column Mediated Immunometric Assay (ACMIA) does not require a pretreatment steps in measurement of tacrolimus. In this study, we evaluated the performance of tacrolimus assay using ACMIA (Dimension RxL Max, Dade Behring). METHODS: The imprecision, the linearity and the detection limits and the interferences by bilirubin and chyle, and correlation with hematocrit for tacrolimus by ACMIA were evaluated according to Clinical and Laboratory Standards Institute guidelines EP5-A2, EP6-A, EP17-A, EP9-A2, and EP7-A2. Method comparison studies with microparticle enzyme immunoassay (MEIA) (IMx Tacrolimus II, Abbott Laboratories) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Waters 2795 Quattromicro API, Micromass) were also performed. RESULTS: The total imprecision for low, middle and high level was 12.8%, 9.0% and 6.7%, respectively. The range of tacrolimus from 3.1 ng/mL to 35.4 ng/mL showed a clinically relevant linearity. The limit of detection and the functional sensitivity were 0.24 ng/mL and 0.72 ng/mL, respectively. Tacrolimus concentration measurement (Tac-CM) with ACMIA did not show significant interferences with bile and chyle and also did not show significant correlation with hematocrit. In comparison study for Tac-CM with MEIA and LC-MS/MS, Tac-CM with ACMIA showed a good correlation with MEIA (r=0.950) and LC-MS/MS (r=0.946). CONCLUSIONS: The imprecision, linearity, detection limits, interference and correlation of Tac-CM with ACMIA were suitable for clinical use. Tac-CM with ACMIA could reduce turn around time and help clinicians to manage transplant patients on immunosuppressant therapy.

A systematic approach to the investigation and diagnosis of a unilateral pleural effusion.

Fluid in the pleural space is a common sequela of a wide range of diseases which may be pulmonary, pleural or extrapulmonary. As the differential diagnosis is wide, a systematic approach to investigation and diagnosis is recommended. This review highlights the important features and recommendations for the investigation of a unilateral pleural effusion, a common condition encountered by the general physician. The aim of this study was to assist with a speedy diagnosis of the underlying pathology, using appropriate investigative techniques, while minimising the use of invasive procedures.

Chyle and gout causing acute monoarthritis: some unusual findings.

A 67-year-old man presented with acute monoarthritis of the right knee. Aspiration was carried out under aseptic precautions. This yielded a milky appearing fluid. Polarized microscopic examination confirmed uric acid crystals. The patient had a history of trauma to the joint. Acute monoarthritis of the knee can occur due to gout. Chylous effusions in the knee are rare. This combination of findings in the same joint has not been described in the literature. We emphasise the importance of history of trauma in acute monoarthritis. We discuss the unusual features of this case.

Pleural effusions: the role of biochemical analysis.

Biochemical analysis of pleural fluid may provide answers to important clinical questions. This review summarizes these questions and outlines the value and limitations of pleural fluid analysis.

Post-mastectomy chylous fistula: anatomical and clinical implications.

A chylous fistula after a modified radical mastectomy is a rare occurrence; however, major anatomical variations in the termination of the thoracic duct may occur, rendering it susceptible to injury. High output chylous fistulae are difficult to manage and have local, metabolic, and immunologic complications with a mortality rate varying from 12.5-50%. Herein such a case of postmastectomy chylous fistula and its management are discussed. A 56-year-old postmenopausal woman with invasive duct carcinoma of the left breast underwent modified radical mastectomy with complete axillary clearance (Level I, II, III nodes). The operative procedure was uneventful. On the commencement of a normal diet, however, the patient started exuding milky fluid from the axillary drain and analysis of the fluid revealed biochemical features compatible with chyle. After 2 weeks of failed conservative management, the axilla was re-explored. A continuous flow of clear fluid was observed originating from a single major lymphatic trunk inferior to the axillary vein in the region of the former Level II nodes. The leak was controlled by the application of multiple mass ligatures using 2-0 silk suture. A part of the pectoralis major muscle was rotated and sutured over the area of the leak as additional reinforcement. Suturing a muscle flap over the leak has been described previously and functions theoretically by causing fibrosis. The chylous fistula in the present case was managed successfully with mass ligatures and muscle flap reinforcement.

Thoracic duct cyst presenting as a left supraclavicular mass.

Thoracic duct cysts may occur either in the mediastinum or in the neck. The majority of such lesions occurring in the neck consist of chylous fistulae and are secondary to surgery on the neck. Fewer than five cases have been reported in the literature of primary thoracic duct cysts occurring in the neck (1).

Pseudochylous pleural effusion with fat-fluid levels: report of six cases.

The authors report the clinical and computed tomographic (CT) findings in six patients with chyliform pleural effusion. All six patients had a medical history of pleurisy before presentation; five of them had tuberculous pleural effusion. The CT scans of all six patients showed variable amounts of pleural fluid collection with a layering of fat at the nondependent site.

Computed tomography demonstration of a fat-fluid level in tuberculous chylous ascites.

The occurrence of fat-fluid levels in ascites, although rare, is pathognomic of chylous ascites. The ultrasound and CT scan findings of a fat-fluid level in the ascitic fluid of a patient with abdominal tuberculosis are described here. Recognition of this important sign, in conjunction with other ancillary findings of abdominal tuberculosis, assist in establishing the correct diagnosis. Anti-tuberculous chemotherapy suffices in treating the condition, thus obviating the need for surgical intervention.

Therapeutic digoxin level in chylous drainage with no detectable plasma digoxin level.

A patient receiving digoxin for long-standing congestive heart failure developed a chylothorax following removal of an infected aortic graft. Drainage of the chylothorax resulted in plasma digoxin concentrations which were near zero while the digoxin levels in the chylous drainage fluid were therapeutic. The sequestration of even low lipid-soluble drugs, such as digoxin, in chyle should be recognized to prevent subtherapeutic plasma levels in patients undergoing chylothorax drainage.

Do we still need to collect stool? Evaluation of visualized fatty acid absorption: experimental studies using rats.

BACKGROUND: Short-gut syndrome is likely to impair enteric fat utilization. This study was undertaken to develop a clinical test of lipid absorption without fecal collection. METHODS: The absorption of enterally fed radioactive long-chain fatty acid, beta-methyl-p-(123I)-iodophenylpentadecanoic acid was investigated with continuous chyle collection in rats. The changes in excretion and time-dependent biodistribution of radioactivity of the enterally fed agent were assessed in normal control animals. Similarly, sequential urinary excretion and biodistribution were studied along with scintigraphy using sham-operated and short-gut animals. RESULTS: Approximately 64% of the enterally fed radioactivity was recovered in the collected chyle (24 hours). A comparison of normal control, sham-operated, and short-gut animals showed significantly less urinary and greater fecal excretions of radioactivity in short-gut animals. With the use of sequential scintigraphy, the small intestine, whole-body soft tissues, and urinary bladder were well visualized in sham-operated animals, whereas the large intestine and feces were demonstrated earlier in short-gut animals. CONCLUSIONS: Our results suggest that enteral feeding of the agent might be feasible for determining lipid absorption from the the dynamic changes of radioactivity in visualized abdominal organs and in urine.

Congenital chylothorax.

Congenital chylothorax is a rare condition in which chyle accumulates in the pleural space because of an intrauterine obstruction or anomalies of the thoracic duct. This paper presents a case of congenital chylothorax diagnosed antepartum echographically. The patient's history revealed a previous sibling with a similar diagnosis. The baby developed respiratory distress after delivery and the diagnosis was established by thoracentesis. Computed tomography of the chest and nuclear lymphangiography were obtained to evaluate the origin of the pleural effusion, but a congenital fistula or other pathology of the thoracic duct could not be demonstrated. Management of the baby consisted of ventilatory support in the delivery room, repeated thoracentesis and thoracostomy tube drainage, total parenteral nutrition and formula containing medium-chain triglycerides. The infant was discharged six weeks after birth in good condition.