Pharmacokinetics of doxorubicin in pregnant women.

PURPOSE: Our objective was to evaluate the pharmacokinetics (PK) of doxorubicin during pregnancy compared to previously published data from non-pregnant subjects. METHODS: During mid- to late-pregnancy, serial blood and urine samples were collected over 72 h from seven women treated with doxorubicin for malignancies. PK parameters were estimated using non-compartmental techniques. Pregnancy parameters were compared to those previously reported non-pregnant subjects. RESULTS: During pregnancy, mean (±SD) doxorubicin PK parameters utilizing 72 h sampling were: clearance (CL), 412 ± 80 mL/min/m(2); steady-state volume of distribution (Vss), 1,132 ± 476 L/m(2); and terminal half-life (T1/2), 40.3 ± 8.9 h. The BSA-adjusted CL was significantly decreased (p < 0.01) and T1/2 was not different compared to non-pregnant women. Truncating our data to 48 h, PK parameters were: CL, 499 ± 116 ml/min/m(2); Vss, 843 ± 391 L/m(2); and T1/2, 24.8 ± 5.9 h. The BSA-adjusted CL in pregnancy compared to non-pregnant data was significantly decreased in 2 of 3 non-pregnant studies (p < 0.05, < 0.05, NS). Vss and T1/2 were not significantly different. CONCLUSIONS: In pregnant subjects, we observed significantly lower doxorubicin CL in our 72 h and most of our 48 h sampling comparisons with previously reported non-pregnant subjects. However, the parameters were within the range previously reported in smaller studies. At this time, we cannot recommend alternate dosage strategies for pregnant women. Further research is needed to understand the mechanism of doxorubicin pharmacokinetic changes during pregnancy and optimize care for pregnant women.

Conservative management of a retroperitoneal hemorrhage following a ruptured renal angiomyolipoma in pregnancy.

Retroperitoneal hemorrhage following ruptured renal angiomyolipoma is usually managed surgically or by embolization. But when the same episode occurs in pregnancy, surgery which predisposes to preterm delivery and its subsequent sequelae, the unknown influences of radiation exposure on the fetus makes the management of such cases very challenging. A 21-year-old woman was seen in the emergency unit at the 25th week of her pregnancy with complaints of sudden onset left flank pain radiating to the back, nausea and hematuria. Abdominal magnetic resonance imaging (MRI) revealed masses consistent with angiomyolipoma in the upper pole of the left kidney with evidence of recent bleeding and the center of the right kidney measuring 11.5 × 9.5 cm and 3.5 cm, respectively. The patient received three units of red blood cell concentrate due to fall in hematocrit level resulting in hemodynamically stable condition until term. At term, an infant weighing 3510 g was delivered through elective cesarean section. To avoid iatrogenic preterm delivery and unnecessary fetal exposure to radiation, conservative management of ruptured angiomyolipoma in pregnancy may be considered as a treatment option in hemodynamically stable patients.

Cardiovascular magnetic resonance and PET-CT of left atrial paraganglioma.

Cardiac paragangliomas are among the rarest primary cardiac tumors. We present a case of left atrial paraganglioma in a patient who presented with symptoms and signs of catecholamine excess in which cardiovascular magnetic resonance in multiple orientations and PET-CT played an important role in the diagnosis and tissue characterization.

Myomectomy at caesarean section: descriptive study of clinical outcome in a tropical setting.

BACKGROUND: In the tropics, leiomyoma are commonly encountered in women of the reproductive age group, although they are mostly asymptomatic. Surgery for uterine fibroid at caesarean section has remained controversial. OBJECTIVE: To analyse the clinical outcome of women that had selective caesarean myomectomy in a community teaching hospital. METHOD: Twenty-two women that had selective myomectomy at caesarean section between January 2002 and October 2007 were analysed. RESULTS: The patients mean age was 31.5 years with age range of 27-44 years. Of the 22 patients, 16 (72.7%) were primigravida, 19 (86.4%) of the patients had caesarean section at term, 2 (9.1%) and 1 (4.5%) ofthe patients were preterm and post term respectively. A significant number of the patients (16/22, 72.7%) had elective caesarean section and the remaining 6 (27.3%) patients had emergency caesarean section. The 3 leading indications for caesarean section among the patients were malpresentation/abnormal lie 36.4%, uterine fibroids 18.2%, and a previous caesarean section with complication in 13.6% ofthe patients. Indications for myomectomy at caesarean section were fibroid in lower uterine segment in 15 (68.2%) patients, pedunculated uterine fibroid in 4 (18.2%) patients and anterior subserous fibroid in 3 (13.6%) patients. Intraopertively in the 22 patients, 10 (45.5%) had fibroid(s) removed only in the lower uterine segment; while 6 (27.3%) patients each, had it removed in the upper uterine segment and both upper and lower uterine segments respectively. A total of 46 fibroids were removed in the 22 patients, of which 24 (52.2%) were subserous/pedunculated, 16 (34.8%) intramural and 6 (13.0%) were submucous. Of the 46 fibroids, 32 (69.9%) were between 6 to 10 cm size. Sixteen (72.2%) of the 22 patients lost between 751 to 1000 ml of blood intraoperatively with an average of 806.8 ml of blood loss. Two (9.1%) of the 22 patients had blood transfusion due to anaemia. Other complications encountered were puerperal pyrexia and sepsis in 2 (9.1%) patients, and fracture of the humerus and clavicle of the baby in 1 (2.3%) patient. There was no maternal and perinatal mortality. CONCLUSION: Selection of patients for caesarean myomectomy reduces blood loss, anaemia and other complications.

Pheochromocytoma with negative urinalysis in pregnancy.

We present a rare case of adrenal pheochromocytoma in pregnancy, with serial 24-h urine specimen collections showing normal concentrations of catecholamine metabolites. The diagnosis was based on clinical presentation, abdominal ultrasound, and magnetic resonance imaging, and was confirmed on post-operative pathohistological examination. Clinical suspicion of pheochromocytoma in pregnancy should be sufficient to implement adequate therapeutic measures, regardless of urine catecholamine concentrations.

Adrenal tumors and pregnancy.

Although adrenal tumors detected during pregnancy are extraordinarily rare, the pathophysiologic repercussions of untreated adrenal neoplasms are enormous to both mother and fetus. From our computer-based registry of pregnant patients from 1975 through 1996 (n = 30,246), four cases of adrenal neoplasms associated with pregnancy were identified (0.013%), analyzed, and compared with the current medical literature. Four women ages 36, 29, 22, and 21 years had adrenal neoplasms diagnosed with pregnancy. Patient 1 had an unsuspected pheochromocytoma identified at autopsy. At 27 weeks into her pregnancy the patient suffered a myocardial infarction, and both she and the fetus died. Patient 2 was incidentally found to have adrenal and pancreatic neoplasms on screening abdominal computed tomography for von Hippel-Lindau disease. The study identified a pregnancy. She elected to terminate the pregnancy and underwent resection of both tumors. She died 3 years later of metastatic islet cell cancer. Both of these patients had previously delivered healthy babies, but both pregnancies were complicated by hypertension. Patient 3 had a functional adrenal tumor identified initially by urinary aldosterone studies because of symptoms of severe hypertension, and patient 4 had an adrenal mass diagnosed via ultrasonography at 30 weeks' gestation because of concerns for right-sided pyelonephritis. These two women underwent careful monitoring throughout the remainder of their pregnancies with eventual delivery of healthy babies. Both women later underwent successful operative resection of benign adrenal adenomas. Adrenal neoplasms discovered during pregnancy are rare. The onus, however, is on physicians to consider this diagnosis in pregnant women with hypertension, headaches, or other manifestations of adrenal disorders. Surgical management of identified adrenal lesions is thereafter straightforward. Missing the diagnosis has grave implications for these young women and their fetuses.

Pregnancy complicated by multiple endocrine neoplasia type IIA (Sipple's syndrome).

A patient with preexisting multiple endocrine neoplasia type IIA had normal 24-hour urinary metanephrine and vanillylmandelic acid excretions before and during pregnancy. After a benign prenatal course, the patient had a term spontaneous vaginal delivery. Multiple endocrine neoplasia type IIA antedating pregnancy may be associated with a normal obstetric outcome in the absence of a phenochromocytoma.

Carbohydrate and peptide structure of the alpha- and beta-subunits of human chorionic gonadotropin from normal and aberrant pregnancy and choriocarcinoma.

Human chorionic gonadotropin (hCG), purified from the urine of 14 individuals with normal pregnancy, diabetic pregnancy, hydatidiform mole, or choriocarcinoma, plus two hCG standard preparations, was examined for concurrent peptide-sequence and asparagine (N)- and serine (O)-linked carbohydrate heterogeneity. Protein-sequence analysis was used to measure amino-terminal heterogeneity and the "nicking" of internal peptide bonds. The use of high-pH anion-exchange chromatography coupled with the increased sensitivity of pulsed amperometric detection (HPAE/PAD) revealed that distinct proportions of both hCG alpha- and beta-subunits from normal and aberrant pregnancy are hyperglycosylated, and that it is the extent of the specific subunit hyperglycosylation that significantly increases in malignant disease. Peptide-bond nicking was restricted to a single linkage (beta 47-48) in normal and diabetic pregnancy, but occurred at two sites in standard preparations, at three sites in hydatidiform mole, and at three sites in choriocarcinoma beta-subunit. In the carbohydrate moiety, alpha-subunit from normal pregnancy hCG contained nonfucosylated, mono- and biantennary N-linked structures (49.3 and 36.7%, means); fucosylated biantennary and triantennary oligosaccharides were also identified (7.3 and 6.9%). In choriocarcinoma alpha-subunit, the level of fucosylated biantennary increased, offset by a parallel decrease in the predominant biantennary structure of normal pregnancy (P < 0.0001). The beta-subunit from normal pregnancy hCG contained fucosylated and nonfucosylated biantennary N-linked structures; however, mono- and triantennary oligosaccharides were also identified (4.6 and 13.7%). For O-linked glycans, in beta-subunit from normal pregnancy, disaccharide-core structure predominated, whereas tetrasaccharide-core structure was also detected (15.6%). A trend was demonstrated in beta-subunit: the proportions of the nonpredominating N- and O-linked oligosaccharides increased stepwise from normal pregnancy to hydatidiform mole to choriocarcinoma. The increases were: for monoantennary oligosaccharide, 4.6 to 6.8 to 11.2%; for triantennary, 13.7 to 26.7 to 51.5% and, for O-linked tetrasaccharide-core structure, 15.6 to 23.0 to 74.8%. For hCG from individual diabetic pregnancy, the principal N-linked structure (34.7%) was consistent with a biantennary oligosaccharide previously reported only in carcinoma; and sialylation of both N- and O-linked antennae was significantly decreased compared to that of normal pregnancy. Taken collectively, the distinctive patterns of subunit-specific, predominant oligosaccharides appear to reflect the steric effect of local protein structure during glycosylation processes. The evidence of alternative or "hyperbranched" glycoforms on both alpha- and beta-subunits, seen at low levels in normal pregnancy and at increased or even predominant levels in malignant disease, suggests alternative substrate accessibility for Golgi processing enzymes, alpha 1,6 fucosyltransferase and N-acetylglucosaminyltransferase IV, in distinct proportions of subunit molecules.

Immunochemical analysis of the human chorionic gonadotrophin-like material secreted by 'normal' and neoplastic urothelial cells.

Material with the immunochemical characteristics of human chorionic gonadotrophin (hCG) is produced by bladder tumour cells in vitro and in vivo. In order to characterize this material further, media were collected from 17 cell cultures (three choriocarcinomas, seven bladder carcinomas and seven 'normal' urothelium). The hCG-like material was compared with pregnancy hCG and purified alpha-and beta-subunits by specific radioimmunoassays. Media were also submitted to affinity chromatography and the fractions further analysed by SDS-PAGE and Western blotting. It was shown that both the neoplastic and normal urothelium produced only free beta-subunit-like material. This urothelial 'beta-hCG' has the same molecular weight and electrophoretic mobility as that present in the intact hCG of pregnancy.

Phaeochromocytoma: a review of the St Vincent's Hospital, Melbourne experience (1969-84) and of recent advances in management.

Phaeochromocytoma is an unusual tumour which is eminently curable by surgical means. It is difficult to diagnose clinically because it mimics other illnesses. The clinical features of 13 cases of phaeochromocytoma diagnosed at St Vincent's Hospital, Melbourne, between 1969 and 1984 are briefly described. This review emphasizes the several major improvements in both diagnostic and localizing tests which have occurred over the 16 year period of the series. These include the clonidine suppression test and plasma and urine catecholamine estimations in diagnosis and techniques such as CT scanning and the I131-meta-iodobenzyl-guanidine scan used for localization of the tumour. Careful pre-operative preparation, based on adequate alpha blockade and intra-operative monitoring, is essential for the safe and successful removal of the tumour, which was eventually accomplished for all 12 cases in which removal was attempted. However, the most important step in the diagnosis and treatment of phaeochromocytoma is the initial consideration of the diagnosis. This step depends on the level of awareness of the disorder amongst clinicians.

Unusual molecular forms of hCG in gestational trophoblastic neoplasia.

We have observed unusual forms of human choriogonadotropin (hCG) in the urine of patients with gestational trophoblastic neoplasia. These molecules were of two types: Carboxyterminal fragments of hCG beta-subunit and desialylated forms of hCG. Substantial amounts of these materials were found in the urines of 83% and 50%, respectively, of the patients (n = 12) studied. In contrast, negligible quantities were found in the urine of 14 healthy pregnant women. Also, these unusual forms were not detectable in normal controls given an infusion of hCG. These findings indicate that these forms have clinical potential for diagnosing gestational trophoblastic neoplasia and differentiating it from normal pregnancy.

[Detection of hCG production in trophoblastic diseases by HCG beta carboxyl-terminal peptide].

A radioimmunoassay (CTP-RIA) for urinary human chorionic gonadotropin (hCG) with the use of an antiserum to be carboxyl-terminal peptide of hCG beta subunit was employed to detect hCG production in patients with gestational trophoblastic disease. In urine samples obtained from normal subjects, the upper limit of hCG-immunoactivity detected by this assay system was 1.1 IU/24h. More than 90% of the subjects tested had values lower than 0.5 IU/24h. Based on these data, we selected urinary hCG levels below 1.1 IU/24 h as the normal range for clinical applications. The utility of this new assay system was assessed in 50 cases of gestational trophoblastic disease. In patients with hydatidiform mole, invasive mole and undetermined cases, the urinary hCG level declined to be normal range following the therapy and stayed there afterwards without any sign of recurrence. However, in a woman with a long history of metastatic choriocarcinoma, we noted the reappearance of hCG even after the hCG level once declined to the normal range. It therefore seems that cell viability will persist even in the normal range determined by CTP-RIA. Therefore, therapeutic decisions should take into account these points. This specific and sensitive CTP-RIA method for the detection of hCG production was found to improve the ability to diagnose persistent or recurrent trophoblastic disease.