Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer.

PURPOSE: We wished to critically examine the level of activity of weekly paclitaxel in a patient population with well-characterized platinum/paclitaxel-resistant (3-week schedule) ovarian cancer. PATIENTS AND METHODS: Eligibility criteria for this phase II trial included the following: ovarian and fallopian tube cancers or primary carcinoma of the peritoneum; prior initial therapy with platinum/paclitaxel; and failure to respond to treatment (progression or stable disease as best response), or a response duration of less than 3 months, or if the response was more than 3 months, retreatment with both agents required and failure to respond a second time or the response duration was less than 3 months. Measurable or assessable disease (CA-125 response criteria) was required. Patients received weekly paclitaxel (80 mg/m(2)) until disease progression, unacceptable toxicity developed, or they elected to discontinue treatment. RESULTS: Fifty-three patients (52 assessable for toxicity and 51 for response) were entered onto this multi-institution trial. Of 248 total cycles (887 doses), only 13 (1%) were modified (dose reduction or treatment delay) because of side effects. Therapy was discontinued in five patients because of toxicity (four because of peripheral neuropathy, and one because of painful fingernail beds). Thirteen patients (25%; 95% confidence interval, 13.5% to 37.5%) achieved an objective response (four by CA-125 criteria, and nine by > or = 50% reduction of measurable disease). CONCLUSION: Weekly paclitaxel (80 mg/m(2)) is generally well tolerated and is an active second-line regimen against ovarian cancer that has demonstrated resistance to platinum/paclitaxel delivered on an every-3-week schedule.     

p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.

PURPOSE: Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used. EXPERIMENTAL DESIGN: Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing. RESULTS: Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion. CONCLUSIONS: p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.     

Antipsychotics and the risk of sudden cardiac death

BACKGROUND: Case reports link antipsychotic drugs with sudden cardiac deaths, which is consistent with dose-related electrophysiologic effects. Because this association has not been confirmed in controlled studies, we conducted a retrospective cohort study in Tennessee Medicaid enrollees, which included many antipsychotic users; there were also computer files describing medication use and comorbidity. The study was conducted before the introduction of risperidone and, thus, did not include the newer atypical agents. METHODS: The cohort included 481,744 persons with 1,282,996 person-years of follow-up. This included 26,749 person-years for current moderate-dose antipsychotic use (>100-mg thioridazine equivalents), 31,864 person-years for current low-dose antipsychotic use, 37,881 person-years for use in the past year only, and 1 186,501 person-years for no use. The cohort had 1487 confirmed sudden cardiac deaths; from these, we calculated multivariate rate ratios adjusted for potential confounding factors. RESULTS: When current moderate-dose antipsychotic use was compared with nonuse, the multivariate rate ratio was 2.39 (95% confidence interval, 1.77-3.22; P<.001). This was greater than that for current low-dose (rate ratio, 1.30; 95% confidence interval, 0.98-1.72; P=.003) and former (rate ratio, 1.20; 95% confidence interval, 0.91-1.58; P<.001) use. Among cohort members with severe cardiovascular disease, current moderate-dose users had a 3.53-fold (95% confidence interval, 1.66-7.51) increased rate relative to comparable nonusers ( P<.001), resulting in 367 additional deaths per 10,000 person-years of follow-up. CONCLUSIONS: Patients prescribed moderate doses of antipsychotics had large relative and absolute increases in the risk of sudden cardiac death. Although the study data cannot demonstrate causality, they suggest that the potential adverse cardiac effects of antipsychotics should be considered in clinical practice, particularly for patients with cardiovascular disease.     

Solitary osteosclerotic plasmacytoma: association with demyelinating polyneuropathy and amyloid deposition

A 51-year-old man presented with a 1-year history of polyneuropathy necessitating the use of a wheelchair. Initial diagnosis was idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and associated monoclonal gammopathy. Investigations for multiple myeloma, including bone marrow aspiration and biopsy, were negative. What was initially felt to be an incidental osteosclerotic focus noted on the radiographic bone survey was eventually shown to be a solitary osteosclereotic plasmacytoma with associated amyloid. This dramatically altered treatment. This case emphasizes the importance of including osteosclerotic plasmacytoma in the differential diagnosis of a focal sclerotic bone lesion in the clinical setting of polyneuropathy. These lesions are less likely to progress to multiple myeloma than lytic plasma cell neoplasms, and the presence of polyneuropathy often results in earlier diagnosis and treatment with enhanced prospect of cure. The finding of amyloid deposition within the osteosclerotic lesion may be of prognostic importance. Received: 30 November 2000 Revision requested: 15 January 2001 Revision received: 16 April 2001 Accepted: 18 April 2001     

Brain biopsy sampling by using prospective stereotaxis and a trajectory guide

OBJECT: The authors describe their initial results obtained using a skull-mounted trajectory guide for intraoperative magnetic resonance (MR) imaging-guided brain biopsy sampling. The device was used in conjunction with a new methodology known as prospective stereotaxis for surgical trajectory alignment. METHODS: Between January 1999 and March 2000, 38 patients underwent 40 brain biopsy procedures in which prospective stereotaxis was performed with the trajectory guide in a short-bore 1.5-tesla MR imager. In most cases, orthogonal T2-weighted half-Fourier acquisition single-shot turbo spin-echo (HASTE) images were used to determine the desired trajectory and align the device. The surgical trajectory was defined as a line connecting three points: the target, pivot, and alignment stem points. In all cases, surgical specimens were submitted for frozen section and pathological examination. Postoperative turbofluid-attenuated inversion-recovery and gradient-echo images were obtained to exclude the presence of hemorrhage. Trajectory determination and alignment was simple and efficient, requiring less than 5 minutes. Confirmatory HASTE images were obtained along the biopsy needle as it was being advanced or after reaching the target. All biopsy procedures yielded diagnostic tissue. One patient with a lesion near the motor strip experienced a transient hemiparesis of the hand related to passage of the biopsy needle, and another sustained a fatal postoperative myocardial infarction. No patient suffered a clinically significant or radiologically visible hemorrhage. CONCLUSIONS: In combination with prospective stereotaxis, the trajectory guide provided a safe and accurate way to perform brain biopsy procedures.     

Initial and subsequent dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic study of new dose recommendations

BACKGROUND: Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors' previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10-20 microg/ml, without evidence of accumulation. METHODS: Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration. RESULTS: All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 +/- 25% of the time. With subsequent dosing, the target range was maintained 60 +/- 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 microg/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses. CONCLUSIONS: A rectal acetaminophen loading dose of 40 mg/kg followed by 20-mg/kg doses every 6 h results in serum concentrations centered at the target range of 10-20 microg/ml. There was large interindividual variability in pharmacokinetic characteristics. There was no evidence of accumulation during the 24-h sampling period.     

Ciliocytophthoria in clinical virology

Direct immunofluorescence assays (DFAs) are used in the clinical virology laboratory for the rapid detection of viruses. An assessment of the cellularity of specimens submitted for DFA is necessary for the most effective use of this assay. This assessment ensures that an adequate number of the appropriate cells are present for examination. During this assessment, clinical virologists may encounter unfamiliar cellular elements or cellular fragments. One of these elements, ciliocytophthoria, has been misinterpreted as a parasite in specimens submitted for cytologic testing. We describe a similar case in which a technologist thought that ciliocytophthoria possibly represented a ciliated parasite in a nasopharyngeal specimen sent for respiratory syncytial virus DFA. After a thorough morphologic examination, the staff dismissed the possibility of a ciliated parasite. We confirmed this entity as ciliocytophthoria using morphologic criteria and the Diff-Quik stain. This near misidentification of ciliocytophthoria as a ciliated parasite affords us the opportunity to raise the awareness of clinical virologists about ciliocytophthoria. Additionally, we briefly review useful features for differentiating ciliocytophthoria from the only ciliate parasitic for humans, Balantidium coli. Finally, we present the utility of a commonly used cytologic stain, the Diff-Quik stain, for the confirmation of ciliocytophthoria.     

Antibody reactivity against human and guinea pig tissue transglutaminase in children with celiac disease

BACKGROUND: Highly discriminatory markers for celiac disease are needed to identify children with early mucosal lesions. The purposes of this study were to evaluate the clinical potential of circulating anti-tissue transglutaminase (tTG) immunoglobulin (Ig)A antibodies in the diagnosis of childhood celiac disease and to investigate the extent of autoreactivity of these antibodies. METHODS: Included in this retrospective study were samples from 22 children with biopsy-verified celiac disease, 23 control subjects with disease, and 22 healthy control subjects without any known gastrointestinal or inflammatory disorders. An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of IgA antibodies specific for human and guinea pig tTGs. All samples were also analyzed for antibodies to gliadin and endomysium (EMA). RESULTS: The concentrations of IgA specific for human and guinea pig tTGs correlated with the small intestinal villous structure and the serum levels of IgA EMA. The tTG ELISAs exhibited a high specificity and sensitivity for detection of untreated celiac disease. The human erythrocyte IgA tTG ELISA had the highest sensitivity (100%) and a specificity of 98%. The IgA EMA method had a sensitivity of 95% and the highest specificity (100%) of all tests. CONCLUSIONS: Our results provide additional support to the concept that anti-tTG IgA antibodies can be used as a highly discriminatory serologic marker for celiac disease and that measurements of these autoreactive antibodies may in the future be used as an alternative to the EMA test.