Cognitive deterioration in adults with Down syndrome: effects on the individual, caregivers, and service use

Individuals with Down syndrome (N = 49) who had participated in serial neuropsychological assessments were assigned to one of three groups comparable in level of premorbid mental retardation: those showing cognitive deterioration, those comparable in age but not showing cognitive deterioration, and those not showing cognitive deterioration but younger. Those experiencing cognitive deterioration were less likely to receive day services, had more impoverished life experiences, and required more support compared to groups without cognitive deterioration. When age was controlled for, cognitive deterioration was significantly positively associated with caregiver difficulties and service use and negatively associated with life experiences for the individual. Results suggest a potential role for caregiver difficulties in influencing life experiences of adults with Down syndrome showing cognitive decline.     

Prospects for herpes-simplex-virus thymidine-kinase and cytokine gene transduction as immunomodulatory gene therapy for prostate cancer

In completed and ongoing clinical trials, adenovirus-mediated (Ad.) expression of herpes-simplex-virus thymidine-kinase (HSV-tk) gene transduction followed by ganciclovir (GCV) therapy has produced limited toxicity and evidence of antitumor activity following injection of the prostate. Furthermore, this system has been shown to direct systemic antitumor activity in several experimental cancer models, including that of prostate cancer, which may serve as the basis for in-situ immunomodulatory gene therapy. In a mouse model of prostate cancer, natural killer (NK) cells have been identified as the mediator of antimetastatic activity following Ad.HSV-tk + GCV, resulting in the combination of Ad.HSV-tk and adenovirus-mediated expression of interleukin 12 (Ad.IL-12) to exploit this cytokine's ability to enhance NK proliferation and cytotoxicity. Combination therapy demonstrated superior local and systemic growth suppression over that obtained with either therapy alone. Importantly, when the metastatic tumor burden was increased to an extent that negated the growth-suppressive activity directed by Ad.HSV-tk + GCV or Ad.IL-12 alone, combination therapy continued to demonstrate significant growth suppression. Examination of tumor-infiltrating lymphocytes documented enhanced NK lytic activity following combination therapy. Therefore, it appears that the combination of Ad.HSV-tk and Ad.IL-12 should be validated in a clinical trial for the treatment of prostate cancer.     

Primary prostate stromal cells modulate the morphology and migration of primary prostate epithelial cells in type 1 collagen gels.

The effects of human primary prostatic stromal cells on the migration and morphogenesis of human prostatic epithelial cells, derived from tumor or benign prostatic hyperplasia tissue, were studied using a three-dimensional coculture system. Epithelial cells from tumor or benign tissue migrated efficiently into collagen gels populated with stromal cells from benign tissue. Only epithelial cells from benign prostate formed acinus-like structures that exhibited differentiated prostatic function and strong expression of membrane-associated E-cadherin. In gels populated by stromal cells from tumor tissue, migration of primary prostatic epithelial cells did not occur. In the absence of stromal cells, primary epithelial cells were unable to proliferate. This three-dimensional culture system allows closely controlled manipulation and analysis in vitro of interactions between prostatic epithelial and stromal cells.     

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.