Tamoxifen elicits rapid transmembrane lipid signal responses in human breast cancer cells

The antiestrogen tamoxifen competes with estrogen for receptor occupancy, although reports indicate that not all effects of tamoxifen are mediated via this specific interaction. In the present study we sought to determine whether tamoxifen can initiate transmembrane lipid signals. Lipid signaling is a prominent mode by which hormones, growth factors, and phorbol diesters transduce messages. Using the human mammary carcinoma cell line MDA-MB-231, phospholipid metabolism was analyzed in cells prelabeled with³H-fatty acid. After short-term (10 min) exposure to tamoxifen (10 µM), cellular phosphatidic acid (PA) increased by approximately 50%. Dose-response kinetics for PA formation were obtained over a tamoxifen range of 2.5-20 µM. Treatment of MDA-MB-231 cells with phorbol diester (12-O-tetradecanoylphorbol-13-acetate, TPA) also elicited PA generation (60% above control). Interestingly, addition of tamoxifen, a purported protein kinase C inhibitor, to TPA-treated cells, caused further increase in PA (approximately 100% above control). PA, a second messenger lipid produced upon effector-receptor coupling, shares a prominent role in signal transduction events that govern cellular proliferation. It is therefore suggested that some actions of tamoxifen are mediated by promoting production of second messenger lipids that elicit transmembrane signal transduction cascades. This view is in line with ideas on non-estrogen receptor associated actions of tamoxifen by way of alternate binding sites.     

Interobserver interpretative reproducibility of GOLDFISH,a first generation gold-facilitated autometallographic bright field in situ hybridization assay for HER-2/neu amplification in invasive mammary carcinoma

Clinical laboratory testing for HER-2/neu gene amplification by fluorescence in situ hybridization is not widely used in diagnostic pathology laboratories. A bright field alternative permitting direct visualization of gene amplification using conventional microscopy may be more readily incorporated into routine diagnostic pathology practice. Interobserver reproducibility represents an important component of the validation of such an assay. We tested the hypothesis that a first-generation bright field alternative to fluorescence in situ hybridization, a Nanogold (Nanoprobes, Inc, Yaphank, NY, USA) (or gold-label)/autometallographic assay for HER-2/neu gene amplification in breast carcinoma, can be reproducibly interpreted by pathologists. Reference standard was direct fluorescence in situ hybridization supplemented by RNA/RNA in situ hybridization. Reproducibility of selected conventional histologic parameters was captured based on a hematoxylin and eosin slide accompanying the GOLDFISH preparation (gold-facilitated autometallographic in situ hybridization) as an indication of comparative reproducibility. The average kappa among GOLDFISH observers was 0.84, which was at least or concordant of observers scoring nuclear grade (kappa = 0.50) and the presence of in situ carcinoma (kappa = 0.57) by conventional histopathology. The GOLDFISH assay was specifically designed for qualitative interpretation, thus obviating the need for oil immersion microscopy and signal enumeration, and its interpretation was highly reproducible among five pathologists.     

Meningioma involving Meckel's cave: transpetrosal surgical anatomy and clinical considerations

Meningiomas originating in Meckel's cave (MC) are uncommon lesions that represent 1% of all intracranial meningiomas. Innovations in skull base surgery have enabled resection of these lesions with less morbidity, but require an intimate knowledge of both lesional pathology and regional microneuroanatomy. To review the surgical and clinical considerations involved in the management of MC meningiomas, we retrospectively reviewed data from patients who underwent transpetrosal resection of primary MC meningiomas between 1984 and 1998. Of 146 patients who underwent transpetrosal removal of meningiomas, 7 were believed to have tumors originating in MC. All 7 patients presented with trigeminal dysfunction, facial pain, and/or headache. Complete tumor removal was achieved in 5 of the 7 patients. Facial hypoesthesia or anesthesia, paralysis of cranial nerve VI, and ophthalmoplegia were among the postoperative complications encountered. Meningiomas of MC represent treatable lesions whose diagnosis requires prompt imaging of patients with trigeminal dysfunction and symptoms of facial pain and headache.     

Optimizing epilepsy surgery with intraoperative MR imaging

PURPOSE: The surgical treatment of medically intractable temporal lobe epilepsy includes the resection of temporal lobe structures. Although the reported seizure-free outcomes are highly variable, there is growing evidence that the extent of resection of the mesiotemporal lobe directly correlates with seizure control. METHODS: A moveable, high-field intraoperative magnetic resonance (MR) system was used to monitor and optimize the resection of the amygdala and hippocampus in 14 epilepsy patients. Fourteen patients with intractable seizures of temporal lobe origin underwent standard preoperative investigations including MR imaging, EEG telemetry, single-photon emission computed tomography, and neuropsychologic and sodium amytal testing. Anterior temporal lobectomy was performed on 10 patients, whereas four were treated with selective amygdalohippocampectomy. Intraoperative electrocorticography was applied as required. For all procedures, the objective was to resect the amygdala completely, and hippocampus to the posterior margin of the brainstem. RESULTS: Interdissection intraoperative MR imaging taken when optimal resection was thought to have been achieved revealed residual unresected amygdala or hippocampus in seven of 14 patients. An unexpected acute hematoma was found in one patient. At 17 months' follow-up, 13 (93%) of 14 patients are seizure free or have significantly improved seizure control. CONCLUSIONS: The mobile high-field intraoperative MR system provides high-resolution images without restriction on surgical instruments or techniques. The ability to identify and resect residual mesial temporal lobe targets before craniotomy closure is of potentially tremendous value in optimizing seizure control.     

Dosimetry and toxicity of Quadramet for bone marrow ablation in multiple myeloma and other haematological malignancies

Standard treatment regimens for haematological malignancies include myeloablative chemoradiotherapy and subsequent rescue by stem cell transplantation. However, these treatment regimens have significant associated mortality and morbidity, and disease recurrence remains a problem. One alternative approach is the targeted delivery of radiotherapy to the marrow using a bone-seeking agent labelled with an appropriate radioisotope, with the aim of delivering a potentially ablative radiation dose to marrow while minimising non-haematological toxicity. Pharmacokinetics and radiation dosimetry for a commercial preparation of samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet) were evaluated in 43 tracer (average dose 740 MBq) studies of 42 patients with haematological malignancies. Measurements of 24-h retention were also available following infusion of 18-48 GBq in 15 patients. Quadramet cleared rapidly from the tissue, with a median biological half-life of 1.4 h. Activity taken up by the skeleton was firmly bound, with activity decreasing according to physical half-life at 24 h in 29 of the 43 cases. The percentage activity retained in the skeleton at 24 h with tracer doses was high (62%+/-13%), although this decreased to approximately 30% with therapy infusions. Because of this decrease in retention, the maximum feasible therapy activity for this formulation of Quadramet is 35 GBq. Median absorbed marrow radiation dose was 0.78 Gy/GBq in tracer studies: the decreased retention at high activities means that this corresponds to a median dose of 12 Gy for 35 GBq administered activity. It is possible to use 24-h retention as a rough guide to marrow dose in individual patients. In tracer studies, median bladder radiation dose was 0.22 Gy/GBq and radiation dose to the liver was very conservatively estimated at 0.2 Gy/GBq. After therapy infusions of up to 50 GBq in 37 patients, non-haematopoietic toxicity was not seen in any patient. In addition, myelosuppression was achieved without evidence of myelofibrosis. The residual dose rate to marrow fell to a level acceptable for stem cell re-infusion by 2 weeks after administration.     

Reliability of epigastric auscultation to detect gastric insufflation

Background. We studied the reliability of epigastric auscultationto detect gastric insufflation in 30 anaesthetized, paralysedintubated patients. Methods. A 16FG gastric tube was positioned with the tip inthe mid-oesophagus with the proximal end attached to an injectionport with a one-way valve. Four observers participated in thestudy. Observers were paired and each pair studied 15 patients.Each patient underwent four test sequences in random order,two by each observer. Each test sequence comprised one observerinjecting different volumes of air (0.25 ml, 0.5 ml,1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 10 ml,15 ml and 0 ml as a control) in random order whilstthe second blinded observer listened with a stethoscope overthe epigastrium. Each randomized volume was injected rapidlyat 5 s intervals for 1 min. The number of injectionsrequired to detect air entering the stomach was recorded. Thestomach was deflated between each test sequence. Results. To detect air entering the stomach with 95% confidence,11 injections were required for 0.25 ml; 7 for 0.5 ml;3 for 1 ml; 2 for 2 ml and 3 ml, and 1 for     

Validity and reliability of a postoperative quality of recovery score: the QoR-40

Quality of recovery after anaesthesia is an important measure of the early postoperative health status of patients. We attempted to develop a valid, reliable and responsive measure of quality of recovery after anaesthesia and surgery. We studied 160 patients and asked them to rate postoperative recovery using three methods: a 100-mm visual analogue scale (VAS), a nine-item questionnaire and a 50-item questionnaire; the questionnaires were repeated later on the same day. From these results, we developed a 40-item questionnaire as a measure of quality of recovery (QoR-40; maximum score 200). We found good convergent validity between QoR-40 and VAS (r = 0.68, P < 0.001). Construct validity was supported by a negative correlation with duration of hospital stay (rho = -0.24, P < 0.001) and a lower mean QoR-40 score in women (162 (SD 26)) compared with men (173 (17)) (P = 0.002). There was also good test-retest reliability (intra-class ri = 0.92, P < 0.001), internal consistency (Cronbach's alpha = 0.93, P < 0.001) and split-half coefficient (alpha = 0.83, P < 0.001). The standardized response mean, a measure of responsiveness, was 0.65. The QoR-40 was completed in less than 6.3 (4.9) min. We believe that the QoR-40 is a good objective measure of quality of recovery after anaesthesia and surgery. It would be a useful end-point in perioperative clinical studies.