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Biomedical subjects

A Kennedy

Publications and source records attributed to A Kennedy.

At least 91 records · Page 5Linked to original sources
PubMed1998

Phase 2 trial of moderately high dose single agent mitoxantrone in platinum and paclitaxel-refractory ovarian cancer.

In the human clonogenic assay, mitoxantrone possesses among the steepest dose-response curves of any cytotoxic agent against ovarian cancer. To test the potential clinical relevance of this observation, we conducted a phase 2 trial of moderately high dose single agent mitoxantrone (28 mg/m2 delivered every 3-4 weeks) along with granulocyte-macrophage colony stimulating factor (250 micrograms/m2/day beginning 24 h after mitoxantrone and continuing until neutrophil recovery) in 34 patients with clinically defined platinum and paclitaxel-refractory ovarian cancer. The major toxicity of treatment was severe neutropenia which was almost universal. However, there were no treatment-related infectious deaths. Significant cardiac toxicity was not observed. Five of 33 evaluable patients demonstrated objective evidence of a response to treatment (1 patient achieving a partial response of measurable tumor masses, 4 patients achieving a > or = 50% reduction in CA-125 antigen level), with a median duration of response of 3 months (range 2-5 months). We conclude that moderately high dose mitoxantrone has definite, although very limited, single agent activity in platinum and paclitaxel-refractory ovarian cancer. Unfortunately, as this regimen produces severe hematologic toxicity and response durations are short, it cannot be recommended for routine clinical use. The role of an even higher dose mitoxantrone schedule employed as a component of a high dose chemotherapy program with bone marrow or peripheral progenitor cell protection in the treatment of ovarian cancer remains to be defined.

Adult↗
PubMed1998

Phase 2 trial of single agent ifosfamide/mesna in patients with platinum/paclitaxel refractory ovarian cancer who have not previously been treated with an alkylating agent.

Ifosfamide has been shown to possess modest activity in patients with platinum/cyclophosphamide refractory ovarian cancer. Current standard initial chemotherapy for ovarian cancer does not include an alkylating agent (paclitaxel substituting for cyclophosphamide). To evaluate the activity of ifosfamide in patients with refractory ovarian cancer who had not previously received an alkylating agent, 21 patients with platinum/paclitaxel refractory disease were treated with the drug as a single agent (1.8 g/m2/day x 3 days, with treatment repeated every 28 days). Treatment was reasonably well tolerated in most patients, although 1 individual was removed from study secondary to neurotoxicity. One patient exhibited an objective response of measurable disease, while a second individual had a major decrease in CA-125 levels (no measurable disease present) following therapy. An additional patient experienced disappearance of severe pelvic pain following treatment but failed to meet the criteria for a partial response. We conclude that ifosfamide has modest activity in platinum/paclitaxel refractory ovarian cancer. However, the level of effectiveness does not appear to be increased in individuals who are alkylating-agent naive, compared to previously reported experience in patients with prior exposure to this class of cytotoxic drugs (10-15% response rate).

Adult↗
PubMed1998

Low-dose oral granisetron (1 mg) plus intravenous dexamethasone: efficacy in gynecologic cancer patients receiving carboplatin-based chemotherapy.

OBJECTIVE: The objective of this study was to determine the efficacy of a low-dose oral granisetron plus intravenous dexamethasone prophylactic antiemetic regimen in patients receiving carboplatin-based chemotherapy. PATIENTS AND METHODS: Patients with gynecologic malignancies being treated with either single-agent carboplatin or a carboplatin-paclitaxel regimen received a single 1-mg oral dose of granisetron 30 min prior to chemotherapy plus intravenous dexamethasone (20 mg) as prophylaxis for emesis. Patients either had not previously been treated with chemotherapy or had not received any cytotoxic drugs for >/=4 months prior to study entry. Effectiveness was evaluated based on the degree of control of nausea and vomiting during the 24 h following treatment. RESULTS: Of the 32 patients participating in this phase 2 trial, only 2 (6%) experienced any degree of nausea or vomiting within the first 24 h of chemotherapy administration. Both of these individuals had carcinomatosis and were experiencing emesis prior to chemotherapy. One patient developed mild delayed nausea >24 h after treatment. No major or minor toxic effects of the antiemetic regimen observed. CONCLUSION: A 1-mg dose of oral granisetron plus intravenous dexamethasone (20 mg) is a safe, effective, and relatively inexpensive prophylactic antiemetic regimen for patients receiving single-agent carboplatin or combination carboplatin-paclitaxel chemotherapy.

Adult↗
PubMed1998

Evidence that a "treatment-free interval of less than 6 months" does not equate with clinically defined platinum resistance in ovarian cancer or primary peritoneal carcinoma.

The standard definition of platinum-resistant ovarian cancer or primary peritoneal carcinoma commonly includes patients whose disease initially responded to a platinum-based combination regimen, but recurred less than 6 months after the completion of primary therapy. Recent experience with several patients with these malignancies treated in the Gynecologic Cancer Program of the Cleveland Clinic Foundation, whose disease recurred within this period but who subsequently responded to platinum therapy, calls into question the validity and clinical relevance of this commonly employed definition, both for the conduct of phase 2 trials of new agents in ovarian cancer and primary peritoneal carcinoma, and for the standard management of women in this clinical setting.

Aged↗
PubMed1998

The effects of intermittent illumination on a visual inspection task.

Two experiments are described in which eye movements were monitored as subjects performed a simple target-spotting task under conditions of intermittent illumination produced by varying the display-screen frame rate on a computer VDU. In Experiment 1, subjects executed a saccade from a fixation point to a target which appeared randomly at a fixed eccentricity of 14 character positions to the left or right. Saccade latency did not differ reliably as a function of screen refresh rate, but average saccade extent at 70 Hz and 110 Hz was reliably shorter than at 90 Hz and 100 Hz. Experiment 2 examined the same task using a range of target eccentricities (7, 14, and 28 character positions to the left and right) and across a wider range of screen refresh rates. The results confirmed the curvilinear relationship obtained in Experiment 1, with average saccade extent reliably shorter at refresh rates of 50 Hz and 125 Hz than at 75 Hz and 100 Hz. While the effect was greater for remote targets, analyses of the proportional target error failed to show a reliable interaction between target eccentricity and display refresh rate. In contrast to Experiment 1, there was a pronounced effect of refresh rate on saccade latency (corrected for time to write the screen frame), with shorter latencies at higher refresh rates. It may be concluded that pulsation at frequencies above fusion disrupts saccade control. However, the curvilinear functional relationship between screen refresh rate and saccade extent obtained in these studies differs from previously reported effects of intermittent illumination on the average size of "entry saccades" (the first saccade to enter a given word) in a task involving word identification (Kennedy & Murray, 1993a, 1996). This conflict of data may arise in part because within-word adjustments in viewing position, which are typical of normal reading, influence measures of average saccade extent.

Adult↗
PubMed1998

Reduced quality of clot formation with gelatin-based plasma substitutes.

We have studied, over a wide range of dilutions using techniques of clot weight, thrombelastography and scanning electron microscopy, the physical properties of a blood clot formed in vitro when fresh blood was diluted with gelatin-based colloid solutions compared with crystalloid controls. The colloid solutions tested (3.5% polygeline (Haemaccel) and 4% succinylated gelatin (Gelofusine)) produced clots that had reduced median weight (P < 0.001 and P = 0.018, respectively) and reduced mean shear modulus (P < 0.001) compared with crystalloid controls. Scanning electron microscopy showed that the fibrin formed a less extensive mesh in the presence of the gelatin-based colloids compared with crystalloid. Reduction in clot quality with gelatin-based colloids has not been noted previously and further work is needed to ascertain if this occurs in vivo as these solutions are used frequently in patients who require full haemostatic competence.

Blood Cells↗
PubMed1998

Revision of the 1990 working formulation for cardiac allograft rejection: the Sheffield experience.

OBJECTIVE: To audit the 1990 International Society for Heart and Lung Transplantation cardiac rejection criteria and to evaluate the impact on classification and clinical outcomes of a modification in which grade 2 is abolished and grades 1A and 1B are amalgamated into a single "grade 1." METHODS: 1652 heart biopsies were reviewed over a four year period. The initial 1348 biopsies (group 1), using the original 1990 criteria, were analysed in terms of diagnostic grade and compared with the 304 biopsies analysed with the modified scheme (group 2). Differences in grading with the 1990 scheme were compared between two groups (1.1 and 1.2) reflecting early and late experience with grading. Subsequently all the grade 2 and grade 1B biopsies were rescored in terms of the modified scheme. Clinical results in terms of actuarial patient survival at one year and freedom from 3A rejection were similarly audited. RESULTS: The relative ratios of potentially significant rejection (grade 3A, 3B, 4) remained constant over the entire study in groups 1.1, 1.2, and 2. A 50% reduction in grade 2 biopsy reporting was noted comparing early and late parts of group 1. At subsequent review of the group 1 grade 2 biopsies, 97% could be reassigned to grades 0 or 1 in the modified scheme, with the majority of these diagnoses reflecting Quility effect/biopsy site reactions. Two cases (3%) of the 77 grade 2 biopsies were regraded as grade 3A rejection, with both occurring within three months of transplantation. None of the grade 1B biopsies had high grade cardiac rejection on review, most of these biopsies similarly showing pronounced Quility effect and biopsy site reactions. Actuarial survival at one year rose from 86% to 90% during the study, with freedom from 3A rejection remaining unchanged at 80%. CONCLUSIONS: The original working formulation produces consistent grading except at grade 2, which is judged to be a misnomer resulting from Quility effect and other non-rejection phenomena. While acceptable standardisation can be achieved with the 1990 scheme, the modified scheme has advantages in that it appears to encourage clear discrimination between significant and non-significant cardiac rejection. Overall, elimination of grade 2 did not produce an increase in higher grades of cardiac rejection, and thus the value of this diagnostic grade is questioned.

Graft Rejection↗
PubMed1998

Paclitaxel administration to gynecologic cancer patients with major cardiac risk factors.

PURPOSE: To examine the safety of administering paclitaxel to patients with preexisting significant cardiac risk factors. PATIENTS AND METHODS: The medical records of gynecologic cancer patients with major cardiac risk factors who had been treated with paclitaxel (single-agent or combination regimen with cisplatin or carboplatin) at The Cleveland Clinic Foundation from 1993 through February 1998 were examined to determine the acute toxicity of therapy. RESULTS: A total of 15 patients were found who met these criteria, of whom none were found to have suffered a worsening of cardiac function following treatment with paclitaxel. A single patient developed a severe paclitaxel-associated hypersensitivity reaction, but no cardiac sequela. CONCLUSION: This series suggests that paclitaxel can be safely administered as a single agent or in a combination regimen with a platinum agent to some patients with significant cardiac risk factors, such as those associated with ischemic heart disease. However, since few patients had baseline severe conduction defects before paclitaxel treatment, the safety of this drug in this clinical setting remains to be determined.

Aged↗
PubMed1998

Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens.

PURPOSE: To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS: A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS: Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION: In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.

Adult↗
PubMed1998

Expression of mRNAs encoding uncoupling proteins in human skeletal muscle: effects of obesity and diabetes.

To explore the potential role of the uncoupling protein (UCP) family in human obesity and diabetes, we have used the reverse transcription-polymerase chain reaction to quantify UCP mRNA expression in human skeletal muscle. Levels of mRNA for UCP2, and for both short (UCP3S) and long (UCP3L) forms of UCP3, were highly correlated in individuals, indicating that gene transcription of these UCPs may be coordinately regulated by common mechanisms. In normal glucose-tolerant individuals, muscle UCP2 mRNA levels were positively correlated with percentage of body fat and with BMI (r = 0.6 and P < 0.05 for both). UCP3S mRNA levels were also positively correlated with percentage of body fat (r = 0.52, P < 0.05), and UCP3L mRNA tended to increase as a function of obesity (0.05 < P < 0.1). UCP mRNA levels, however, were not correlated with resting metabolic rate. UCP3S and UCP3L mRNA levels (P < 0.05) and the UCP2 mRNA level (P = 0.09) were increased by 1.8- to 2.7-fold in type 2 diabetes, an effect that could not be explained by obesity. No significant difference was found for UCP2, UCP3S, or UCP3L mRNA levels between insulin-sensitive and insulin-resistant nondiabetic subgroups. We conclude that 1) skeletal muscle mRNA levels encoding UCP2 and UCP3 are correlated among individuals and may be coordinately regulated; 2) UCP3 expression is not regulated by differential effects on UCP3L and UCP3S forms of the mRNA; and 3) UCP mRNA expression tends to increase in muscle as a function of obesity but not of resting metabolic rate or insulin resistance, and is increased in patients with type 2 diabetes.

Adult↗
PubMed1997

An aldose reductase inhibitor and aminoguanidine prevent vascular endothelial growth factor expression in rats with long-term galactosemia.

OBJECTIVE: To study the effects of an aldose reductase inhibitor (ARI-509, Wyeth-Ayerst, Princeton, NJ) and aminoguanidine (AMG), agents that have been reported to prevent or delay diabetic retinopathy, on retinal vascular abnormalities and the immunocytochemical expression in the retina of vascular endothelial growth factor (VEGF) in rats maintained for up to 2 years on a 50% galactose diet. METHODS: Albino rats were placed on a control diet, a diet containing 50% galactose, or the 50% galactose diet containing either ARI-509 or AMG. Treatment with ARI-509 or AMG was initiated at the beginning of the experiment or after 12 months of galactose feeding. After 22 to 24 months, the rats were killed and the retinal vasculature from half of one eye was isolated by trypsin-elastase digestion for semiquantitative evaluation of retinal vascular lesions. The other half of the retina was prepared for immunocytochemistry and stained for the presence of VEGF, factor VIII, vimentin, and glial fibrillary acidic protein. Red blood cells, sciatic nerves, and a portion of the retina from the second eye were assayed for glucose, galactose, fructose, sorbitol, galactitol, and myo-inositol. Red blood cells were also assayed for galactosylated hemoglobin. RESULTS: Galactose-fed animals developed a vascular retinopathy characterized by severe cellular loss in the retinal capillaries and intensification of periodic acid-Schiff staining of the vascular basement membranes. Some animals also displayed dilation and hypercellularity of vessels in the posterior retina. These changes were substantially reduced in animals receiving ARI-509 from the beginning of the galactose diet, but were unaffected in all of the other treatment groups. None of the rats receiving ARI-509 or AMG treatment, whether initiated from the onset or after 12 months of galactosemia, demonstrated VEGF immunoreactivity. With the exception of the animals receiving ARI-509 from the beginning of the experiment, all of the galactose-fed animals developed dense cataracts within 6 weeks of the beginning of the galactose diet. Galactitol levels in animals receiving ARI-509 were 86% to 93% lower in red blood cells, retina, and sciatic nerve than those in the other galactose-fed groups. CONCLUSIONS: Although ARI-509 and AMG have different abilities to delay or prevent the diabetic-like retinopathy in galactosemic rats, even when substantial retinal microvascular acellularity occurs, both drugs prevent the immunocytochemical expression of VEGF. These results suggest that factors other than hypoxia may be responsible for VEGF expression in the retina, and that aldose reductase inhibitors and AMG have potential roles in preventing such expression and, thus, perhaps preventing retinal neovascularization.

Aldehyde Reductase↗
PubMed1997

Cerebral glucose metabolism in corticobasal degeneration: comparison with progressive supranuclear palsy and normal controls.

The regional metabolic rate of glucose was estimated using 18F-labeled 2-deoxyglucose and positron-emission tomography (PET) in eight patients with corticobasal degeneration (CBD). Measures of cerebral glucose metabolism in these patients were compared with those for nine age-matched normal controls and eight patients with progressive supranuclear palsy (PSP). Compared with that in the normal controls, the CBD patients showed significantly reduced cerebral glucose metabolism in the contralateral hemisphere to the clinically most affected side in the dorsolateral frontal, medial frontal, inferior parietal, sensorimotor, and lateral temporal cortex, as well as in the corpus striatum and the thalamus. In comparison with that in PSP, in CBD the glucose metabolism in the contralateral hemisphere was significantly decreased in the inferior parietal, sensorimotor, lateral temporal cortex, and the corpus striatum. These results confirm the marked asymmetric cerebral involvement in CBD and suggest that there are significant differences between CBD and PSP in the cerebral metabolism in some cerebral regions such as the inferior parietal cortex and sensorimotor cortex, which might reflect the differences in their clinical characteristics.

Aged↗
PubMed1997

Continued chemosensitivity to cisplatin/carboplatin in ovarian carcinoma despite treatment with multiple prior platinum-based regimens.

While it is well recognized that individuals with ovarian cancer who have previously responded to platinum-based therapy can achieve a second response to cisplatin or carboplatin at the time of relapse, limited data exist in the oncologic literature regarding the number of times this process can be repeated. We briefly report here three patients with ovarian cancer currently being cared for in the Gynecologic Oncology program of the Cleveland Clinic Foundation who have achieved four (1 patient) or five (2 patients) separate clinical responses to cisplatin or carboplatin-based chemotherapy and have survived >4 years since the date of first relapse. This experience emphasizes the point that platinum resistance cannot be defined based on total treatment courses or the number of prior platinum-based regimens delivered, but only by objective evidence of failure of the drugs in an individual patient.

Aged↗
PubMed1997

Low-dose intravenous ondansetron (8 mg) plus dexamethasone: an effective regimen for the control of carboplatin-induced emesis.

Twenty-nine patients with gynecologic malignancies were treated with a fixed low dose of intravenous ondansetron (8 mg) plus dexamethasone (20 mg) in an effort to develop an effective and less expensive antiemetic regimen for the control of carboplatin-induced emesis. Twenty-six (90%) of the women participating in this trial experienced complete control of both acute nausea and vomiting (developing within the first 24 h after chemotherapy administration), while 27 (93%) patients exhibited either complete or major control (< or = 2 episodes of vomiting, < or = 5 episodes of retching, minimal interference with eating) of emesis. On the basis of our experience in this trial, we conclude that the combination of low dose (8 mg) intravenous ondansetron plus dexamethasone is a well-tolerated and highly cost-effective antiemetic strategy for individuals receiving carboplatin-based chemotherapy.

Adult↗
PubMed1997

Diagnostic value of inhibin immunoreactivity in ovarian gonadal stromal tumours and their histological mimics.

AIMS: Inhibin is a heterodimeric protein hormone which appears to be a sensitive serological and immunohistochemical marker of ovarian granulosa cell tumours. The purposes of this study were to examine inhibin immunoreactivity in a wide range of gonadal stromal neoplasms and to assess its value in the differential diagnosis of problematic ovarian tumours. METHODS AND RESULTS: Inhibin immunostaining was identified in eight cases of stromal hyperthecosis, 24 adult-type granulosa cell tumours, two juvenile granulosa cell tumours, nine Sertoli cell or Sertoli-Leydig cell tumours, one gynandroblastoma, three gonadoblastomas, two cases of sex cord tumour with annular tubules, two steroid cell tumours and two sclerosing stromal tumours. Inhibin was also present in 4/6 fibrothecomas and 2/3 unclassified gonadal stromal tumours. There was no staining of neoplastic cells in any of the problematic ovarian tumours, in many of which a diagnosis of gonadal stromal tumour had been initially considered. However, inhibin was detected in reactive stromal cells in many cases. CONCLUSIONS: Inhibin is a sensitive immunohistochemical marker of a wide range of gonadal stromal tumours and is of value in the differential diagnosis of ovarian neoplasia.

Diagnosis, Differential↗
PubMed1997

Facial distinctiveness and the power of caricatures.

Caricatures, which increase the distinctiveness of faces, are generally recognised at least as well as undistorted images of those faces. However, caricatures seem to facilitate recognition more for some faces than others. An investigation was made into whether the effectiveness of caricaturing depends on a face's initial distinctiveness. In experiments 1-3, subjects learned names for unfamiliar faces (photographs) that varied in distinctiveness, and were tested on recognition of caricatures, anticaricatures, and undistorted images of those faces. The test images were line drawing in experiment 1 and 2 photographic images in experiment 3. Experiments 1 and 2 were identical except that subjects had more exposure to the study photographs in experiment 1. In all three experiments, distinctive faces were recognised (named) more accurately than less-distinctive faces, and caricatures were recognised at least as accurately as undistorted images and better than anticaricatures. However, distinctiveness and caricature level did not interact. Nor did a face's initial distinctiveness correlate with the degree of recognition facilitation produced by caricaturing (experiments 1-3) or with the caricature level chosen as the best likeness (experiment 4). The effectiveness of caricatures varied across faces and experimental conditions, but these differences did not relate to differences in initial distinctiveness. These results prompted a more careful analysis of the expected relationship between initial distinctiveness and the power of caricatures, which indicated that the relationship may be curvilinear rather than linear. In addition, it was found that line-drawing caricatures functioned as superportraits (recognised better than undistorted images--experiment 1) but photographic caricatures did not (experiment 3) suggesting that the forensic potential of caricatures may be limited.

Adult↗