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Biomedical subjects

W Spencer

Publications and source records attributed to W Spencer.

At least 19 recordsLinked to original sources
PubMed2001

Approaches to the sellar and parasellar region: anatomic comparison of endonasal-transsphenoidal, sublabial-transsphenoidal, and transethmoidal approaches.

Various surgical approaches have been described for treating lesions which arise in the sellar region. The popular transnasal-transsphenoidal and transethmoidal-transsphenoidal approaches avoid the morbidity associated with transcranial operations while allowing enough exposure to successfully remove most lesions that arise in and around the sella. The goal of the present study was to accurately quantify the amount of exposure to the sellar and suprasellar region that the transethmoidal-transsphenoidal, endonasal-transphenoidal, and sublabial-transsphenoidal approaches provide. Each of the three approaches was performed on 14 formalin fixed heads with the aid of the operative microscope. The distances of relevant surgical landmarks, and the amount of exposure superior and anterior to the dorsum sella as well as the lateral exposure obtained through each of these approaches was carefully recorded. The mean distances were then used to calculate the volume of exposure offered by each approach. It was found that the sublabial-transsphenoidal approach afforded the greatest volume of exposure superior and anterior to the dorsum sella. The endonasal-transsphenoidal and the transethmoidal approaches were both found to offer less suprasellar volume exposure, with the transethmoidal approach offering the least. The authors believe the information obtained through this study illustrates some important anatomical relationships which can be used to advantage by the surgeon to tailor the most appropriate approach, depending upon the precise location of the lesion either within the sella or suprasellar region.

Brain Neoplasms↗
PubMed2000

Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose-escalating trial.

PURPOSE: We analyzed our institution's experience treating patients with unfavorable prostate cancer in a prospective Phase II dose-escalating trial of external beam radiation therapy (EBRT) integrated with conformal high-dose-rate (HDR) brachytherapy boosts. This interim report discusses treatment outcome and prognostic factors using this treatment approach. METHODS AND MATERIALS: From November 1991 through February 1998, 142 patients with unfavorable prostate cancer were prospectively treated in a dose-escalating trial with pelvic EBRT in combination with outpatient HDR brachytherapy at William Beaumont Hospital. Patients with any of the following characteristics were eligible: pretreatment prostate-specific antigen (PSA) >/= 10.0 ng/ml, Gleason score >/= 7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median total dose of 46.0 Gy. Pelvic EBRT was integrated with ultrasound-guided transperineal conformal interstitial iridium-192 HDR implants. From 1991 to 1995, 58 patients underwent three conformal interstitial HDR implants during the first, second, and third weeks of pelvic EBRT. After October 1995, 84 patients received two interstitial implants during the first and third weeks of pelvic EBRT. The dose delivered via interstitial brachytherapy was escalated from 5.50 Gy to 6.50 Gy for each implant in those patients receiving three implants, and subsequently, from 8.25 Gy to 9.50 Gy per fraction in those patients receiving two implants. To improve implant quality and reduce operator dependency, an on-line, image-guided interactive dose optimization program was utilized during each HDR implant. No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 2.1 years (range: 0.2-7.2 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. RESULTS: The pretreatment PSA level was >/= 10.0 ng/ml in 51% of patients. The biopsy Gleason score was >/= 7 in 58% of cases, and 75% of cases were clinical stage T2b or higher. Despite the high frequency of these poor prognostic factors, the actuarial biochemical control rate was 89% at 2 years and 63% at 5 years. On multivariate analysis, a higher pretreatment PSA level, higher Gleason score, higher PSA nadir level, and shorter time to nadir were associated with biochemical failure. In the entire population, 14 patients (10%) experienced clinical failure at a median interval of 1.7 years (range: 0.2-4.5 years) after completing RT. The 5-year actuarial clinical failure rate was 22%. The 5-year actuarial rates of local failure and distant metastasis were 16% and 14%, respectively. For all patients, the 5-year disease-free survival, overall survival, and cause-specific survival rates were 89%, 95%, and 96%, respectively. The 5-year actuarial rate of RTOG Grade 3 late complications was 9% with no patient experiencing Grade 4 or 5 acute or late toxicity. CONCLUSION: Pelvic EBRT in combination with image-guided conformal HDR brachytherapy boosts appears to be an effective treatment for patients with unfavorable prostate cancer with minimal associated morbidity. Our dose-escalating trial will continue.

Aged↗
PubMed1999

The role of androgen deprivation in the definitive management of clinically localized prostate cancer treated with radiation therapy.

PURPOSE: Multiple studies exploring the use of androgen deprivation given in combination with radiotherapy (RT) for localized prostate cancer have reported significant improvements in the rates of local, regional, and biochemical control (BC). The impact of this therapeutic strategy on overall and cancer specific survival (CSS) has not been established, however. We performed a MEDLINE search of all available studies on this topic to determine if any conclusions could be reached on the efficacy of this treatment approach and the patients most suitable for its application. MATERIALS AND METHODS: A MEDLINE search was conducted to obtain all articles in the English language on the use of androgen deprivation in combination with RT for the treatment of localized prostate cancer. The medical subject headings (MeSH) used to search the MEDLINE database included: a) prostatic neoplasms; b) prostatic neoplasms/radiotherapy; c) prostatic neoplasms/androgen deprivation; d) hormone therapy; e) English; and f) 1980 to 1998. RESULTS: A total of 14 retrospective studies were identified that compared some form of androgen deprivation given in combination with RT. Most studies showed significant improvements in various measures of local/regional control and disease-free survival (DFS). Three of four studies that analyzed BC rates showed significant improvements in this endpoint but conflicting results were obtained for overall survival (OS). No study showed an improvement in CSS. Six prospective randomized trials were identified that directly compared RT with or without androgen deprivation. Again, all six studies showed improvements in some measure of local/regional control or DFS but only two studies showed an improvement in OS. One study reported a statistically significant improvement in CSS and another study showed an improvement in the rate of negative biopsies with combined treatment. CONCLUSIONS: When all available literature on androgen withdrawal given in combination with RT for the definitive treatment of localized prostate cancer was reviewed, no definite conclusions could be reached on the impact of this treatment approach on OS and CSS. However, local/regional control, DFS, and BC were almost uniformly improved with the use of androgen withdrawal suggesting that these impressive early results may translate into improved cure rates. Data from recently initiated and completed randomized trials will be needed, however, to define the impact of this approach on cancer specific mortality and the patients most suitable for it's use.

Androgen Antagonists↗
PubMed1999

Taxol selectively blocks microtubule dependent NF-kappaB activation by phorbol ester via inhibition of IkappaBalpha phosphorylation and degradation.

Activation of the NF-kappa-B transcription factors has been shown to be directly influenced by changes in the microtubule cytoskeleton network. To better understand cytoskeletal regulation of NF-kappaB, experiments were performed to determine whether the microtubule (MT) stabilizing agent taxol could modulate NF-kappaB activation in the presence of different NF-kappa-B inducers. Pretreatment of murine NIH3T3 and human 293 cells with 5 microM taxol resulted in complete inhibition of phorbol, 12-myristate, 13-acetate (PMA) mediated NF-kappaB activation, detected as the loss of DNA binding and reduced NF-kappaB dependent reporter gene activity. Furthermore, in COS-7 and NIH3T3 cells, PMA-induced Ikappa-Balpha turnover was dramatically reduced in taxol treated cells, mediated via the inhibition of IkappaBalpha phosphorylation. However, taxol did not prevent TNF-alpha induced Ikappa-Balpha phosphorylation, degradation, or NF-kappaB activation, indicating that TNF-alpha acts through a microtubule-independent pathway. In vitro kinase assays with PMA stimulated cell extracts demonstrated that taxol reduced protein kinase C activity by 30%, thus implicating the loss of PKC activity as a possible regulatory target of taxol-mediated suppression of NF-kappa-B. Since PMA causes modulation of cytoarchitecture through PKC activation, microtubule integrity and cell morphology was analysed by indirect immunofluorescence. Both PMA and nocodazole, a MT depolymerizing agent, caused microtubule depolymerization, whereas TNF-alpha did not alter MT integrity; concomitant taxol treatment blocked both nocodazole and PMA induced depolymerization of MTs, as well as NF-kappaB induction, thus demonstrating a link between microtubule depolymerization and NF-kappaB activation. These observations illustrate a novel biological activity of taxol as a selective inhibitor of NF-kappa-B activity, suggesting a link between the state of microtubule integrity and gene regulation.

3T3 Cells↗
PubMed1997

I kappaB alpha physically interacts with a cytoskeleton-associated protein through its signal response domain.

The I kappaB alpha protein is a key molecular target involved in the control of NF-kappaB/Rel transcription factors during viral infection or inflammatory reactions. This NF-kappaB-inhibitory factor is regulated by posttranslational phosphorylation and ubiquitination of its amino-terminal signal response domain that targets I kappaB alpha for rapid proteolysis by the 26S proteasome. In an attempt to identify regulators of the I kappaB alpha inhibitory activity, we undertook a yeast two-hybrid genetic screen, using the amino-terminal end of I kappaB alpha as bait, and identified 12 independent interacting clones. Sequence analysis identified some of these cDNA clones as Dlc-1, a sequence encoding a small, 9-kDa human homolog of the outer-arm dynein light-chain protein. In the two-hybrid assay, Dlc-1 also interacted with full-length I kappaB alpha protein but not with N-terminal-deletion-containing versions of I kappaB alpha. I kappaB alpha interacted in vitro with a glutathione S-transferase-Dlc-1 fusion protein, and RelA(p65) did not displace this association, demonstrating that p65 and Dlc-1 contact different protein motifs of I kappaB alpha. Importantly, in HeLa and 293 cells, endogenous and transfected I kappaB alpha coimmunoprecipitated with Myc-tagged or endogenous Dlc-1. Indirect immunofluorescence analyzed by confocal microscopy indicated that Dlc-1 and I kappaB alpha colocalized with both nuclear and cytoplasmic distribution. Furthermore, Dlc-1 and I kappaB alpha were found to associate with the microtubule organizing center, a perinuclear region from which microtubules radiate. Likewise, I kappaB alpha colocalized with alpha-tubulin filaments. Taken together, these results highlight an intriguing interaction between the I kappaB alpha protein and the human homolog of a member of the dynein family of motor proteins and provide a potential link between cytoskeleton dynamics and gene regulation.

Amino Acid Sequence↗
PubMed1995

Steroid elution improves the stimulation threshold in an active-fixation atrial permanent pacing lead. A randomized, controlled study. Model 4068 Investigators.

BACKGROUND: Prior work suggests that the addition of a steroid-eluting reservoir to a passive-fixation permanent pacemaker lead improves the stimulation threshold; however, no large randomized study has addressed this tissue. Over the last several years, there has been an increase in enthusiasm for the use of active-fixation permanent pacemaker leads for various reasons in spite of the generally accepted notion that active-fixation leads have higher stimulation thresholds. METHODS AND RESULTS: This multicenter, randomized, controlled study examined the difference in performance between a standard active-fixation atrial lead (Medtronic model 4058) and a steroid-eluting lead (Medtronic model 4068). Stimulation thresholds were obtained in a four-point strength-duration fashion. Evaluations of sensing and impedance were performed as well. These evaluations were performed at implantation, at weeks 1 through 4, and at weeks 6, 12, 24, and 52. Stimulation thresholds were significantly better in the steroid lead than in the nonsteroid lead at each measurement point from 1 week to 12 months. The mean 1.6-V stimulation threshold at 12 months was 0.19 +/- 0.2 ms in the steroid lead and 0.41 +/- 0.30 ms in the control lead. No acute peaking was observed with the steroid lead, whereas significant peaking was observed with the control lead. There was no difference in long-term sensing or impedance. CONCLUSIONS: Inclusion of a steroid-eluting reservoir in an active-fixation permanent pacing lead improved stimulation thresholds in both the subacute and chronic periods and therefore should extend pulse-generator longevity.

Aged↗
PubMed1995

Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of a phase I/II clinical trial.

PURPOSE: To improve results for locally advanced prostate cancer, a prospective clinical trial of concurrent external beam irradiation and fractionated iridium-192 (Ir-192) high dose rate (HDR) conformal boost brachytherapy was initiated. METHODS AND MATERIALS: Between November 1991 and February 1994, 99 implants were performed on 33 patients with prostatic adenocarcinoma at William Beaumont Hospital. Using AJCC staging criteria, 9 patients had T2b tumors, 17 patients had T2c tumors, and 7 patients had T3 disease. Patients were treated with (a) 45.6 Gy whole pelvis external irradiation and (b) three HDR fractions of 5.5 Gy each (18 patients) or 6 Gy each (15 patients) to the prostate. Transperineal needle implants using real-time ultrasound guidance with interactive on-line isodose distributions were performed on an outpatient basis during weeks 1, 2, and 3 of external irradiation. Acute toxicity was scored using the Radiation Therapy Oncology Group (RTOG) morbidity grading system. RESULTS: This technique of concurrent external pelvic irradiation and conformal HDR brachytherapy was well tolerated. No significant intraoperative or perioperative complications occurred. Three patients (9%) experienced Grade 3 acute toxicity (two dysuria and one diarrhea). All toxicities were otherwise Grades 1 or 2 and were primarily as expected from pelvic external irradiation. Persistent implant-related toxicities included Grades 1-2 perineal pain (12%) and hematospermia (15%). Median follow-up time was 13 months. Serum prostatic-specific antigen (PSA) levels normalized in 91% of patients (29 out of 32) within 1-14 months (median 2.8 months) after irradiation. PSA levels were progressively decreasing in the other three patients at last measurement. Prospectively planned prostatic rebiopsies done at 18 months in the first 10 patients were negative in 9 out of 10 (90%). CONCLUSIONS: Acute toxicity has been acceptable with this unique approach using conformal high dose rate Ir-192 boost brachytherapy with concurrent external irradiation. The initial tumor response as assessed by serial PSA measurement and rebiopsy is extremely encouraging. Dose escalation will proceed in accordance with the protocol guidelines. Further patient accrual and longer follow-up will allow comparison to other techniques.

Adenocarcinoma↗
PubMed1988

Outpatient angiographic evaluation of living renal donors.

A total of 71 potential living kidney donors was evaluated on an outpatient basis with either a modification of standard catheter angiography (30 patients) or intra-arterial digital subtraction angiography (41 patients). Both procedures provided accurate assessment of the main renal vasculature as proved at the time of donor nephrectomy. Neither technique was associated with any significant morbidity. We conclude that complete angiographic evaluation of potential kidney donors can be performed accurately and safely on an outpatient basis.

Angiography↗
PubMed1986

Photosynthesis and Growth of Water Hyacinth under CO(2) Enrichment.

Water hyacinth (Eichhornia crassipes [Mart.] Solms) plants were grown in environmental chambers at ambient and enriched CO(2) levels (330 and 600 microliters CO(2) per liter). Daughter plants (ramets) produced in the enriched CO(2) gained 39% greater dry weight than those at ambient CO(2), but the original mother plants did not. The CO(2) enrichment increased the number of leaves per ramet and leaf area index, but did not significantly increase leaf size or the number of ramets formed. Flower production was increased 147%. The elevated CO(2) increased the net photosynthetic rate of the mother plants by 40%, but this was not maintained as the plants acclimated to the higher CO(2) level. After 14 days at the elevated CO(2), leaf resistance increased and transpiration decreased, especially from the adaxial leaf surface. After 4 weeks in elevated as compared to ambient CO(2), ribulose bisphosphate carboxylase activity was 40% less, soluble protein content 49% less, and chlorophyll content 26% less; whereas starch content was 40% greater. Although at a given CO(2) level the enriched CO(2) plants had only half the net photosynthetic rate of their counterparts grown at ambient CO(2), they showed similar internal CO(2) concentrations. This suggested that the decreased supply of CO(2) to the mesophyll, as a result of the increased stomatal resistance, was counterbalanced by a decreased utilization of CO(2). Photorespiration and dark respiration were lower, such that the CO(2) compensation point was not altered. The photosynthetic light and CO(2) saturation points were not greatly changed, nor was the O(2) inhibition of photosynthesis (measured at 330 microliters CO(2) per liter). It appears that with CO(2) enrichment the temporary increase in net photosynthesis produced larger ramets. After acclimation, the greater total ramet leaf area more than compensated for the lower net photosynthetic rate on a unit leaf area basis, and resulted in a sustained improvement in dry weight gain.

Journal Article↗
PubMed1979

The peritoneal absorption of insulin in diabetic man: a potential site for a mechanical insulin delivery system.

The potential of the peritoneum as a site for an "artificial beta cell" was studied. Three 14-hr studies were performed in an insulin-dependent diabetic male maintained on chronic peritoneal dialysis. All studies were performed between dialyses and throughout three standard American Diabetes Association (ADA) 600 calorie meals. The degree of insulin absorption from the peritoneal space was assessed by measuring the changes in plasma-free insulin concentration during these studies. The results of this study demonstrate that normalization of plasma insulin profiles may be observed with the administration of insulin into the peritoneal space. This absorbed insulin exerts hypoglycemic activity that suppresses the meal-induced rise in plasma glucose concentration. Thus, the peritoneal space may be a feasible route into which insulin may be delivered by an artificial beta cell.

Absorption↗