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Biomedical subjects

H Nelson

Publications and source records attributed to H Nelson.

At least 19 recordsLinked to original sources
PubMed1997

Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU.

PURPOSE: For locally advanced primary colorectal cancer, our institution has combined intraoperative electron irradiation (IOERT) with external beam irradiation (EBRT) +/- 5-fluorouracil (5-FU) and surgical resection. Disease control and survival were compared with the current IOERT and prior non-IOERT regimens. METHODS AND MATERIALS: From April 1981 through August 1995, 61 patients received an IOERT dose of 10-20 Gy, usually combined with 45-55 Gy of fractionated EBRT; 56 had minimum follow-up of 18 months. The amount of residual disease remaining at IOERT after exploration and maximal resection in the 56 patients was gross in 16, < or = microscopic in 39, and unresected in 1. RESULTS: Survival (SR) and disease control were analyzed as a function of potential prognostic factors. Factors that achieved statistical significance for improved overall survival included treatment sequence of preop EBRT + 5-FU (vs. postoperative EBRT + 5-FU, p = 0.003) and < or = microscopic residual disease after maximal resection (vs. gross residual, p = 0.005). Those that appeared to favorably impact disease-free survival included EBRT + 5-FU (vs. EBRT alone, p = 0.01), < or = microscopic residual (vs. gross, p = 0.0014), and colon site of primary (vs. rectum, p = 0.009). Failures within an irradiation field have occurred in 4 of 16 patients (25%) who presented with gross residual after partial resection vs. 2 of 39 (5%) with < or = microscopic residual after gross total resection (p = 0.01). The significant prognostic factors for a decrease in distant metastases were the same as for disease-free SR with respective p-values of 0.013 (EBRT + 5-FU), 0.008 (microscopic residual), and 0.03 (colon primary). The current data suggests a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (< or = 12.5 Gy--1 of 29 or 3%, > or = 15 Gy--6 of 26 or 23%, p = 0.03). CONCLUSIONS: Both overall survival and disease control appear to be improved with the addition of IOERT to standard treatment. More routine use of systemic therapy is indicated as a component of IOERT containing treatment regimens because the incidence of distant metastases was 50% of patients at risk.

Adult↗
PubMed1997

The treatment of locally advanced colon cancer.

PURPOSE: The results of therapy for 103 patients with locally advanced colon cancer who received radiotherapy were analyzed to determine the outcome and tolerance of therapy. METHODS AND MATERIALS: Between 1974 and 1994, 103 patients received radiotherapy and maximal resection of locally advanced colon cancers. Following resection, 50 patients had no residual disease, 18 patients had microscopic residual disease, and 35 patients had gross residual disease. External beam radiotherapy was initiated 1 to 4 months following resection except in two patients who received preoperative radiotherapy. Treatment was delivered to the tumor bed and adjacent lymph nodes using 4 to 18 MV X-rays with doses ranging from 16.2 to 60 Gy. Intraoperative electron radiotherapy (IOERT) was also administered to 11 of the patients with doses ranging from 10 to 20 Gy. Chemotherapy was administered to 77 patients. Follow-up in survivors ranged from 0.5 to 17 years (median: 5.8 years). RESULTS: The 5-year actuarial local failure rate was 10% for patients with no residual disease, 54% for patients with microscopic residual disease, and 79% for patients with gross residual disease (p < 0.0001). For patients with residual disease, local failure occurred in 11% of patients receiving IOERT compared with 82% of patients receiving only external beam therapy (p = 0.02). The 5-year actuarial survival rate was 66% for patients with no residual disease, 47% for patients with microscopic residual disease, and 23% for patients with gross residual disease (p = 0.0009). The 5-year survival rate in patients with residual disease was 76% for patients receiving IOERT and 26% for patients receiving external beam therapy alone (p = 0.04). CONCLUSIONS: Patients with locally advanced colon cancer who have had a complete resection have a high probability of local control after external beam irradiation +/- 5 fluorouracil (5FU)-based systemic therapy. The toxicity of therapy can be minimized with attention to treatment technique and dose. Local control and survival rates in patients with residual disease who received IOERT appear to be significantly greater than for those patients who received external beam radiotherapy therapy alone.

Adult↗
PubMed1997

Gastrointestinal carcinoid tumors: current management strategies.

BACKGROUND: Carcinoid or neuroendocrine tumors of the gastrointestinal tract, although characteristically indolent, are also quite heterogeneous both with respect to histologic and endocrine features and with respect to clinical presentation and behavior. PURPOSE: This study was undertaken to review and summarize the current literature on classification controversies, site-specific carcinoid presentation and behavior, and diagnostic and management strategies for primary and advanced carcinoid tumors and the carcinoid syndrome. RESULTS: For carcinoid tumors, oncologic results depend on the location of the primary tumor, extent of locoregional and metastatic disease, functioning status of the tumor, and the feasibility of complete surgical extirpation. Whereas favorable survival rates are typically observed for appendiceal and rectal primaries, less favorable rates are often observed for colonic and ileal tumors. A search for additional tumors is generally advised because multiple carcinoids and second neoplasms are not uncommon. Because of the indolent nature of the tumor and because these therapies have been shown to improve quality and quantity of life, otherwise fit patients with advanced carcinoid disease should be treated with aggressive medical and surgical therapies. Development of a malignant carcinoid syndrome indicates the presence of a functionally active carcinoid tumor and portends a poor prognosis. CONCLUSION: Gastrointestinal carcinoids, although malignant, behave differently from other carcinomas. Results are highly variable and must be individualized according to the site of the primary tumor, extent of spread, and general condition of the patient. A prolongation of quality life can often be accomplished through aggressive medical and surgical therapies.

Biomarkers↗
PubMed1997

Avoiding a stoma: role for segmental or abdominal colectomy in Crohn's colitis.

UNLABELLED: Total proctocolectomy and ileostomy for Crohn's colitis offers a low recurrence rate but commits patients to a permanent ileostomy. In contrast, segmental resection may predispose patients to recurrence and further surgery but may delay or avoid a stoma in select individuals. AIM: This study was undertaken to determine the risk of recurrence and the need for permanent stoma in patients treated with segmental or abdominal colectomy for Crohn's colitis. METHODS: Between 1976 and 1985, 699 patients underwent surgery for Crohn's colitis at the Mayo Clinic. Patients who had a total proctocolectomy and end ileostomy or primary ileal or anorectal disease were excluded from further study. Fifty-three patients had a colon resection without a permanent stoma, and 49 were alive and available for follow-up. During a mean follow-up of 14 years, completed questionnaires provided current details on subsequent medical and surgical therapies and/or stomas that were required. In these 49 patients, Crohn's of the colon involved the right, left, and both sides of the colon in 12, 31, and 6 patients, respectively, and involved less than one-third, one to two-thirds, and greater than two-thirds of the colon in 23, 25, and 1 patients, respectively. RESULTS: Twenty-two of forty-nine patients (45 percent) required no further therapy. In 27 patients (55 percent), further treatment was required, including 11 (22 percent) patients who were managed medically (only 4 >1 year) and 16 (33 percent) patients who were managed surgically. Three recurrences developed in the small bowel; the remaining 24 developed in the colon. For the 16 patients with recurrence requiring surgery, mean time to recurrence was 51 +/- 14 months; in all cases, recurrent disease involved the colon, with four anastomotic recurrences. At first recurrence, ten patients underwent another limited colon resection, and six patients underwent completion proctectomy with permanent ileostomy. Five patients required a third procedure, only one of which resulted in a permanent ileostomy. Therefore, 42 patients (86 percent) remained stoma-free, and 7 (14 percent) ultimately required permanent ileostomy, with a mean stoma-free interval of 23 +/- 4 months. CONCLUSION: Colon resection without proctectomy in select patients with limited colonic Crohn's disease can delay or avoid the necessity of a permanent stoma.

Adolescent↗
PubMed1997

Laparoscopic colectomy shortens postoperative ileus in a canine model.

BACKGROUND: Proponents of laparoscopic colectomy claim a more rapid return of gastrointestinal function, but objective data supporting this contention are lacking. Our aim was to compare the duration of delay in gastrointestinal transit after total laparoscopic, laparoscopic-assisted, and open colonic resection. METHODS: Thirty-nine female dogs were assigned to three groups: group 1, laparoscopic colectomy; group 2, laparoscopic-assisted colectomy; and group 3, open colectomy. Transit studies were performed before operation and on days 1, 2, 3, and 5 after a mid-descending colectomy with end-to-end anastomosis. Gastric emptying of liquids and small bowel transit of liquids were determined by means of radionuclide techniques. Gastric emptying of solids and colonic transit were measured by following transit of radiopaque spheres instilled into the stomach and proximal colon, respectively. RESULTS: With each dog as its own control, gastric emptying returned to preoperative values by 2 days in group 1, 3 days in group 2, and 5 days in group 3. Small bowel transit returned to preoperative values on day 3 for groups 1 and 2 and on day 5 for group 3. Gastric emptying of solids and colonic transit returned to preoperative values on day 3 for group 1 and on day 5 for groups 2 and 3. CONCLUSIONS: These observations show that laparoscopic resection techniques in this canine model resulted in a more rapid return to normal gastrointestinal transit compared with open colectomy.

Animals↗
PubMed1997

Chromosomal deletion complexes in mice by radiation of embryonic stem cells.

Chromosomal deletions ("deficiencies') are powerful tools in the genetic analysis of complex genomes. They have been exploited extensively in Drosophila melanogaster, an organism in which deficiencies can be efficiently induced and selected. Spontaneous deletions in humans have facilitated the dissection of phenotypes in contiguous gene syndromes and led to the positional cloning of critical genes. In mice, deletion complexes created by whole animal irradiation experiments have enabled a systematic characterization of functional units along defined chromosomal regions. However, classical mutagenesis in mice is logistically impractical for generating deletion sets on a genome-wide scale. Here, we report a high-throughput method for generating radiation-induced deletion complexes at defined regions in the genome using ES cells. Dozens of deletions of up to several centiMorgans, encompassing a specific locus, can be created in a single experiment and transmitted through the germline. The ability to rapidly create deletion complexes along chromosomes will facilitate systematic functional analyses of the mammalian genome.

Animals↗
PubMed1997

Pharmacokinetics of allopurinol in Dalmatian dogs.

The pharmacokinetics of allopurinol were studied in Dalmatian dogs. Eight dogs were given allopurinol orally at a dose of 10 mg/kg for seven doses prior to sample collection. After a period of at least two weeks, four of these dogs and four additional Dalmatians were later given a single intravenous (i.v.) dose of allopurinol (6 mg/kg) prior to sample collection. Allopurinol was found to follow first-order absorption and elimination kinetics. In the i.v. kinetic study, the elimination constant (Kel) = 0.31 +/- 0.03 per h, the half-life (t1/2) = 2.22 +/- 0.20 h, the initial concentration (C0) = 5.26 +/- 0.34 micrograms/mL and the specific volume (Vd) = 1.14 +/- 0.07 L/kg. Clearance of allopurinol was estimated to be 0.36 +/- 0.03 L/kg.h. In the oral kinetic study, the absorption rate constant (Kab) = 1.06 +/- 0.13 per h, the elimination rate constant (Kel) = 0.26 +/- 0.01 per h, the absorption half-life (t1/2ab) = 0.66 +/- 0.06 h, and the elimination half-life (t1/2el) = 2.69 +/- 0.14 h. Peak plasma concentrations (Cmax) = 6.43 +/- 0.18 micrograms/mL were obtained within 1 to 3 h (mean time of maximum concentration (Tmax) = 1.9 +/- 0.1 h). The volume of distribution corrected by the fraction of dose absorbed (Vd/F) was estimated to be 1.17 +/- 0.07 L/kg. Good agreement was obtained between mean kinetic parameters in the oral and i.v. studies. There was little variation between individual dogs in the i.v. study, whereas the rate of absorption and elimination of orally administered allopurinol was more varied among individual dogs. Because of this, and the fact that the magnitude of hyperuricosuria varies among Dalmatians, it is not possible to specify an exact dose of allopurinol that will effectively lower the urinary uric acid concentration to acceptable values in all Dalmatians with hyperuricosuria; rather, the dose must be titrated to the needs of each dog.

Administration, Oral↗
PubMed1997

Liver-directed therapies for gastrointestinal malignancies.

Although surgery remains the treatment of choice for hepatic malignancy, both primary and secondary, the majority of patients presenting with hepatic tumors are unfortunately not candidates for resection. A number of alternative hepatic-directed therapies are assessed for their role in the following settings: as primary treatment modalities; as treatment adjuvants to surgical resection, including neoadjuvant therapy to downstage tumors prior to planned resection; and as a means of palliation when tumors are incurable. Non-surgical hepatic-directed therapies demonstrated to prolong survival include adjuvant portal vein chemotherapy infusion at the time of resection of primary colorectal cancer, and hepatic artery infusion in the setting of established hepatic metastases. Several other therapies are described but remain incompletely evaluated, including transplantation, microwave coagulation, injection of radiolabeled particles, chemoembolization, percutaneous ethanol injection, and cryosurgery. Due to the rarity of these tumors, many studies present results of heterogeneous populations of patients, making meaningful comparison difficult. Finally, it must be said that screening asymptomatic patients after resection of colorectal cancer with a view to application of hepatic-directed therapy in the setting of colorectal metastases is costly.

Carcinoma, Hepatocellular↗
PubMed1997

Detection of colorectal polyps with CT colography: initial assessment of sensitivity and specificity.

PURPOSE: To estimate the sensitivity and specificity of computed tomographic (CT) colography in detection of colorectal polyps and to compare these findings with those at axial CT. MATERIALS AND METHODS: In 70 consecutive patients, CT colography and colonoscopy were performed. Helical axial CT images and CT colographic images (multiplanar two- and three-dimensional endoluminal images) were evaluated separately by two radiologists blinded to results from colonoscopy and other imaging studies. Findings were compared with those at colonoscopy, which was the standard. RESULTS: The sensitivity and specificity for the two observers with CT colography averaged 75% and 90% in patients with adenomas 10 mm in diameter or larger, 66% and 63% in patients with adenomas 5 mm in diameter or greater, and 45% and 80% for patients with adenomas less than 5 mm in diameter, respectively. Sensitivity and specificity with axial CT were lower than those with CT colography (58% and 74%, respectively) in patients with adenomas 10 mm in diameter or larger. CONCLUSION: Compared with axial CT, CT colography appears to have superior sensitivity and specificity in detection of clinically important colorectal adenomas. Early performance of CT colography seems promising for detection of colorectal polyps 5 mm and larger.

Adenoma↗
PubMed1997

Function of metal-ion homeostasis in the cell division cycle, mitochondrial protein processing, sensitivity to mycobacterial infection and brain function.

A novel Saccharomyces cerevisiae mutant, unable to grow in the presence of 12.5 mmol l-1 EGTA, was isolated. The phenotype of the mutant is caused by a single amino acid change (Gly149 to Arg) in the essential yeast cell division cycle gene CDC1. The mutant could be suppressed by overexpression of the SMF1 gene, which codes for a plasma membrane Mn2+ transporter. We observed that the yeast SMF1 gene shares homology with the mouse Nramp gene. Nramp (Bcg) was cloned as a gene responsible for mouse resistance to infection with mycobacteria and is identical with the Ity and the Lsh genes conferring resistance to infection by Salmonella typhimurium and Leishmania donovani, respectively. Although the cloning of Nramp identified the gene responsible for the resistance of mice to mycobacteria, its function is unknown. We propose that the mammalian protein, like the yeast transporter, is a Mn2+ and/or Zn2+ transporter. Following the phagocytosis of a parasite into the phagosome, the macrophage produces reactive oxygen and/or nitrogen intermediates that are toxic for the internalized bacteria. The survival of the pathogen during the burst of macrophage respiratory activity is thought to be partly mediated by microbial superoxide dismutase (SOD), which contains Mn2+ or Fe2+ in its active centre. Nramp may transport Mn2+ from the extracellular milieu into the cytoplasm of a macrophage and, after the generation of the phagosome, remove Mn2+ from the organelle. Thus, the Mn(2+)-depletion of the phagosome microenvironment by the Nramp gene product may be a rate-limiting step in the metalloenzyme's production by the engulfed bacteria. This limitation will restrict the mycobacterial ability to produce active enzymes such as SOD and prevent the propagation of the ingested microorganisms. Conversely, an increased concentration of Mn2+ in the phagosome caused by a defective Nramp transporter (Bcgs) may promote the growth of the mycobacteria and render the organism sensitive to the pathogen. We use a similar approach to identify, clone and study other metal-ion transporters.

Animals↗
PubMed1997

Aggressive multimodality treatment for locally advanced irresectable rectal cancer.

BACKGROUND: Local failure rates are high for locally irresectable primary or recurrent colorectal cancer, even when chemoradiation therapy is employed. AIM: This review evaluates evidence supporting aggressive preoperative chemoradiation followed by maximal surgical resection and intraoperative radiation therapy to achieve disease control and cure for patients with locally advanced irresectable primary or recurrent rectal cancer. RESULTS: A 5-year survival rate of 42 per cent with a central failure rate of 2 per cent may be achieved in patients with locally irresectable primary rectal cancer. In patients with locally recurrent disease, these values at 5 years are 18 and 28 per cent respectively. The 5-year incidence of distant metastasis remains high, affecting 64 per cent of patients with primary cancer and 75 per cent of those with recurrent cancer. CONCLUSION: A disease-free surgical resection margin remains paramount to achieve cure. Encouraging trends exist, however, for further evaluation of multimodality therapy as a means of reducing local recurrence of disease.

Brachytherapy↗
PubMed1996

Tumor-infiltrating lymphocytes can be activated in situ by using in vivo activants plus F(ab')2 bispecific antibodies.

In vitro-activated T lymphocytes can be retargeted with anti-CD3 x anti-tumor bispecific antibodies (BsAb) to kill tumor cells in vitro and in vivo. The purpose of the present study was to examine the systemic and intra-tumor effects of in vivo T-cell activation with BsAb, staphylococcal enterotoxin B (SEB), and beta-glucan in combination with BsAb as a retargeting agent. CL-62 melanoma cells were injected subcutaneously into C3H/ HeN mice. Mice were subsequently treated with BsAb alone or with SEB or beta-glucan plus BsAb. Fresh splenocytes, lymph-node cells and tumor-infiltrating lymphocytes (TIL) were tested for their proliferative response using incorporation of 3H-thymidine, and for their ability to lyse CL-62 cells in the presence or absence of BsAb in 4-hr 51Chromium release assays. Toxicity of treatments was assessed in a D-galactosamine model. BsAb, alone or combined with beta-glucan, had essentially no effect on systemic T-cell cytotoxicity, and essentially no effect on systemic proliferation, unless exogenous IL-2 was provided. At the tumor site, BsAb alone, BsAb plus beta-glucan, and SEB plus BsAb all significantly increased BsAb-mediated TIL cytotoxicity. In contrast to the TIL-limited effects of BsAb and of BsAb plus beta-glucan, SEB plus BsAb markedly increased both systemic and intra-tumor T-lymphocyte activation. Toxicity correlated with measures of systemic activation, with limited effects from BsAb alone and from beta-glucan plus BsAb, and with marked lethality from SEB plus BsAb. Overall, these results suggest moderate intra-tumor activation of TIL, but no measurable systemic activation after in vivo treatment with BsAb or beta-glucan plus BsAb. SEB plus BsAb results in complete T-cell activation in both systemic and intra-tumor compartments, but at the expense of increased systemic toxicity. In conclusion, TIL can be activated in situ with different combinations of in vivo activants. In vivo-activated TIL can be retargeted with bispecific antibodies to lyse tumor cells, and may be an alternative to ex vivo T-cell activation and adoptive transfer therapy.

Animals↗
PubMed1996

What ethicists talk about when they talk about managed care.

Defining the values at stake as we move into managed care is an awesome--yet necessary--endeavor. To help sort things out, the Society for Health and Human Values brought together health care ethicists and medical humanists to discuss how human values are being incorporated into health care reform. Here's an excerpt from that conversation.

Ethicists↗
PubMed1996

A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria.

A novel Saccharomyces cerevisiae mutant, unable to grow in the presence of 12.5 mM EGTA, was isolated by replica plating. The phenotype of the mutant is caused by a single amino acid change (Gly149 to Arg) in the essential yeast gene CDC1. The mutant could be suppressed by overexpression of the SMF1 gene, which was isolated as an extragenic high-copy suppressor. The SMF1 gene codes for a highly hydrophobic protein and its deletion renders the yeast cells sensitive to low manganese concentration. In accordance with this observation, the smf1 null mutant exhibits reduced Mn2+ uptake at micromolar concentrations. Using a specific antibody, we demonstrated that Smf1p is located in the yeast plasma membrane. These results suggest that Smf1p is involved in high-affinity Mn2+ uptake. This assumption was also tested by overexpressing the SMF1 gene in the temperature-sensitive mutant of the mitochondrial processing peptidase (MAS1). SMF1 overexpression as well as addition of 1 mM Mn2+ to the growth medium complemented this mutation. This also suggests that in vivo Mas1p is a manganese-dependent peptidase. The yeast Smf1p resembles a protein from Drosophila and mammalian macrophages. The latter was implicated in conferring resistance to mycobacteria. A connection between Mn2+ transport and resistance or sensitivity to mycobacteria is discussed.

Amino Acid Sequence↗