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Biomedical subjects

Andrew K Stewart

Publications and source records attributed to Andrew K Stewart.

14 recordsLinked to original sources
PubMed2006

Use of the National Cancer Data Base to develop clinical trials accrual targets that are appropriate for minority ethnicity patients: a report from the American College of Surgeons Oncology Group (ACOSOG) Special Population Committee.

BACKGROUND: Disparities in cancer outcome among different subsets of the American population related to ethnic background have been well documented. Clinical trials represent the most powerful strategy for improving cancer treatments, but racial and ethnic minority patients are frequently underrepresented among patients accrued to these protocols. Proof of comparable efficacy for a promising cancer therapy in different groups of patients requires diversity in the clinical trial populations so that study results will be generalizable. Appropriate targets for accrual of minority ethnicity patients have not previously been defined. METHODS: The National Cancer Database (NCDB) is maintained jointly by the American Cancer Society and the American College of Surgeons. Information submitted by tumor registries throughout the United States represents an estimated 70% of newly diagnosed cancer cases. The authors analyzed NCDB reports on ethnic distribution of patients with breast, prostate, nonsmall cell lung, and colorectal cancer, stratified by stage of disease at diagnosis. RESULTS: African Americans with cancer of the breast and prostate had the most notable patterns of disproportionate representation among populations with advanced-stage disease. The authors compiled a table of suggested accrual targets for selected solid-organ cancers based on NCDB stage-specific reports. CONCLUSIONS: Clinical trial results will be more meaningful if participating patients reflect the site- and stage-specific populations that are under study. The authors recommended that clinical trial investigators incorporate accrual targets for minority ethnicity populations into the study design.

American Cancer Society↗
PubMed2006

Anion exchangers in flux: functional differences between human and mouse SLC26A6 polypeptides.

The SLC26 anion transporter polypeptides exhibit considerably greater sequence diversity among near-species orthologues than is found among the SLC4 bicarbonate transporters, and among SLC26 transporters is most marked among SLC26A6 orthologues. This observation prompted systematic functional comparison in Xenopus oocytes of mouse Slc26a6 with several human SLC26A6 polypeptide variants. Mouse and human polypeptides exhibited similar rates of bidirectional [14C]oxalate flux, Cl-/HCO3- exchange, and Cl-/OH- exchange, and similar cAMP-stimulation and enhancement of that stimulation by wild-type but not delta F508 CFTR. However, high rates of 36Cl- and 35S-sulfate transport by mouse Slc26a6 contrasted with low transport rates of the human proteins. The high 36Cl- transport phenotype cosegregated with the transmembrane domain of mouse Slc26a6 in chimera studies. Mouse Slc26a6 and human SLC26A6 each mediated electroneutral Cl-/HCO3- and Cl-/OH- exchange. But, whereas Cl-/oxalate exchange by mouse Slc26a6 was electrogenic, that mediated by human SLC26A6 appeared electroneutral. Oocyte expression of either mouse or human orthologue elicited currents that were pharmacologically distinct from the monovalent anion exchange activities measured in the same lots of oocytes. The human SLC26A6 polypeptide variants SLC26A6c and SLC26A6d were inactive in isotopic flux assays. Understanding of SLC26 transport mechanisms and pathophysiology will benefit from recognition of substantial differences in transport properties among orthologues.

Animals↗
PubMed2005

Alkaline-shifted pHo sensitivity of AE2c1-mediated anion exchange reveals novel regulatory determinants in the AE2 N-terminal cytoplasmic domain.

The mouse anion exchanger AE2/SLC4A2 Cl(-)/HCO(-)(3) exchanger is essential to post-weaning life. AE2 polypeptides regulate pH(i), chloride concentration, cell volume, and transepithelial ion transport in many tissues. Although the AE2a isoform has been extensively studied, the function and regulation of the other AE2 N-terminal variant mRNAs of mouse (AE2b1, AE2b2, AE2c1, and AE2c2) have not been examined. We now present an extended analysis of AE2 variant mRNA tissue distribution and function. We show in Xenopus oocytes that all AE2 variant polypeptides except AE2c2 mediated Cl(-) transport are subject to inhibition by acidic pH(i) and to activation by hypertonicity and NH(+)(4). However, AE2c1 differs from AE2a, AE2b1, and AE2b2 in its alkaline-shifted pH(o)((50)) (7.70 +/- 0.11 versus 6.80 +/- 0.05), suggesting the presence of a novel AE2a pH-sensitive regulatory site between amino acids 99 and 198. Initial N-terminal deletion mutagenesis restricted this site to the region between amino acids 120 and 150. Further analysis identified AE2a residues 127-129, 130-134, and 145-149 as jointly responsible for the difference in pH(o)((50)) between AE2c1 and the longer AE2a, AE2b1, and AE2b2 polypeptides. Thus, AE2c1 exhibits a unique pH(o) sensitivity among the murine AE2 variant polypeptides, in addition to a unique tissue distribution. Physiological coexpression of AE2c1 with other AE2 variant polypeptides in the same cell should extend the range over which changing pH(o) can regulate AE2 transport activity.

Animals↗
PubMed2005

Patterns of surgical care of lung cancer patients.

BACKGROUND: This survey was performed to determine the patterns of surgical care provided patients with non-small cell lung carcinoma (NSCLC). METHODS: In 2001, the American College of Surgeons carried out a patient care survey of 729 hospitals to retrieve information of NSCLC patients' history, evaluation, pathology, and surgical treatment. RESULTS: Inclusion criteria were met by 40,090 patients: of whom 11,668 (29.1%) were treated surgically; 74.2% alone and 25.8% as part of multimodality therapy. Of these patients, 59.5% were in stage I, 17.5% in stage II, 17.0% in stage III, and 6.0% in stage IV. Surgery patient demographics were the following: 55% male and 45% female; 46.8% 70 years or older; and 76.3% had significant comorbidities. Tumor characteristics: squamous 28%, adenocarcinoma 37.6%, other 34.4%. Staging: in addition to radiologic examinations, preoperative mediastinoscopy was performed in 27.1% of operated patients with node biopsy in only 46.6% of these procedures. OPERATIONS: wedge resection 15.6%, lobectomy 70.8%, pneumonectomy 13.6%. Surgical margins were positive in 7.8%, but only 65.2% had frozen section analysis. Perioperative mortality was 5.2%, but was 4.0% in nontransfused patients and 12.7% in transfused patients and was 3.2% in high-volume (more than 90 operations per year) versus 4.8% in low-volume hospitals (p < 0.001). CONCLUSIONS: (1) Patients being operated for NSCLC are elderly with significant comorbid conditions. (2) More patients than previously are female and have adenocarcinoma. (3) Mediastinoscopy is infrequently performed and lymph nodes are biopsied in less than 50% of them. (4) Lobectomy is the most common operation, and positive surgical margins are too frequent. (5) Operative mortality is reasonable but transfusion is a marker for increased risk and outcomes are superior in high-volume hospitals. (6) Hospitals with higher volume had fewer perioperative deaths.

Adolescent↗
PubMed2004

Acute pH-dependent regulation of AE2-mediated anion exchange involves discrete local surfaces of the NH2-terminal cytoplasmic domain.

We have previously defined in the NH2-terminal cytoplasmic domain of the mouse AE2/SLC4A2 anion exchanger a critical role for the highly conserved amino acids (aa) 336-347 in determining wild-type pH sensitivity of anion transport. We have now engineered hexa-Ala ((A)6) and individual amino acid substitutions to investigate the importance to pH-dependent regulation of AE2 activity of the larger surrounding region of aa 312-578. 4,4'-Diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)-sensitive 36Cl- efflux from AE2-expressing Xenopus oocytes was monitored during changes in pHi or pHo in HEPES-buffered and in 5% CO2/HCO3- -buffered conditions. Wild-type AE2-mediated 36Cl- efflux was profoundly inhibited at low pHo, with a pHo(50) value = 6.75 +/- 0.05 and was stimulated up to 10-fold by intracellular alkalinization. Individual mutation of several amino acid residues at non-contiguous sites preceding or following the conserved sequence aa 336-347 attenuated pHi and/or pHo sensitivity of 36Cl- efflux. The largest attenuation of pH sensitivity occurred with the AE2 mutant (A)6357-362. This effect was phenocopied by AE2 H360E, suggesting a crucial role for His360. Homology modeling of the three-dimensional structure of the AE2 NH2-terminal cytoplasmic domain (based on the structure of the corresponding region of human AE1) predicts that those residues shown by mutagenesis to be functionally important define at least one localized surface region necessary for regulation of AE2 activity by pH.

Amino Acid Sequence↗
PubMed2004

New tumor-node-metastasis staging strategy for node-positive (stage III) rectal cancer: an analysis.

PURPOSE: The tumor-node-metastasis system for staging rectal cancer is based on invasion, number of involved nodes, and metastasis. Nodes are classified as N1 or N2 according to the number involved with metastases. Nodal positivity defines stage III regardless of depth of invasion or number of positive nodes. Our purpose was to analyze overall survival when node-positive patients were stratified into three new subsets. METHODS: We analyzed data entered into the National Cancer Data Base for 5,987 stage III patients with rectal cancer between 1991 and 1993. Survival was calculated using three new subgroups (IIIA: T1/2, N1; IIIB: T3/4, N1; IIIC: any T, N2). Survival following surgery and adjuvant therapy was assessed. The observed survival rates were calculated and compared using the log-rank method. The Cox regression model assessed subgroup differences. RESULTS: Five-year observed survival rates for stage III subcategories were 55.1% in IIIA; 35.3% in IIIB; and 24.5% in IIIC. Stratifying for treatment outcome, stage IIIA patients having surgery alone (n = 278) had poorer observed 5-year survival (39%) than patients treated with surgery and adjuvant chemotherapy or radiation therapy (chemo/XRT; n = 765; 60%). Similar outcomes occurred in IIIB (surgery-alone [n = 726; 21.7%] and chemo/XRT [n = 2,130; 40.9%] groups) and in IIIC (surgery-alone [n = 467; 12.2%] and chemo/XRT [n = 1,621; 28.9%] groups). Differences were significant (P <.0001) in all stages. CONCLUSION: The traditional stage III designation of rectal cancer fails to account for invasion (T1-4) and number of involved nodes (N1, N2). The stratification of stage III patients into three subsets should be used in future analyses of rectal cancer. The effect of postoperative adjuvant therapy was beneficial in all subsets.

Aged↗
PubMed2003

Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes.

Mutations in the human SLC26A3 gene, also known as down-regulated in adenoma (hDRA), cause autosomal recessive congenital chloride-losing diarrhoea (CLD). hDRA expressed in Xenopus oocytes mediated bidirectional Cl--Cl- and Cl--HCO3- exchange. In contrast, transport of oxalate was low, and transport of sulfate and of butyrate was undetectable. Two CLD missense disease mutants of hDRA were nonfunctional in oocytes. Truncation of up to 44 C-terminal amino acids from the putatively cytoplasmic C-terminal hydrophilic domain left transport function unimpaired, but deletion of the adjacent STAS (sulfate transporter anti-sigma factor antagonist) domain abolished function. hDRA-mediated Cl- transport was insensitive to changing extracellular pH, but was inhibited by intracellular acidification and activated by NH4+ at acidifying concentrations. These regulatory responses did not require the presence of either hDRA's N-terminal cytoplasmic tail or its 44 C-terminal amino acids, but they did require more proximate residues of the C-terminal cytoplasmic domain. Although only weakly sensitive to inhibition by stilbenes, hDRA was inhibited with two orders of magnitude greater potency by the anti-inflammatory drugs niflumate and tenidap. cAMP-insensitive Cl--HCO3- exchange mediated by hDRA gained modest cAMP sensitivity when co-expressed with cystic fibrosis transmembrane conductance regulator (CFTR). Despite the absence of hDRA transcripts in human cell lines derived from CFTR patients, DRA mRNA was present at wild-type levels in proximal colon and nearly so in the distal ileum of CFTR(-/-) mice. Thus, pharmacological modulation of DRA might be a useful adjunct treatment of cystic fibrosis.

Animals↗
PubMed2003

Structure-function relationships of AE2 regulation by Ca(i)(2+)-sensitive stimulators NH(4+) and hypertonicity.

We showed previously that the nonerythroid anion exchanger AE2 and the erythroid anion exchanger AE1 differ greatly in their regulation by acute changes in intracellular pH (pH(i)) and extracellular pH (pH(o)). We have now examined how AE2, but not AE1, is activated by two stimuli with opposing effects on oocyte pH(i): an alkalinizing stimulus, hypertonicity, and an acidifying stimulus, NH(4)(+). We find that both NH(2)-terminal cytoplasmic and COOH-terminal transmembrane domains of AE2 are required for activation by either stimulus. Directed by initial deletion mutagenesis studies of the NH(2)-terminal cytoplasmic domain, an alanine scan of AE2 amino acids 336-347 identified residues whose individual mutation abolished or severely attenuated sensitivity to both or only one activating stimulus. Chelation of cytoplasmic Ca(2+) (Ca(i)(2+)) diminished or abolished AE2 stimulation by NH(4)(+) and by hypertonicity. Calmidazolium inhibited AE2 activity, but not that of AE1. AE2 was insensitive to many other modifiers of Ca(2+) signaling. Unlike AE2 stimulation by NH(4)(+) and by hypertonicity, AE2 inhibition by calmidazolium required only AE2's COOH-terminal transmembrane domain.

Animals↗
PubMed2003

Modelling intracellular H(+) ion diffusion.

Intracellular pH, an important modulator of cell function, is regulated by plasmalemmal proteins that transport H(+), or its equivalent, into or out of the cell. The pH(i) is also stabilised by high-capacity, intrinsic buffering on cytoplasmic proteins, oligopeptides and other solutes, and by the extrinsic CO(2)/HCO(3)(-) (carbonic) buffer. As mobility of these buffers is lower than for the H(+) ion, they restrict proton diffusion. In this paper we use computational approaches, based on the finite difference and finite element methods (FDM and FEM, respectively), for analysing the spatio-temporal behaviour of [H(+)] when it is locally perturbed. We analyse experimental data obtained for various cell-types (cardiac myocytes, duodenal enterocytes, molluscan neurons) where pH(i) has been imaged confocally using intracellular pH-sensitive dyes. We design mathematical algorithms to generate solutions for two-dimensional diffusion that fit data in terms of an apparent intracellular H(+) diffusion coefficient, D(H)(app). The models are used to explore how the spatial distribution of [H(+)](i) is affected by membrane H(+)-equivalent transport and by cell geometry. We then develop a mechanistic model, describing spatio-temporal changes of [H(+)](i) in a cardiac ventricular myocyte in terms of H(+)-shuttling on mobile buffers and H(+)-anchoring on fixed buffers. We also discuss how modelling may include the effects of extrinsic carbonic-buffering. Overall, our computational approach provides a framework for future analyses of the physiological consequences of pH(i) non-uniformity.

Animals↗
PubMed2002

Does aggressive local therapy improve survival in metastatic breast cancer?

BACKGROUND: Women with metastatic breast cancer and an intact primary tumor are currently treated with systemic therapy. Local therapy of the primary tumor is considered irrelevant to the outcome, and is recommended only for palliation of symptoms. METHODS: We have examined the use of local therapy, and its impact on survival in patients presenting with stage IV breast cancer at initial diagnosis, who were reported to the National Cancer Data Base (NCDB) between 1990 and 1993. RESULTS: A total of 16,023 patients with stage IV disease were identified in the NCDB during this period, of whom 6861 (42.8%) received either no operation or a variety of diagnostic or palliative procedures, and 9162 (57.2%) underwent partial (3513) or total (5649) mastectomy. The presence of free surgical margins was associated with an improvement in 3-year survival in partial or total mastectomy groups (26% vs 35%, respectively). A multivariate proportional hazards model identified the number of metastatic sites, the type of metastatic burden, and the extent of resection of the primary tumor as significant independent prognostic covariates. Women treated with surgical resection with free margins, when compared with those not surgically treated, had superior prognosis, with a hazard ratio of 0.61 (95% confidence interval 0.58,0.65). CONCLUSIONS: These data suggest that the role of local therapy in women with stage IV breast cancer needs to be re-evaluated, and local therapy plus systemic therapy should be compared with systemic therapy alone in a randomized trial.

Breast Neoplasms↗
PubMed2002

A new TNM staging strategy for node-positive (stage III) colon cancer: an analysis of 50,042 patients.

OBJECTIVE: To analyze a large cohort of patients with stage III colon cancer to determine whether subgroup stratification better defines outcome. SUMMARY BACKGROUND DATA: The Tumor (T), Node (N), Metastasis (M) system is based on depth of tumor invasion into the colonic wall, the number of regional lymph nodes involved, and distant metastasis. Traditionally, colon cancer has been designated as stage III based on nodal involvement regardless of the depth (T1-4) of tumor penetration. Treatment decisions have been based on nodal involvement with less emphasis on colonic wall penetration in stage III patients. METHODS: Patients (n = 50,042) with stage III colon cancer reported to the National Cancer Data Base from 1987 through 1993 were analyzed. Observed survival was calculated by actuarial life table methods for three new node-positive subgroups (IIIA: T1/2, N1; IIIB: T3/4, N1; IIIC: any T, N2). The Cox proportional hazards model was used to test the prognostic strength of selected covariates. RESULTS: Three distinct subcategories within a traditional stage III cohort of colonic cancer were identified. Five-year observed survival rates for these three subcategories were 59.8%, IIIA; 42.0%, IIIB; and 27.3%, IIIC. Differences between subgroups were significant ( <.0001). Similar differences were calculated after stratification for treatment. A multivariate proportional hazards model identified the new stage III subgroups, modality of the first course of therapy, patient age, and tumor grade as significant independent prognostic covariates. CONCLUSIONS: The current stage III designation of colon cancer excludes prognostic subgroups stratified for mural penetration (T1-4) or nodal involvement (N1 vs. N2). Analysis of a large data set supports stratification into three subsets, confirming the benefit of adjuvant chemotherapy in each subgroup. This strategy should be used in the reporting and staging of node-positive colon cancers.

Age Factors↗
PubMed2002

How pH regulates a pH regulator: a regulatory hot spot in the N-terminal cytoplasmic domain of the AE2 anion exchanger.

Regulation of cell pH and cell volume require homeostatic control of intracellular cations and anions. Bicarbonate transporters play an important role in these cellular functions. The SLC4 and SLC26 gene families both encode bicarbonate transporter polypeptides. The SLC4 gene family includes four Na+-independent chloride-bicarbonate exchanger genes and multiple Na+-bicarbonate cotransporter and Na+-dependent anion-exchanger genes. The acute regulatory properties of the recombinant polypeptides encoded by these genes remain little studied. The most extensively studied among them are the Na+-independent anion exchangers AE1, AE2, and AE3. The widely expressed AE2 anion exchanger participates in recovery from alkaline load and in regulatory cell volume increase following shrinkage. AE2 can also be regulated by the ammonium ion. These properties are not shared by the closely related AE1 anion exchanger of the erythrocyte and the renal collecting duct Type A intercalated cell. Structure-function studies of recombinant proteins involving chimeras, deletions, and point mutations have delineated regions of AE2, which are important in the exhibition of the regulatory properties absent from AE1. These include regions of the transmembrane domain and the N-terminal cytoplasmic domain. Noncontiguous regions in the middle of the N-terminal cytoplasmic domain are of particular importance for acute regulation by several types of stimulus.

Animals↗
PubMedDate not supplied

The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined.

BACKGROUND: T3N0 colon cancer is the target of many adjuvant studies. Very few studies have examined the relationship of the number of lymph nodes examined to the prognosis of this stage. We examined data from the National Cancer Data Base (NCDB) to determine whether the number of examined lymph nodes is prognostic for T3N0 colon cancer. METHODS: A total of 35,787 prospectively collected cases of T3N0 colon cancer that were surgically treated and pathologically reported from 1985 to 1991 to the NCDB as T3N0M0 were analyzed. RESULTS: The 5-year relative survival rate for T3N0M0 colon cancer varied from 64% if 1 or 2 lymph nodes were examined to 86% if > 25 lymph nodes were examined. Three strata of lymph nodes (1-7, 8-12, and > or = 13) distinguished significantly different observed 5-year survival rates. CONCLUSIONS: These results demonstrate that the prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. A minimum of 13 lymph nodes should be examined to label a T3 colon cancer as node negative. These data suggest that adjuvant trials for T3N0 colon cancer should stratify according to the number of lymph nodes examined.

Aged↗