Laryngeal cancer treatment and survival differences across regional cancer centres in Ontario, Canada.

AIMS: We conducted a population-based study of practice patterns and outcome across the regional cancer centres providing care to patients with laryngeal cancer in the Province of Ontario, Canada. MATERIALS AND METHODS: : This was a retrospective cohort study of 1547 patients with cancers of the glottic or supraglottic larynx diagnosed between 1982 and 1995. Data were collected via chart review, including: patient and disease characteristics, treatment, waiting times and treatment volumes. Vital status was obtained from the Ontario Cancer Registry. Variations across the nine regional cancer centres are described and their effect on outcome explored. All analyses were stratified by stage I and II separately from stage III and IV. RESULTS: Treatments differed across centres (P<0.0001); for instance, in the stage I and II group, use of a daily dose of >2.54Gy varied from 0 to 87.6% and in the stage III and IV group, total laryngectomy rates varied from a low of 6% to a high of 53%. The percentage of patients waiting more than 6 weeks from diagnosis to first treatment varied from 17 to 49% (P<0.0001). Multivariate analysis revealed cause-specific survival differences that were not explained by control for case mix, treatment or waiting times. Differences ranged from an 82% risk reduction in one centre compared with the reference (stage I and II group, P=0.008) to a 153% increase in risk (stage III and IV group, P=0.02). Centre case volumes were not associated with cause-specific survival. CONCLUSIONS: This study quantifies the degree of variation that can occur in the treatment and outcome of people with cancer. We cannot properly assess whether care delivery is of high quality until we have a better understanding of the factors that drive such variations.

Explaining socioeconomic status effects in laryngeal cancer.

INTRODUCTION: People with lower socioeconomic status (SES) experience shorter survival times after a cancer diagnosis for many disease sites. We determined whether area-level SES was associated with the outcomes: cause-specific survival and local-regional failure in laryngeal cancer in Ontario, Canada. When we found an association we sought explanations that might be related to access to care including age, sex, rural residence, tumor stage, lymph node status, use of diagnostic imaging, treatment type, percentage of prescribed radiotherapy delivered, number of radiotherapy interruption days, treatment waiting time, and treating cancer center. MATERIALS AND METHODS: The study population consisted of 661 glottic and 495 supraglottic stage-stratified randomly-sampled patients identified using the Ontario Cancer Registry. Area-level SES quintiles were assigned using adjusted median household income from the Canadian Census. Other data were collected from patient charts. Explanations for SES effects were determined by measuring whether the effect moved toward the null value by at least 10% when an access indicator was added to a the model. RESULTS: Socioeconomic status was not related to either outcome for those with supraglottic cancer, but an association was present in glottic cancer. With the highest socioeconomic status quintile as the referent group, the relative risks for patients in the lowest socioeconomic quintile were 2.75 (95% CI 1.48, 5.12) for cause-specific survival and 1.90 (95% CI 1.24, 2.93) for local-regional failure. Disease stage as measured by T-category explained between 3% and 23% of these socioeconomic effects. None of the other access indicators met our 10% change criterion. CONCLUSION: We question why people in lower socioeconomic quintiles were not diagnosed earlier in the disease progression. Having ruled out several variables that may be related to access to care, additional biologic and social variables should be examined to further understand socioeconomic status effects.

Radiotherapy patterns of practice: T1N0 glottic cancer in Ontario, Canada.

AIMS: To describe the variation in the delivery of radiation therapy to patients with T1N0 glottic cancer who were diagnosed in Ontario, Canada, between 1982 and 1995. MATERIALS AND METHODS: The patient population consisted of a random sample of 461 patients treated with curative intent from the nine cancer centres that administer radiation therapy in the province. Abstracted variables included prescribed dose (Gy) and fractionation (f), beam energy and arrangement, set-up, field size, beam modifiers, positioning and treatment interruptions. RESULTS: Thirteen prescribed dose-fractionation schemes (> or = four cases each) were identified, including 50.0-53.0 Gy/20 f (54.5%), 55.0-61.0 Gy/25 f (30.3%), and 60.0-66.0 Gy/30-33 f (7.7%). All regimens used one fraction per day, 5 days per week. An isocentric set-up was used (94.3%), with megavoltage (MV) beam energies of Cobalt-60 (87.9%), 6 MV (6.1%) and 4 MV (6.1%). A lateral parallel-opposed pair of beams was the predominant technique (76.4%) versus an anterior oblique pair (17.2%) or angle-down pair (caudally directed fields to achieve shoulder clearance, 5.7%). Wedging (96.3%) and bolus (11.8%) were used as beam-modifying devices. Predominant field-width dimensions were 5.0-6.0 cm (43.4%) and 6.5-7.0 cm (43.1%), and field length dimensions were 5.0-6.0 cm (49.5%) and 6.5-7.0 cm (35.0%). Head, neck or chin immobilisation was used in 86.9% of the cases, with 94.6% of these being custom-made. We found that radiotherapy practice was stable over time, except for a trend of increasing field size and increasing use of immobilisation. In contrast, we found practice variations among the province's cancer centres. On the basis of our findings, we defined a predominant technical practice consisting of Cobalt-60 (reflecting machine availability during the period of the study), an isocentric set-up, a lateral parallel-opposed pair technique with wedging, and supine-head neutral positioning with custom immobilisation. Forty-two per cent of the cases had one or more components of treatment that differed from this definition. CONCLUSIONS: Description of practice variation can provoke discussion about unrecognised differences in practice policies, perhaps identifying the need for better evidence, treatment guidelines, or both.

Relationship between human immunodeficiency virus type 1 (HIV-1)-specific memory cytotoxic T lymphocytes and virus load after recent HIV-1 seroconversion.

Human immunodeficiency virus type 1 (HIV-1)-specific memory, or precursor, cytotoxic T lymphocytes (CTL) in 14 subjects who had recently experienced seroconversion were evaluated with respect to virus set point, defined as plasma HIV-1 RNA level 6 months after seroconversion. Env-, Gag-, Pol-, and Nef-specific precursor CTL were detected in (51)Cr-release assays, using antigen-stimulated peripheral blood mononuclear cells as effectors and B cell lines infected with HIV-1-vaccinia recombinants as targets. All subjects tested had precursor CTL specific to at least 2 HIV-1 antigens. Detection of Env-specific precursor CTL was associated with a high set point (P=.0221). The number of antigens recognized tended to be greater in subjects with higher set points (rho=.45621; P=.1171). Gag-specific precursor CTL frequency correlated inversely with set point (rho=-.8478; P=.0003). Two heterozygotes for a 32-bp deletion in CCR5 had the lowest set points (P=.0220) and highest Gag precursor CTL frequencies (P=.0128). These data suggest that host factors that restrict viral replication may be important determinants of the level of HIV-1-specific precursor CTL.

The role of computed tomography in the T classification of laryngeal carcinoma.

BACKGROUND: The objectives of this study were 1) to describe patterns of use of computed tomography (CT) in laryngeal carcinoma, and 2) to characterize the contribution of CT to the T classification of laryngeal carcinoma. METHODS: The study population comprised 1195 patients with laryngeal carcinoma diagnosed from 1982 through 1995 chosen randomly from the Ontario provincial cancer registry. A chart review was conducted to obtain data on each case. Patient-related, tumor-related, and health-system-related factors were analyzed to identify factors associated with the use of CT. Descriptions of clinical exams and CT reports were reviewed to see how CT information modified T classification. Actuarial local control and cause specific survival curves were plotted by clinical T classification without and with CT to evaluate stage migration. The percentage of the variance in outcome explained by T classification in a Cox analysis was used to evaluate whether the prognostic accuracy of T classification was improved with the use of information from CT. RESULTS: Patients with glottic (20.1%) and supraglottic (41.7%) carcinoma underwent CT. The use of CT increased over time in glottic and supraglottic carcinoma combined from 17.2% in 1982-5 to 33.9% in 1991-5. Computed tomography was used less often in older patients with a 16% (95% confidence interval, 5-27%) decrease in the odds of having CT with each 10-year age increment. Computed tomography use varied considerably across the cancer center regions in Ontario. Computed tomography altered the T classification in 20.2% of those patients who had CT, with most being "upstages." Stage migration due to CT was demonstrated. Using information from CT in the assignment of T classification for 27.8% of this study population did not make a significant contribution to the ability of T classification to predict outcome over the entire group. CONCLUSIONS: There is large variation in the use of CT among different age groups and regions. The ability to compare outcomes by stage across geographic areas is compromised when the use of CT varies.

Glottic cancer in Ontario, Canada and the SEER areas of the United States. Do different management philosophies produce different outcome profiles?

We compared the management and outcome of glottic cancer in Ontario, Canada to that in the Surveillance, Epidemiology and End Results (SEER) Program areas in the United States to determine whether the greater use of primary radiotherapy with surgery reserved for salvage in Ontario was associated with similar survival and better larynx retention rates than the U.S. approach where primary surgery is used more often. Electronic, clinical and hospital data were linked to cancer registry data and supplemented by chart review where necessary. Initial treatment and survival in patients diagnosed in the SEER areas from 1988 through 1994 were compared to patients from Ontario diagnosed from 1982 through 1995. Actuarial laryngectomy rates were compared for patients over 65 at diagnosis in the two regions. Analyses were conducted over all cases and stratified by disease stage. In localized disease (T1 or T2), conservative treatment was the most common initial treatment in both regions, although total laryngectomy was used more often in SEER than Ontario (6.2% vs. 0.2%, respectively, P <.001). In advanced disease (T3 or T4), total laryngectomy was more commonly used as initial treatment in SEER (62.9% vs. 21.0% in Ontario, P < or =.001). Over all cases, the relative survival rate was 80% in Ontario at 5 years compared to 78% in SEER (P =.33). In localized disease, the relative survival rates were 4 to 5% higher in Ontario from the second year on, while in advanced disease 2 to 3% higher rates in SEER did not approach statistical significance. Actuarial laryngectomy rates at 3 years differed between the two regions, with a 4% higher rate in SEER (P =.01). In localized disease, 12.6% of Ontario patients had a laryngectomy by 3 years postdiagnosis compared to 17.9% in SEER (P =.05). In advanced disease, the rates were 63.3% and 79.2%, respectively (P =.07). There are large differences in the management of glottic cancer between the SEER areas of the U.S. and Ontario and no evidence that a policy emphasizing radiotherapy with surgery reserved for salvage is associated with worse survival. Ultimate laryngectomy rates are lower in Ontario for localized disease and may be lower for advanced disease. Conservation treatment should be used for localized disease while the treatment decision in advanced disease may be especially sensitive to patient values for voice retention versus initial cure.

Methods for evaluating the provision of well child care.

BACKGROUND: Well child visits are important for reducing the incidence of avoidable illness and disease. The Omnibus Reconciliation Act of 1989 (OBRA '89) set goals for well child or Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) visits. Many health plans are evaluated in terms of the number of well child visits provided, yet the method used for collecting the data influences the indicator results and conclusions drawn from them. METHODS: In a retrospective cohort design, medical record review and administrative data were compared as methods for ascertaining the number of well child visits received by Iowa Medicaid-eligible children for the period from July 1, 1997 through December 31, 1998. Compliance with the American Academy of Pediatrics' "Recommendations for Preventive Pediatric Health Care" periodicity guidelines was assessed. RESULTS: Using administrative data, 29.6% (n = 1,489) of children received a well child visit. If medical record review was used, 39.6% (n = 1,003) of children had a visit. The concordance between the rates was quite low (kappa = 0.30). Medical record review supported that an EPSDT visit was provided for only 68% of the children who had a claim or encounter billed as providing well child care (n = 441). DISCUSSION: Administrative data may underestimate the performance of EPSDT visits in comparison to medical record review. In addition, having a claim for an EPSDT visit did not necessarily mean the child received the basic components of a well child exam. The methodology for performance indicators used to evaluate health plans should be carefully validated.

Plasmapheresis and immunoadsorption: different techniques and their current role in medical therapy.

In the last 30 years, several studies have documented the effect of plasmapheresis and immunoadsorption in eliminating pathogenic autoantibodies (ABs) and immune complexes (ICs) from circulation. These extracorporeal therapies are still not accepted as first line options, which may be due to existing controlled studies failing to confirm any obvious benefit. Today, indications for plasmapheresis are idiopathic-thrombocytopenic purpura (ITP), thrombotic-thrombocytopenic purpura (TTP), and also cryoglobulinemia during the course of systemic rheumatic diseases and Goodpasture's syndrome. In acute flares and severe organ manifestations, extracorporeal therapies may be helpful as a complement to immunosuppressive therapy. Immunoadsorption offers some advantages compared with plasmapheresis; however, to date only avoidance of substitution fluids has really been used. The new therapeutic options given by immunoadsorbers, that is, a continuous application in acute disease states or chronic use instead of immunosuppressive drugs, have still to be evaluated in systemic autoimmune diseases. Most experiences have used immunoadsorbent columns in the pretransplantation treatment of patients with high panel reactivity and in patients with ITP. Results indicate excellent biocompatibility and a good clinical response. Randomized controlled trials are mandatory to give continued support to the therapeutic opportunities offered only by immunoadsorption; the limited number of patients suitable for this therapy necessitates multicentric cooperation.

Evidence that abscisic acid does not regulate a centralized whole-plant response to low soil-resource availability.

It has been suggested that abscisic acid (ABA) regulates a centralized response of plants to low soil resource availability that is characterized by decreased shoot growth relative to root growth, decreased photosynthesis and stomatal conductance, and decreased plant growth rate. The hypothesis was tested that an ABA-deficient mutant of tomato (flacca; flc) would not exhibit the same pattern of down-regulation of photosynthesis, conductance, leaf area and growth, as well as increased root/shoot partitioning, as its near isogenic wild-type in response to nitrogen or water deficiency, or at least not exhibit these responses to the same degree. Plants were grown from seed in acid-washed sand and exposed to control, nutrient stress, or water stress treatments. Additionally, exogenous ABA was sprayed onto the leaves of a separate group of flc individuals in each treatment. Growth analysis, based on data from frequent harvests of a few individuals, was used to assess the growth and partitioning responses of plants, and gas exchange characteristics were measured on plants throughout the experiment to examine the response of photosynthesis and stomatal conductance. Differences in growth, partitioning and gas exchange variables were found between flc and wild-type individuals, and both nutrient and water treatments caused significant reductions in relative growth rate (RGR) and changes in biomass partitioning. Only the nutrient treatment caused significant reductions in photosynthetic rates. However, flc and wild-type plants responded identically to nutrient and water stress for all but one of the variables measured. The exception was that flc showed a greater decrease in the relative change in leaf area per unit increase of plant biomass (an estimate of the dynamics of leaf area ratio) in response to nutrient stress-a result that is opposite to that predicted by the centralized stress response model. Furthermore, addition of exogenous ABA to flc did not significantly alter any of the responses to nutrient and water stress that we examined. Although it was clear that ABA regulated short-term stomatal responses, we found no evidence to support a pivotal role for ABA, at least absolute amounts of ABA, in regulating a centralized whole-plant response to low soil resource availability.

Evaluating multiple outcomes and gender differences in alcoholism treatment.

This study followed 592 alcoholics (180 women and 412 men) after discharge from inpatient treatment. Multiple measures of treatment outcome were used to broaden our understanding of the process of recovery from alcohol abuse, and how that process differs for men and women. Patients were interviewed by telephone between 3 and 15 months after discharge to gather information about post-treatment experiences including: relationship with family, role performance, psychological impairment, and effort toward recovery. Additionally, if any alcohol use took place after treatment, information was collected about the pattern of alcohol consumption. Results indicated being married is consistently related to less drinking for men, while for women, being married contributes to relapse in the short term. The determinants of each measure of outcome were different for women and men, indicating that the process of recovery is not the same for both genders. The study confirms that drinking is related to other adverse outcomes for men, but not necessarily for women. It is evidence that women and men have different post-treatment functioning, and that different characteristics are predictive of these outcomes.

Functional and morphologic effects of ioxilan, iohexol, and diatrizoate on endothelial cells.

The effects of a new contrast agent, ioxilan, on vascular endothelium were compared with those of iohexol and diatrizoate. Rabbit aortic rings were incubated in contrast medium (CM) (350 mgI/mL) or Krebs solution as a control agent, for 5 minutes. Scanning and transmission electron micrographs showed that iohexol and ioxilan produced irregularities in the cell borders and in some vesicles, whereas diatrizoate produced intercellular gaps and numerous vesicles containing myelin figures. The ability of the endothelial cells to release endothelium-derived relaxing factor was tested by measuring the dilator response to acetylcholine. Incubation of aortic rings in CM for 5 minutes caused no changes in responses. However, 15-minute contact with diatrizoate irreversibly reduced the dilator response to 49%, and contact with sucrose (2100 mOsm/kg) reduced it to 9%. After incubation for 60 minutes, iohexol reduced the dilator response to 43%, while ioxilan caused no change. Since the hydrophilicity of the nonionic compounds, ioxilan and iohexol, is similar, while ioxilan's osmolality is substantially lower, the endothelial changes detected by electron microscopy and induced by the CM are attributable to their chemical properties, whereas the loss of dilator response appears to be mediated by high osmolality.

Vasodilatation and vasoconstriction in the rabbit isolated aorta. Effects of ioxilan, iohexol, and diatrizoate.

The vasomotor effects of contrast media (CM), ioxilan, iohexol, and diatrizoate, and their isoosmotic sucrose solutions as controls, were studied in vitro in rings of thoracic aortas of rabbits. When the osmotic pressure of CM or controls reached the region of 380 mOsm/kg, vasoconstriction developed, reaching a maximum in about 1 hour; it was reversible. It could not be blocked by phentolamine, and therefore did not involve alpha-adrenoceptors. When added to aortic rings precontracted with noradrenaline, all of the CM produced vasodilatation, while reactions to sucrose varied. When endothelium was removed, CM still produced vasodilatation, suggesting a direct chemotoxic effect on smooth muscle. The dilatation effect does not involve the muscarinic receptors, beta-adrenoceptors, or stimulation of prostacyclin synthesis, since the vasodilator response was not blocked by atropine, propranolol, or indomethacin. Blockage of calcium channels did not appear to be a contributing factor. Since the dilator response to all CM was augmented in the presence of the phosphodiesterase inhibitor, iso-butylmethylxanthine (IBMX), it is likely that CM produce vasodilatation chemotoxically by activating the production of a cyclic nucleotide.

The neurotoxicity of tunicamycin.

The neurotoxicity of tunicamycin, an inhibitor of glycosylation of glycoproteins and a potential anti-tumour agent, was investigated by injection of the chemical directly into the lateral ventricle of the brain of rats. A delayed neurological syndrome developed due to anoxic necrosis of brain cells and spongy degeneration of the white matter. In many brains the lesion had the characteristic features of an infarct. Since the predominant lesion was vascular, the action of tunicamycin on blood vessels was investigated in vitro using rabbit aortic rings. In this system the normal relaxation response to acetylcholine in aortic rings pre-contracted with noradrenaline was progressively inhibited as exposure of the ring to tunicamycin increased from 2 h to 5 h. This relaxation response depends on the release of endothelium-derived relaxing factor from endothelial cells. Hence it is proposed that the important primary target in tunicamycin neurotoxicity is endothelial cells of the brain microvessels.

Neurological consequences of magnesium deficiency: correlations with epilepsy.

1. The plasma calcium and magnesium concentrations of sheep have been manipulated by feeding liquid diets with various calcium and magnesium concentrations. 2. When the magnesium status of the diet was low, both plasma calcium and magnesium concentrations declined, but the decline in calcium was much more rapid and extensive when the content of calcium in the diet was also low. This loss of calcium control in magnesium deficiency was attributed to end-organ resistance to parathyroid hormone. 3. Correlation between plasma and CSF calcium and magnesium concentrations indicated that convulsions occurred when CSF magnesium and plasma calcium concentrations declined. 4. The neurological mechanisms likely to be responsible for the induction of these convulsions are discussed and the factors precipitating convulsions in magnesium deficiency and epilepsy are compared.

Quantitation of phosphorus excretion in sheep by compartmental analysis.

The control of phosphorus excretion in sheep has been examined by constructing a kinetic model that contains a mechanistic set of connections between blood and gastrointestinal tract. The model was developed using experimental data from chaff-fed sheep and gives an accurate description of the absorption and excretion of phosphorus in feces and urine of the ruminating sheep. Simulation of the response to an intravenous phosphorus infusion by adding an inflow of 2 g/day of phosphorus into the compartment describing blood, predicted values for fecal output of phosphorus lower than found experimentally. However, by alteration of the parameters describing absorption or salivation, the predictions approached experimental values. Similarly simulation of the conditions existing when a liquid diet was infused directly into the abomasum, i.e., a decrease in salivation rate [L(4.1)] and dietary phosphorus entering compartment 5 (abomasum) instead of compartment 4 (rumen), gave incorrect predictions for plasma and urinary phosphorus, but when the parameter for urinary phosphorus was increased the predicted values approached experimental values. These results indicated the main control site for phosphorus excretion in the ruminating sheep was the gastrointestinal tract, whereas for the nonruminating sheep fed the liquid diet, control was exerted by the kidney. A critical factor in the induction of adaptation of phosphorus reabsorption by the kidney was the reduction in salivation, and since this response occurred independently of marked changes in the delivery of phosphorus to the kidney, a humoral factor may be involved in this communication between salivary gland and kidney.

Effect of 1,25 dihydroxyvitamin D3 on the calcium and magnesium metabolism of lactating cows.

Administration of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) to lactating dairy cows resulted in increased dietary calcium absorption and elevated concentrations of plasma calcium. Dietary magnesium absorption was unaffected by 1,25(OH)2D3 however, plasma magnesium concentration was depressed. Injections of 1,25(OH)2D3 were effective in elevating plasma calcium concentrations in both normal and hypomagnesaemic cows. This indicates a potential use for 1,25(OH)2D3 to prevent and treat hypocalcaemic cows with or without concurrent hypomagnesaemia.

1,25 dihydroxyvitamin D3 increases plasma magnesium and calcium in sheep fed liquid diets low in calcium and magnesium.

Sheep given a liquid diet low in calcium and magnesium by infusion directly into the abomasum developed concurrent hypocalcaemia and hypomagnesaemia, with plasma concentrations of calcium and magnesium decreasing to 2.0 and 0.4 mmol/l respectively. Treatment of these hypomagnesaemic sheep with 1,25 dihydroxyvitamin D3 (1,25(OH)2 D3) increased the plasma calcium, magnesium and phosphorus concentrations with plasma calcium increasing to 2.5 mmol/l and plasma magnesium to 0.6 mmol/l. Plasma magnesium increased despite a small but significant increase in the daily excretion of magnesium in the urine, and the amount of magnesium derived from either bone and/or intestine must have been greater than the amount lost in the urine. Since in other experiments we have demonstrated that plasma calcium remains within the normal range when a liquid diet adequate in magnesium but low in calcium is infused, these results imply that either synthesis of and/or end organ response to 1,25(OH2) D3 is impaired in magnesium deficient sheep.

Segmental colonic duplication presenting as a sigmoid volvulus.

This is a case report of a four-year-old girl who presented with severe intermittent abdominal pain. She had an infra-levator imperforate anus repaired as a newborn. Operation demonstrated duplications of the right and left colons, separated by a normal transverse colon. The left colon duplication was closed at both ends, and it contained 500 cc of intestinal secretions. The sigmoid colon and its duplication volvulized. The terminal ileum was also duplicated; one ileum joining a normal ascending colon duplication, which was patent proximally, but closed distally.

Recurrent chylous ascites associated with intestinal malrotation and lymphatic rupture.

An 11-yr-old female with abdominal distension since birth, underwent four operations because of intractable and debilitating chylous ascites. The curative procedure consisted of preoperative ingestion of the lipophilic dye, a secondary Ladd's procedure, lysis of extensive adhesions, and ligation of an easily identifiable ruptured lymphatic.

Arteriohepatic dysplasia. I. Pitfalls in diagnosis and management.

Differentiating intrahepatic cholestasis from extrahepatic biliary tract obstruction may be difficult. Four patients with intraoperative cholangiographic evidence of extrahepatic ductal atresia who underwent hepatoportoenterostomy are described. All were ultimately shown to have arteriohepatic dysplasia with hypoplastic but patent extrahepatic ductal systems. The difficulty in establishing an accurate diagnosis, hazards associated with hepatoportoenterostomy, and suggestions for evaluation and management are discussed.