Carolyn K. Wells

New Clinical Severity Staging System for Cancer of the Larynx Five-Year Survival Rates

Although statistics for cancer of the larynx are reported according to the tumor, node, metastasis (TNM) morphological staging system, functional clinical distinctions can identify major prognostic differences within the same morphological stage. This study was done to improve the staging system by incorporating pertinent clinical variables. In 193 patients with cancer of the larynx first treated between 1973 and 1985, the total 5-year survival was 66% (127/193). By TNM stage it was I, 78% (60/77); II, 67% (32/48); III, 60% (27/45); and IV, 35% (8/23). In three new functional severity stages that combined symptom severity and comorbidity, the corresponding rates were alpha, 83% (89/107); beta, 58% (34/59); and gamma, 15% (4/27). The functional severity stages could be combined with TNM stages to create a powerful new clinical severity staging system, in which the survival results were A, 88% (53/60); B, 80% (24/30); C, 63% (38/60); and D, 28% (12/43). These results demonstrate that inclusion of clinical variables in a formal staging system can strikingly improve prognostic estimations and classification of patients.

A new prognostic staging system for the acquired immunodeficiency syndrome.

An improved prognostic staging system is needed for patients with the acquired immunodeficiency syndrome (AIDS). To construct such a system, we analyzed the course of 117 consecutive adults who received a diagnosis of AIDS at Yale-New Haven Hospital from 1981 through 1987. The staging system was developed from the data on the first 76 patients, confirmed in the remaining 41 patients, and then applied to the entire cohort. The staging system, which is based on physiologic deficits rather than demographic or diagnostic features, gives one point for each of the following: severe diarrhea or serum albumin level under 2.0 g per deciliter, any neurologic deficit, arterial oxygen tension of 50 mm Hg or less, hematocrit below 30 percent, lymphocyte count below 150 per microliter, white-cell count below 2500, and platelet count below 140,000. The total score determines the presence of Stages I (0 points), II (1 point), or III (2 to 7 points). The three stages had distinctive prognostic gradients in our cohort. For patients in Stages I, II, and III, the median survival times were 11.6, 5.1, and 2.1 months, respectively, with one-year survival rates of 50, 30, and 8 percent. When the staging system was tested with a proportional-hazards model, no other descriptive or laboratory variable added any additional predictive power. Although this new staging system requires further validation in other populations, we believe it will be useful in evaluating new therapies and improving the precision of prognosis in patients with AIDS.

Racial Disparities in Stroke Risk Factors The Impact of Socioeconomic Status

Background and Purpose— In the US, blacks have a higher incidence of stroke and more severe strokes than whites. Our objective was to determine if differences in income, education, and insurance, as well as differences in the prevalence of stroke risk factors, accounted for the association between ethnicity and stroke. Methods— We used data from the Third National Health and Nutrition Survey (NHANES III), a cross-sectional sample of the noninstitutionalized US population (1988–1994), and included blacks and whites aged 40 years or older with a self-reported stroke history. Income was assessed using a ratio of income to US Census Bureau annual poverty threshold. Results— Among 11 163 participants, 2752 (25%) were black and 619 (6%) had a stroke history (blacks: 160/2752 [6%]; whites: 459/8411 [6%]; P=0.48). Blacks had a higher prevalence of 5 risk factors independently associated with stroke: hypertension, treated diabetes, claudication, higher C-reactive protein, and inactivity; whites had a higher prevalence of 3 risk factors: older age, myocardial infarction, and lower high-density lipoprotein cholesterol. Ethnicity was independently associated with stroke after adjusting for the 8 risk factors (adjusted odds ratio, 1.32; 95% CI, 1.04 to 1.67). Ethnicity was not independently associated with stroke after adjustment for income and income was independently associated with stroke (adjusted odds ratios for: ethnicity, 1.15; 95% CI, 0.88 to 1.49; income, 0.89; 95% CI, 0.82 to 0.95). Adjustment for neither education nor insurance altered the ethnicity–stroke association. Conclusions— In this study of community-dwelling stroke survivors, ethnic differences exist in the prevalence of stroke risk factors and income may explain the association between ethnicity and stroke.

Cancer of the larynx: a new staging system and a re-appraisal of prognosis and treatment.

Abstract In an inception cohort of 192 patients with carcinoma of the larynx, we have examined the prognostic role of the diverse clinical manifestations that were present before the first therapeutic decision. Subsequent survival was found to be most prominently related to the types of symptoms, anatomic topography, and associated major co-morbid ailments. These symptomatic, anatomic, and co-morbid aspects of classification were combined to form a new composite 4-category staging system that produces a more quantitatively distinctive prognostic gradient than the conventional TNM anatomic arrangements. The Composite S-A-C Stage Delta is demarcated by either extra-laryngeal anatomic spread or major co-morbidity or both. The remaining three stages depend on symptomatic patterns. S-A-C Stage Gamma contains patients with pharyngo-esophageal or ‘external’ symptoms. S-A-C Stage Beta is demarcated by respiratory, systemic, or regionally ‘referred’ symptoms. S-A-C Stage Alpha is reserved for patients with only local or cord symptoms. The 5-yr survival rates, regardless of therapy, in the four stages were: Alpha , 36 41 (88%); Beta , 35 58 (60%); Gamma , 17 39 (44%) and Delta , 8 54 (15%) . Although the S-A-C stages produced important prognostic gradients within the same TNM stage, survival rates within the same S-A-C stage were not substantially affected by differences either in TNM stage or in the duration of symptoms before treatment. In addition to showing distinctive trends in the rates of subsequent metastasis and deaths due to cancer, the S-A-C stages were associated with a prognostic gradient for other forms of death, due to non-neoplastic disease. The choice of treatment was related to the S-A-C stage in which a patient was encountered. Surgery was selected most often for patients in stages Beta and Gamma, whereas radiotherapy was chosen most often for the Alpha and Delta stages. Within the Alpha and Beta S-A-C stages, the outcomes of radiotherapy seemed at least as successful as those of surgery; but in stages Gamma and Delta, surgery seemed superior to radio-therapy. These analyses indicate that careful history taking and attention to the patients total clinical state provide crucial data for estimating prognosis and evaluating treatment in patients with laryngeal cancer.

Processes of Care Associated With Acute Stroke Outcomes

BACKGROUND Many processes of care have been proposed as metrics to evaluate stroke care. We sought to identify processes of stroke care that are associated with improved patient outcomes after adjustment for both patient characteristics and other process measures. METHODS This retrospective cohort study included patients 18 years or older with an ischemic stroke or transient ischemic attack (TIA) onset no more than 2 days before admission and a neurologic deficit on admission. Patients were excluded if they resided in a skilled nursing facility, were already admitted to the hospital at stroke onset, or were transferred from another acute-care facility. The combined outcome included in-hospital mortality, discharge to hospice, or discharge to a skilled nursing facility. Seven processes of stroke care were evaluated: fever management, hypoxia management, blood pressure management, neurologic evaluation, swallowing evaluation, deep vein thrombosis (DVT) prophylaxis, and early mobilization. Risk adjustment included age, comorbidity (medical history), concomitant medical illness present at admission, preadmission symptom course, prestroke functional status, code status, stroke severity, nonneurologic status, modified APACHE (Acute Physiology and Chronic Health Evaluation) III score, and admission brain imaging findings. RESULTS Among 1487 patients, the outcome was observed in 239 (16%). Three processes of care were independently associated with an improvement in the outcome after adjustment: swallowing evaluation (adjusted odds ratio [OR], 0.64; 95% confidence interval [CI], 0.43-0.94); DVT prophylaxis (adjusted OR, 0.60; 95% CI, 0.37-0.96); and treating all episodes of hypoxia with supplemental oxygen (adjusted OR, 0.26; 95% CI, 0.09-0.73). CONCLUSION Outcomes among patients with ischemic stroke or TIA can be improved by attention to swallowing function, DVT prophylaxis, and treatment of hypoxia.

Molecular Markers and Death From Prostate Cancer

Context Whether molecular markers distinguish indolent from aggressive prostate cancer is unclear. Contribution This observational study of U.S. veterans found that markers of cell cycle regulation (bcl-2 and p53) and high microvessel density in biopsy specimens obtained at diagnosis were associated with increased risk for death from prostate cancer. Caution Some factors that might affect prognosis, such as family history, other molecular markers, and prostate-specific antigen velocity, were not assessed. Implication We need studies assessing whether molecular features that are associated with increased risk for death from prostate cancer are clinically useful in distinguishing patients who might and might not benefit from particular therapies. The Editors The spectrum of severity in prostate cancer is highly variable, ranging from indolent to aggressive. Some men with prostate cancer have longevity similar to the general population, whereas others develop metastatic disease that can lead to death within months (13). Clinicians have limited ability to estimate survival in patients with newly diagnosed prostate cancer, and uncertainty therefore exists about optimal treatment decisions (4), especially for men with localized disease. Current clinical strategies (5) for evaluating prognosis in prostate cancer at the time of diagnosis include determining anatomical extent, histologic grade (Gleason score), and serum levels of prostate-specific antigen (PSA). As a novel approach, molecular featuressuch as markers of cell cycle regulation and blood vessel formationare potentially relevant prognostic factors. A recent review (6) reported that abnormal expression of various molecular markers is related to increasing stage and grade of prostate cancer but may or may not influence long-term health outcomes. We sought to examine whether selected molecular factors are independently associated with death in men with prostate cancer. In particular, abnormal markers involved in apoptosis, tumor suppression, and angiogenesis may indicate poor prognosis. To evaluate this hypothesis, we identified a sample of men with prostate cancer; reviewed medical records to account for pertinent clinical characteristics of patients and their tumors; examined tissue obtained at the time of diagnosis for evidence of molecular markers; and measured long-term, cause-specific, and all-cause mortality. Methods Study Sample The source sample included all 64545 male veterans who were receiving ambulatory care linked to 9 Veterans Affairs (VA) medical centers in New England as of 1 January 1991. The institutional review board at each institution approved the research protocol with a waiver of informed consent. Pathology registries identified 1313 men with incident prostate cancer diagnosed from 1991 to 1995 (Figure 1). Medical records were unavailable (after at least 3 requests) for 16 (1.2%) men and were inadequate for 27 (2.1%) men (for example, missing entire sections). We collected data on candidate prognostic variables among the remaining 1270 men by using strategies for prognostic studies (7). Figure 1. Study flow diagram. Data Collection We analyzed 3 sources of data: paper and electronic medical records, immunohistochemical staining of prostatic tissue from which the initial diagnosis of cancer was made, and determination of vital status according to national databases. We first obtained clinical data before primary treatment (designated as zero-time [7]) through a comprehensive medical record review by using a standardized extraction form adapted from a previous study (8). We recorded each mans age (years), race (black or other), and comorbid condition (Charlson comorbidity index [9]). We recorded the anatomical extent (clinical stage) and histologic grade (Gleason score) of cancer on the basis of classification systems in use at the time. We also documented PSA levels and cancer-related symptoms (8). We always found certain factors, such as age, in the medical record. Other factors, such as at least 2 PSA tests before diagnosis (to calculate PSA velocity), were sometimes not available. Although our study was not designed to assess the effect of therapy, we coded initial treatment as surgery (prostatectomy), radiation therapy (nonadjuvant), hormone ablation, watchful waiting, or none. We also requested diagnostic tissue blocks and slides for the men: 1149 (90.5%) from needle biopsies, 114 (9.0%) from transurethral resections of the prostate, 6 (0.5%) from prostatectomies for presumed benign disease, and 1 (0.1%) from a metastatic lesion. After confirming the presence of a tumor, our institutional pathology laboratory did immunohistochemical staining by using indirect immunoperoxidase methods with antibodies against selected factors and by blocking nonspecific staining (10). We evaluated the tissue for bcl-2 (11), an apoptosis-related molecule (dilution, 1:160; Dako, Carpinteria, California); p53 (12), a tumor-suppressor oncogene (dilution, 1:3000; Dako); -3 integrin (13) (measured as CD-61), an adhesion molecule implicated in tumor invasion and angiogenesis (dilution, 1:40; Vector Laboratories, Burlingame, California); and soluble vascular endothelial growth factor (14), an angiogenic cytokine (dilution, 1:1; BioGenex, San Ramon, California). We recorded intensities of staining in areas of carcinoma on a scale from 0 to 3. In addition, we evaluated microvessel density (15) as a manifestation of tumor angiogenesis by using antibodies to factor VIII (dilution, 1:4000; Dako) in a more labor-intensive process of counting the number of antigen-stained blood vessel cross-sections seen on high-powered magnification (original magnification,400). A pathologist blinded to patient outcome did all of the readings. We assessed the vital status of each patient by using the VA Patient Treatment File, the VA Beneficiary Identifier Locator System (16), and the National Death Index (17). Death from prostate cancer was determined while investigators were blinded to marker status through posttreatment medical record review and consensus decision (8). A censoring date of 31 December 2006 provided an 11- to 16-year range of potential follow-up after zero-time for each patient. Statistical Analysis On the basis of earlier work (8), we expected to identify as many as 1350 men with prostate cancer and observe an overall annual survival rate of 93%. For a type I error of 5%, 80% power, and at least an 8-year follow-up, we calculated the minimum detectable relative risks as 1.20, 1.17, 1.16, and 1.15 for a prevalence of molecular markers equal to 20%, 30%, 40%, and 50%, respectively. In addition, for as many as 13 variables (7 baseline + treatment + 5 markers) in a multivariable analysis, and based on an established criterion (18, 19) of at least 10 outcome events per independent variable, the anticipated number of deaths would exceed the suggested minimum threshold (1310= 130). Analyses of clinical data used a complete case approach for 1172 (among 1270) men with no missing information for any factor. We calculated descriptive results as percentages or median values and interquartile ranges. A category of too small to grade was used for molecular markers if only a single microscopic focus of cancer was found; molecular data were coded as not available if technical problems occurred. Molecular markers that did not yield any usable staining after 50 specimens were abandoned. By using proportional hazards regression analysis, we first assessed traditional patient- and tumor-related characteristics for their association with death from prostate cancer. We subsequently used another multivariable proportional hazards model to evaluate the independent association of novel molecular markers with the same outcome, adjusting for the traditional prognostic factors. We also examined death from any cause as an outcome variable, and we included treatment as an adjustment variable in a sensitivity analysis (using death from prostate cancer). In post hoc exploratory analyses, we assessed results on the basis of a validated system (20) for classifying low-, intermediate-, and high-risk groups according to combinations of clinical stage, Gleason score, and PSA level. We assessed key variables for interobserver variability in a 10% sample of medical records and intraobserver variability in a 10% sample of immunohistochemical stains. We did analyses by using SAS, version 9.1 (SAS, Cary, North Carolina). Role of the Funding Source The Office of Research and Development in the Veterans Health Administration funded the study. The funding source had no role in the study design, data collection, data analysis, data interpretation, or decision to submit the manuscript for publication. Results Baseline Factors Table 1 shows the characteristics of 1172 men with a prostate cancer diagnosis from 1991 to 1995. The median age at diagnosis was 72 years; 127 men (11%) were black, 672 (57%) had no or mild comorbid conditions, 1040 (89%) had clinically localized cancer, and 711 (61%) had moderately differentiated tumors (Gleason score, 5 to 7); and the median PSA level was 10.0 g/L. Initial treatment included prostatectomy or radiation therapy in 632 (54%) men, hormonal ablation in 215 (18%) men, and watchful waiting or no treatment in 325 (28%) men. Among the latter group, 106 (33%) subsequently received therapy. The statistics for concordance (21) were 0.77 for comorbid conditions, 0.92 for histologic grade, and 0.80 for immunohistochemical readings. Table 1. Characteristics of Men With Prostate Cancer Table 1 also shows results of the immunohistochemical analyses. Positive staining was found for bcl-2 in 67 (6%) and p53 in 245 (21%) specimens; coding of any or no staining was used in analyses of these factors because of low observed prevalence. Quartiles of vessels per high-powered field were used to code microvessel density. No positive staining in areas of carcinoma was seen for CD-61. Although

Derivation and Validation of a Clinical System for Predicting Pneumonia in Acute Stroke

Aims: We derived and validated a clinical prediction rule that can be used to predict post-stroke pneumonia. Methods: We conducted a retrospective cohort study of patients admitted to hospital with a stroke. The cohort was subdivided into a derivation group and a validation group. Within the derivation group, a point scoring system was developed to predict pneumonia based on a logistic regression model. The point scoring system was then tested within the validation group. Results: Of the 1,363 patients with stroke, 10.5% of patients experienced new pneumonia. The most points were assigned for abnormal swallowing result and history of pneumonia (4 points), followed by greater NIHSS score (3 points), patient being ‘found down’ at symptom onset (3 points), and age >70 years (2 points). A 3-level classification system was created denoting low, medium and high risks of pneumonia, which accurately predicted pneumonia in the validation group. The discriminatory accuracy of the 3-level clinical prediction rule exceeded the acceptable range in both the derivation group (c statistic: 0.78) and validation group (c statistic: 0.76). Conclusion: A simple scoring system was derived and validated. This clinical scoring system may better identify stroke patients who are at high risk of developing new pneumonia.

Prediction of bile duct stones and complications in gallstone pancreatitis using early laboratory trends.

OBJECTIVES: We aimed to determine whether early trends in the serum pancreatic enzymes and liver tests of patients with gallstone pancreatitis predict persistent common bile duct (CBD) stones and complications. METHODS: Medical records of patients with gallstone pancreatitis were reviewed retrospectively. Serial serum pancreatic enzymes and liver tests were recorded until the time of cholangiography. Laboratory trends were analyzed by comparing initial results obtained in the emergency department to subsequent results obtained 8-24 h, 24-48 h, and 48-72 h after presentation. RESULTS: Of 154 patients with gallstone pancreatitis, 28 (18%) had persistent CBD stones at cholangiography. Complications and death were more frequent in patients with persistent CBD stones than in those without CBD stones (29% and 11% vs 12% and 1%, respectively; p < 0.05). Laboratory trends predicted both persistent CBD stones and complications of pancreatitis. When any laboratory value rose between admission and 24-48 h of hospitalization, persistent CBD stones were present in 31% of cases, versus 8% of those in whom all laboratory values remained constant or fell (p = 0.001). Likewise, complications occurred in 21% of those with any rising laboratory value, versus 8% of those in whom all values remained constant or fell (p < 0.05). CONCLUSIONS: Patients with gallstone pancreatitis and rising serum chemistries had a 4-fold risk of persistent CBD stones and a nearly 3-fold risk of complications compared to patients in whom all chemistry values remained constant or fell. This simple prediction rule may identify patients with biliary pancreatitis who are most likely to benefit from early interventions to diagnose and remove persistent CBD stones.

A Quality-of-Life Instrument for Young Hemorrhagic Stroke Patients

Background and Purpose— Hemorrhagic stroke has a high initial mortality rate. While survivors often recover motor function, many experience significant changes in their quality of life (QOL). Available outcome measures assess neurological impairment, disability, or handicap, yet often inadequately characterize the full impact of a stroke on patients’ lives. In this study, we develop and validate a QOL instrument specific for young patients with hemorrhagic strokes. Methods— Methodological guidelines for instrument development were initially established. Based on the content of 40 open-ended patient interviews, a 54-item instrument (HSQuale) was developed. The reliability (test-retest and internal consistency) and validity (content and construct) of HSQuale were assessed in another 71 patients (18 to 49 years of age, 63% women, 77% white), at 1 year after their hemorrhagic stroke. Comparisons were made between HSQuale and other commonly used outcome measures. Results— HSQuale demonstrated reproducibility (test-retest &kgr;, 0.40 to 0.96) and internal consistency (Cronbach &agr; ≥0.80 for 5 of 7 domains). HSQuale scores had broad frequency distributions (≤33% of subjects scored in any single score decile), avoided ceiling effects found for other outcome measures (Barthel Index and Short Form-36), and discriminated among clinically distinct subject groups (eg, intracerebral versus subarachnoid hemorrhage patients). Conclusions— HSQuale is a reliable and valid QOL instrument. Compared with other outcome measures, it assesses a broader range of deficits and is better able to discriminate among subgroups of hemorrhagic stroke survivors.

A comparison of multivariable mathematical methods for predicting survival--II. Statistical selection of prognostic variables.

Abstract The introductory abstract for Parts I–III in this series appears at the beginning of Part I. The concluding summary appears at the end of Part III.