The Prognostic Importance of Bronchoalveolar Lavage Fluid CXCL9 During Minimal Acute Rejection on the Risk of Chronic Lung Allograft Dysfunction.

The clinical significance and treatment strategies for minimal acute rejection (grade A1), the most common form of acute rejection (AR), remain controversial. In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between minimal AR and chronic lung allograft dysfunction (CLAD) and test a novel hypothesis using bronchoalveolar lavage (BAL) CXCL9 concentration during minimal AR as a biomarker of subsequent CLAD development. In univariable and multivariable models adjusted for all histopathologic injury patterns, minimal AR was not associated with CLAD development. However, minimal AR with elevated BAL CXCL9 concentrations markedly increased CLAD risk in a dose-response manner. Minimal AR with CXCL9 concentrations greater than the 25th, 50th, and 75th percentile had adjusted hazard ratios (HRs) for CLAD of 1.1 (95% confidence interval [CI] 0.8-1.6), 1.6 (95% CI 1.1-2.3), and 2.2 (95% CI 1.4-3.4), respectively. Thus we demonstrate the utility of BAL CXCL9 measurement as a prognostic biomarker that allows discrimination of recipients at increased risk of CLAD development after minimal AR. BAL CXCL9 measurement during transbronchial biopsies may provide clinically useful prognostic data and guide treatment decisions for this common form of AR, as a possible strategy to minimize CLAD development.

Impact of Allograft Injury Time of Onset on the Development of Chronic Lung Allograft Dysfunction After Lung Transplantation.

The impact of allograft injury time of onset on the risk of chronic lung allograft dysfunction (CLAD) remains unknown. We hypothesized that episodes of late-onset (≥6 months) allograft injury would produce an augmented CXCR3/ligand immune response, leading to increased CLAD. In a retrospective single-center study, 1894 transbronchial biopsy samples from 441 lung transplant recipients were reviewed for the presence of acute rejection (AR), lymphocytic bronchiolitis (LB), diffuse alveolar damage (DAD), and organizing pneumonia (OP). The association between the time of onset of each injury pattern and CLAD was assessed by using multivariable Cox models with time-dependent covariates. Bronchoalveolar lavage (BAL) CXCR3 ligand concentrations were compared between early- and late-onset injury patterns using linear mixed-effects models. Late-onset DAD and OP were strongly associated with CLAD: adjusted hazard ratio 2.8 (95% confidence interval 1.5-5.3) and 2.0 (1.1-3.4), respectively. The early-onset form of these injury patterns did not increase CLAD risk. Late-onset LB and acute rejection (AR) predicted CLAD in univariable models but lost significance after multivariable adjustment for late DAD and OP. AR was the only early-onset injury pattern associated with CLAD development. Elevated BAL CXCR3 ligand concentrations during late-onset allograft injury parallel the increase in CLAD risk and support our hypothesis that late allograft injuries result in a more profound CXCR3/ligand immune response.

The Role of TGF-ß in the Association Between Primary Graft Dysfunction and Bronchiolitis Obliterans Syndrome.

Primary graft dysfunction (PGD) is a possible risk factor for bronchiolitis obliterans syndrome (BOS) following lung transplantation; however, the mechanism for any such association is poorly understood. Based on the association of TGF-ß with acute and chronic inflammatory disorders, we hypothesized that it might play a role in the continuum between PGD and BOS. Thus, the association between PGD and BOS was assessed in a single-center cohort of lung transplant recipients. Bronchoalveolar lavage fluid concentrations of TGF-ß and procollagen collected within 24 h of transplantation were compared across the spectrum of PGD, and incorporated into Cox models of BOS. Immunohistochemistry localized expression of TGF-ß and its receptor in early lung biopsies posttransplant. We found an association between PGD and BOS in both bilateral and single lung recipients with a hazard ratio of 3.07 (95% CI 1.76-5.38) for the most severe form of PGD. TGF-ß and procollagen concentrations were elevated during PGD (p < 0.01), and associated with increased rates of BOS. Expression of TGF-ß and its receptor localized to allograft infiltrating mononuclear and stromal cells, and the airway epithelium. These findings validate the association between PGD and the subsequent development of BOS, and suggest that this association may be mediated by receptor/TGF-ß biology.

Multicenter Selective Lymphadenectomy Trial-I confirms the central role of sentinel node biopsy in contemporary melanoma management: response to 'No survival benefit for patients with melanoma undergoing sentinel lymph node biopsy: critical appraisal of the Multicenter Selective Lymphadenectomy Trial-I final report'.

Sentinel lymph node (SLN) biopsy has become a standard procedure for many patients with melanoma and is recommended in numerous national and professional melanoma guidelines. The Multicenter Selective Lymphadenectomy Trial (MSLT-1) confirms earlier large database studies and prospective clinical trials in demonstrating the independent and unequalled prognostic value of the SLN. It also demonstrates the ability of biopsy-directed management to provide effective regional disease control with the least possible morbidity. These benefits are not in question and provide ample justification for the procedure, even without evidence of a survival benefit. However, MSLT-1 also provides strong evidence of a substantial reduction in the risk of melanoma death for patients with intermediate thickness melanomas who harbour occult nodal metastases at the time of presentation. Denying appropriately selected patients with melanoma the opportunity to undergo SLN biopsy is no longer reasonable or acceptable.

Colonization with small conidia Aspergillus species is associated with bronchiolitis obliterans syndrome: a two-center validation study.

Aspergillus colonization after lung transplantation may increase the risk for bronchiolitis obliterans syndrome (BOS), a disease of small airways. We hypothesized that colonization with small conidia Aspergillus species would be associated with a greater risk of BOS, based upon an increased likelihood of deposition in small airways. We studied adult primary lung recipients from two large centers; 298 recipients at University of California, Los Angeles and 482 recipients at Duke University Medical Center. We grouped Aspergillus species by conidia diameter≤3.5 µm. We assessed the relationship of colonization with outcomes in Cox models. Pre-BOS colonization with small conidia Aspergillus species, but not large, was a risk factor for BOS (p=0.002, HR 1.44, 95% CI 1.14-1.82), along with acute rejection, single lung and Pseudomonas. Colonization with small conidia species also associated with risk of death (p=0.03, HR 1.30, 95% CI 1.03-1.64). Although other virulence traits besides conidia size may be important, we have demonstrated in two large independent cohorts that colonization with small conidia Aspergillus species increases the risk of BOS and death. Prospective evaluation of strategies to prevent Aspergillus colonization of small airways is warranted, with the goal of preserving lung allograft function as long as possible.

CXCR3 chemokine ligands during respiratory viral infections predict lung allograft dysfunction.

Community-acquired respiratory viruses (CARV) can accelerate the development of lung allograft dysfunction, but the immunologic mechanisms are poorly understood. The chemokine receptor CXCR3 and its chemokine ligands, CXCL9, CXCL10 and CXCL11 have roles in the immune response to viruses and in the pathogenesis of bronchiolitis obliterans syndrome, the predominant manifestation of chronic lung allograft rejection. We explored the impact of CARV infection on CXCR3/ligand biology and explored the use of CXCR3 chemokines as biomarkers for subsequent lung allograft dysfunction. Seventeen lung transplant recipients with CARV infection had bronchoalveolar lavage fluid (BALF) available for analysis. For comparison, we included 34 BALF specimens (2 for each CARV case) that were negative for infection and collected at a duration posttransplant similar to a CARV case. The concentration of each CXCR3 chemokine was increased during CARV infection. Among CARV infected patients, a high BALF concentration of either CXCL10 or CXCL11 was predictive of a greater decline in forced expiratory volume in 1 s, 6 months later. CXCR3 chemokine concentrations provide prognostic information and this may have important implications for the development of novel treatment strategies to modify outcomes after CARV infection.

Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.

Multiple infections have been linked with the development of bronchiolitis obliterans syndrome (BOS) post-lung transplantation. Lung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We hypothesized that Aspergillus colonization may promote the development of BOS and may decrease survival post-lung transplantation. We reviewed all lung transplant recipients transplanted in our center between January 2000 and June 2006. Bronchoscopy was performed according to a surveillance protocol and when clinically indicated. Aspergillus colonization was defined as a positive culture from bronchoalveolar lavage or two sputum cultures positive for the same Aspergillus species, in the absence of invasive pulmonary Aspergillosis. We found that Aspergillus colonization was strongly associated with BOS and BOS related mortality in Cox regression analyses. Aspergillus colonization typically preceded the development of BOS by a median of 261 days (95% CI 87-520). Furthermore, in a multivariate Cox regression model, Aspergillus colonization was a distinct risk factor for BOS, independent of acute rejection. These data suggest a potential causative role for Aspergillus colonization in the development of BOS post-lung transplantation and raise the possibility that strategies aimed to prevent Aspergillus colonization may help delay or reduce the incidence of BOS.

CXCR3 ligands are augmented during the pathogenesis of pulmonary sarcoidosis.

We and other investigators have hypothesised that the CXC chemokine receptor (CXCR)3/CXCR3 ligand biological axis is involved in the formation of sarcoid lung granulomas; however, significant discrepancies in the current literature remain. In an effort to clarify previous conflicting findings, we performed the largest observational study to date of interferon-inducible ELR(-) (lacking the sequence glutamic acid-leucine-arginine) CXC chemokines in sarcoid bronchoalveolar fluid (BALF). BALF chemokine levels from sarcoid patients (n = 72) and healthy controls (n = 8) were measured with the ELISA method. Immunohistochemical staining was performed for CXCR3 and its ligands. BALF CXC chemokine ligand (CXCL)10 levels from sarcoid patients were not significantly increased compared with controls. BALF CXCL11 levels from sarcoid patients demonstrated a trend towards elevation; subgroup analysis by stage showed significant BALF CXCL11 elevation in stage I sarcoid patients compared with controls. BALF CXCL9 levels were elevated from sarcoid patients compared with controls. CXC11, CXCL9 and CXCR3 were expressed from epithelioid histiocytes, multinucleated giant cells and other inflammatory cells forming sarcoid lung granulomas. Our data suggest that CXCL9 and CXCL11 are important mediators in recruiting CXCR3-expressing cells. Importantly, we have made the novel observation that both lymphocytes and cells of monocyte linage express CXCR3 and are involved in the formation of sarcoid lung granulomas.

Altered levels of CC chemokines during pulmonary CMV predict BOS and mortality post-lung transplantation.

Pulmonary CMV infection (CMVI) and disease (CMVD) is associated with reduced long-term survival post-lung transplantation, however, the specific biologic mechanisms remain unclear. We have demonstrated a role of CC chemokines during lung allograft dysfunction. Based on these findings, we hypothesized that pulmonary CMV upregulates the expression of multiple CC chemokines that leads to allograft dysfunction and decreased long-term survival. We performed a nested case control study in lung transplant recipients to investigate alterations in CC chemokine biology during pulmonary CMV. Levels of CC chemokines were measured in bronchoalveolar lavage fluid (BALF) from recipients with CMVI (n = 33), CMVD (n = 6), and in healthy lung transplant controls (n = 33). We found a trend toward increased levels of MIP-1alpha/CCL3 during pulmonary CMVI. Levels of MCP-1/CCL2 and RANTES/CCL5 were significantly elevated during pulmonary CMV. Interestingly, elevated levels of CCL3 in BALF were protective with regards to survival. Importantly, elevated levels of CCL2 in BALF predicted the development of BOS, while elevated levels of CCL5 in BALF predicted an increase in mortality post-lung transplant. Altered levels of specific CC chemokines during pulmonary CMV are associated with future clinical outcomes. These results suggest a possible utility of BALF CC chemokines as biomarkers for guiding risk assessment during pulmonary CMV post-lung transplantation.

Effects of leptin replacement on macro- and micronutrient preferences.

BACKGROUND: The mechanisms underlying food choices are complex and involve neuroendocrine and biochemical signaling. Among neuroendocrine signals, leptin may play a prominent role in food preference. OBJECTIVE: This study was designed to obtain an understanding of the effects of leptin replacement on macro- and micronutrient preferences in leptin-deficient adults. DESIGN: We studied the effects of leptin replacement on three adults with genetic leptin deficiency during the initial 12 months of treatment. Dietary intake was measured in our study by weighed food consumption records. Nutrient intake was calculated using a nutrition analysis software. RESULTS: After leptin replacement was started, all patients had initially a marked reduction in food intake. The reduction in caloric intake differentially affected intake of macro- and micronutrients. There was an initial shift toward a higher percentage consumption of fats and a decrease in the intake of carbohydrates. Significant differences also occurred in 7 distinct types of macronutrients, 12 vitamins, 11 minerals and 1 amino acid. CONCLUSIONS: We documented several specific leptin-induced changes in macro- and micronutrients intake during the course of leptin-replacement treatment, the majority of which were not related to the decrease in total caloric consumption.

Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans.

Leptin signals the status of energy reserves to the brain. Leptin stimulates biosynthesis of TRH in vitro and influences the activity of the hypothalamic-pituitary-thyroid axis in vivo in rodents. Because blood levels of both leptin and TSH display diurnal variation with a distinct nocturnal rise, we sought to determine whether a relationship exists between fluctuations in circulating leptin and TSH. We measured serum leptin and TSH levels every 7 min for 24 h in five healthy men and found that both leptin and TSH levels are highly organized and pulsatile. A similar pattern of leptin and TSH rhythms was observed, with TSH and leptin levels reaching a nadir in late morning and a peak in the early morning hours. Importantly, cosinor analysis on the absolute leptin and TSH levels revealed a statistically significant fit for a 24-h period and the two hormones showed similar probabilities of rhythm and superimposable peak values. Furthermore, this study shows a strong positive Pearson correlation between the 24-h patterns of variability of leptin and TSH in healthy subjects. Finally, the ultradian fluctuations in leptin levels showed pattern synchrony with those of TSH as determined by cross-correlation analysis, by cross-approximate enthropy and Bayessian analysis applied independently. To further explore whether these associations could reflect an underlying regulation of TSH secretion by leptin, we also studied frequently sampled leptin and TSH levels in four brothers, members of a family with leptin deficiency (one normal homozygote, two heterozygotes, and one leptin-deficient homozygote). Leptin levels of the homozygous leptin-deficient subject are detectable but bioinactive, and the rhythm of his TSH is disorganized. 24-h pattern of leptin and TSH variability in the heterozygous subjects, although significantly correlated, showed a weaker correlation compared with the strong correlation in the normal subjects. These data are consistent with the possibility that leptin may regulate TSH pulsatility and circadian rhythmicity, but interventional studies are needed to definitively prove whether leptin regulates the minute-to-minute oscillations and ultradian rhythm of TSH levels.

CancerVax, an allogeneic tumor cell vaccine, induces specific humoral and cellular immune responses in advanced colon cancer.

BACKGROUND: The immunogenicity of the polyvalent tumor cell vaccine CancerVax has been correlated with the survival of patients receiving active immunotherapy for melanoma. Because the various antigens expressed on the vaccine are common to colon adenocarcinoma cells, we examined the survival impact of immune responses elicited by CancerVax in patients with advanced colon cancer refractory to standard therapy. METHODS: Twenty-seven patients with American Joint Committee on Cancer (AJCC) stage IV colorectal adenocarcinoma were entered prospectively into the study. CancerVax was coadministered with bacille Calmette-Guerin (BCG) for the first 2 weeks of vaccine treatment. Blood was drawn at the start of therapy and every 2 weeks thereafter to measure serum titers of immunoglobulin (Ig)G and IgM against TA90 (a 90-kD immunogen common to colon cancer and CancerVax cells) and against purified protein derivative (PPD), a nontumor control antigen. Cellular immune responses were evaluated by delayed-type hypersensitivity (DTH) reaction to vaccine cells and to PPD. Mean follow-up time was 17.5 months. RESULTS: There was a significant (P = .0001) increase in anti-TA90 IgG and IgM titers and in DTH response to vaccine cells. Humoral and skin responses to TA90 did not correlate with responses to PPD (P = .199 for IgM, P = .958 for IgG, and P = .149 for DTH). This suggests that these responses are not a manifestation of general immune competence. The median overall survival (OS) was 21.9 months for the entire group. Overall survival was higher among patients whose IgMTA90 titer was >800 (P = .003) or whose disease-free interval exceeded 12 months (P = .031). Multivariate Cox regression analysis-using age, sex, disease-free interval, disease status, extent of metastasis, humoral responses, and DTH responses-found only peak IgMTA90 titer to be a significant predictor of overall survival (P = .0365). CONCLUSIONS: CancerVax can induce measurable humoral and cellular immune responses to tumor-associated antigens in patients with advanced-stage colon cancer. These responses correlate with overall survival. This novel therapeutic regimen for patients with advanced colon cancer merits further investigation.

Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.

BACKGROUND: Cardiovascular disease is common in older adults with end-stage renal disease who are undergoing regular dialysis, but little is known about the prevalence and extent of cardiovascular disease in children and young adults with end-stage renal disease. METHODS: We used electron-beam computed tomography (CT) to screen for coronary-artery calcification in 39 young patients with end-stage renal disease who were undergoing dialysis (mean [+/-SD] age, 19+/-7 years; range, 7 to 30) and 60 normal subjects 20 to 30 years of age. In those with evidence of calcification on CT scanning, we determined its extent. The results were correlated with the patients' clinical characteristics, serum calcium and phosphorus concentrations, and other biochemical variables. RESULTS: None of the 23 patients who were younger than 20 years of age had evidence of coronary-artery calcification, but it was present in 14 of the 16 patients who were 20 to 30 years old. Among those with calcification, the mean calcification score was 1157+/-1996, and the median score was 297. By contrast, only 3 of the 60 normal subjects had calcification. As compared with the patients without coronary-artery calcification, those with calcification were older (26+/-3 vs. 15+/-5 years, P<0.001) and had been undergoing dialysis for a longer period (14+/-5 vs. 4+/-4 years, P< 0.001). The mean serum phosphorus concentration, the mean calcium-phosphorus ion product in serum, and the daily intake of calcium were higher among the patients with coronary-artery calcification. Among 10 patients with calcification who underwent follow-up CT scanning, the calcification score nearly doubled (from 125+/-104 to 249+/-216, P=0.02) over a mean period of 20+/-3 months. CONCLUSIONS: Coronary-artery calcification is common and progressive in young adults with end-stage renal disease who are undergoing dialysis.

Disenrollment from an HMO and its relationship with the characteristics of Medicare beneficiaries.

To examine the relationship between Medicare beneficiaries' characteristics and disenrollment, a longitudinal study was conducted in an HMO in California. Approximately 10 percent of the Medicare beneficiaries disenrolled within the first year of enrollment. There was no difference between those who continuously enrolled and those who disenrolled in terms of age, gender, mental and physical health status, previous utilization, and anticipated utilization in the coming year. However, people with limited social activities and people not living in a single-family house were more likely to disenroll. The authors also examined the disenrollment rates among physicians groups. The rates were significantly different.

Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement.

BACKGROUND: We examined the cholesterol-lowering effects of a proprietary Chinese red-yeast-rice supplement in an American population consuming a diet similar to the American Heart Association Step I diet using a double-blind, placebo-controlled, prospectively randomized 12-wk controlled trial at a university research center. OBJECTIVE: We evaluated the lipid-lowering effects of this red-yeast-rice dietary supplement in US adults separate from effects of diet alone. DESIGN: Eighty-three healthy subjects (46 men and 37 women aged 34-78 y) with hyperlipidemia [total cholesterol, 5.28-8.74 mmol/L (204-338 mg/dL); LDL cholesterol, 3.31-7.16 mmol/L (128-277 mg/dL); triacylglycerol, 0.62-2.78 mmol/L (55-246 mg/dL); and HDL cholesterol 0.78-2.46 mmol/L (30-95 mg/dL)] who were not being treated with lipid-lowering drugs participated. Subjects were treated with red yeast rice (2.4 g/d) or placebo and instructed to consume a diet providing 30% of energy from fat, <10% from saturated fat, and <300 mg cholesterol daily. Main outcome measures were total cholesterol, total triacylglycerol, and HDL and LDL cholesterol measured at weeks 8, 9, 11, and 12. RESULTS: Total cholesterol concentrations decreased significantly between baseline and 8 wk in the red-yeast-rice-treated group compared with the placebo-treated group [(x+/-SD) 6.57+/-0.93 mmol/L (254+/-36 mg/dL) to 5.38+/-0.80 mmol/L (208+/-31 mg/dL); P < 0.001]. LDL cholesterol and total triacylglycerol were also reduced with the supplement. HDL cholesterol did not change significantly. CONCLUSIONS: Red yeast rice significantly reduces total cholesterol, LDL cholesterol, and total triacylglycerol concentrations compared with placebo and provides a new, novel, food-based approach to lowering cholesterol in the general population.

Decreased growth of human prostate LNCaP tumors in SCID mice fed a low-fat, soy protein diet with isoflavones.

Epidemiological studies suggest that high intake of dietary fat is a risk factor for the development of clinical prostate cancer. Soy protein has also been proposed to play a role in the prevention of prostate cancer, and one of the isoflavones in soy protein, genistein, inhibits the growth of human prostate cancer cell lines in vitro. This study was designed to evaluate whether altering dietary fat, soy protein, and isoflavone content affects the growth rate of a human androgen-sensitive prostate cancer cell line (LNCaP) grown in severe-combined immunodeficient (SCID) mice. SCID mice were randomized into four dietary groups: high-fat (42.0 kcal%) + casein, high-fat (42.0 kcal%) + soy protein + isoflavone extract, low-fat (12.0 kcal%) + casein, and low-fat (12.0 kcal%) + soy protein + isoflavone extract. After two weeks on these diets, the mice were injected subcutaneously with 1 x 10(5) LNCaP tumor cells and placed in separate cages (1 mouse/cage) to strictly control caloric intake. Isocaloric diets were given 3 days/wk, and tumor sizes were measured once per week. The tumor growth rates were slightly reduced in the group that received the low-fat + soy protein + isoflavone extract diet compared with the other groups combined (p < 0.05). In addition, the final tumor weights were reduced by 15% in the group that received the low-fat + soy protein + isoflavone extract diet compared with the other groups combined (p < 0.05). In this xenograft model for prostate cancer, there were statistically significant effects on tumor growth rate and final tumor weight attributable to a low-fat + soy protein + isoflavone extract diet.

Preventive pharmacologic therapy among asthmatics: five years after publication of guidelines.

BACKGROUND: Guidelines from the National Heart, Lung, and Blood Institute first published in 1991 have recommended anti-inflammatory (AI) agents as a first-line therapy and the bronchodilator as an acute reliever of symptoms. OBJECTIVE: To examine the current usage of anti-inflammatory steroids (inhaled corticosteroids, Cromolyn, systemic steroids) and bronchodilators and compare them with the national guidelines. The relationship between preventive AI usage and the characteristics of the asthma patients and their providers was also examined. METHODS: Cross-sectional survey data linked with 6-month pharmacy claims of asthmatic members at an HMO in California. RESULTS: AI usage increased with current severity (mild, 36.9%; moderate, 47.3%; and severe, 56.8%), though a large percentage are not receiving this emphasized treatment. Bronchodilators were used at a higher rate and 24% of asthmatics relied solely on bronchodilators. Use of bronchodilators without AI (BWAI) was present at all severity levels (mild, 19.5%; moderate, 24.6%; and severe, 24.7%). Advancing age, increasing severity, care by an asthma specialist, and not smoking increased the likelihood of using AIs. Increasing severity, longer duration of asthma, smoking, younger age group, care by a generalist, and no chronic bronchitis increased the likelihood of BWAI. CONCLUSIONS: These results suggest that there is a low level of AI usage despite emphasis in guidelines. Current asthma management in a community-based setting depicts a significant underutilization of long-term control agents and, conversely, an overutilization of symptom relief agents compared with guidelines published 5 years ago. Actively involving patients in the guideline dissemination process, rather than just the medical community, may increase preventive medication usage.

Identifying predictive factors in melanoma progression.

Identification of risk factors is a fundamental goal of melanoma studies. The current understanding of melanoma progression is based primarily on two-stage modeling. A multistate Markov chain process combined with Cox proportional hazard regression is used to model the melanoma progression. The model is applied to 3,434 patients initially diagnosed as AJCC stage I or stage II. Parameter estimates are obtained using Cox regression and supplemented by plots of survival probabilities. Age is associated with increased risk of progression from stage I, II to stage III and from stage III to stage IV. Males experienced an increased risk of stage I, II to stage III progression. Primary tumor located on extremities decreased the risk of all transitions. Clark's level of invasion >III and Breslow's depth >1 mm increased the risk of progression from stage I, II to stage III and stage IV. The following interactions among the prognostic factors were identified for the first time in this research: interaction of age and gender in progression from stage I, II to stage III; interactions of level and depth and site by gender were found in the progression from stage I, II to stage III; interaction of site and gender in progression from stage III to stage IV and stage IV to death. Also we identified primary site as a new prognostic factor for the progression from stage IV to death. The study employed a multistate model in order to identify prognostic factors relevant for disease progression. The unique feature is the modeling of interactions among the prognostic factors and their identification.

Hospital- and patient-related characteristics determining maternity length of stay: a hierarchical linear model approach.

OBJECTIVES: The purpose of this study was to identify factors related to pregnancy and childbirth that might be predictive of a patient's length of stay after delivery and to model variations in length of stay. METHODS: California hospital discharge data on maternity patients (n = 499,912) were analyzed. Hierarchical linear modeling was used to adjust for patient case mix and hospital characteristics and to account for the dependence of outcome variables within hospitals. RESULTS: Substantial variation in length of stay among patients was observed. The variation was mainly attributed to delivery type (vaginal or cesarean section), the patient's clinical risk factors, and severity of complications (if any). Furthermore, hospitals differed significantly in maternity lengths of stay even after adjustment for patient case mix. CONCLUSIONS: Developing risk-adjusted models for length of stay is a complex process but is essential for understanding variation. The hierarchical linear model approach described here represents a more efficient and appropriate way of studying interhospital variations than the traditional regression approach.