Robert J. Weyant

Vascular endothelial growth factor expression in stage I non-small cell lung cancer correlates with neoangiogenesis and a poor prognosis.

Background: Vascular endothelial growth factor (VEGF) plays an important role in tumor growth and metastasis. We investigated the prognostic significance of VEGF overexpression, intratumoral microvessel density (MVD), and angiolymphatic invasion in stage Ia-b non-small cell lung cancer (NSCLC).Methods: Eighty-five patients undergoing complete surgical resection of pathologic stage Ia-b NSCLC were evaluated. The mean and median clinical follow-up were 37.1 and 39.0 months (range, 30–44 months), respectively. Paraffin-embedded tumor specimens were stained with VEGF and CD31 (a specific endothelial marker) using immunohistochemical methods. VEGF staining was evaluated, by combining both percentage of positive tumor cells and staining intensity, as low (negative and < 20% of tumor cells showing weak positivity), or high (>20% of tumor cells showing strong positivity). CD31 staining was expressed as MVD per high power field at 400× magnification. Angiolymphatic invasion was expressed as either presence or absence.Results: Low VEGF expression was seen in 25 (29%) patients, and high VEGF expression was seen in 60 (71%) patients. The survival rate in patients with low VEGF expression was significantly higher (80%) than that in those with high VEGF expression (48%, P = .018). The mean MVD in the low VEGF group was 23.7 ± 5.7 vs. 34.4 ± 9.3 in the high VEGF group (P = .001). Patients with high MVD also had a significantly lower survival rate than did those with low MVD count (46% vs. 73%, P = .0053). Age, sex, tumor type, and tumor differentiation were not found to be associated with overall survival. The presence of angiolymphatic invasion and T2 stage (i.e., tumor size > 3 cm) were associated with decreased survival. High VEGF expression, tumor size, and angiolymphatic invasion emerged as three independent factors predicting worsening prognosis using multivariate analysis.Conclusion: High VEGF expression within stage I NSCLC is closely associated with high intratumoral angiogenesis and poor prognosis. Immunohistochemical evaluation of T stage and VEGF expression along with examination of angiolymphatic invasion perioperatively may aid in predicting prognosis. Adjuvant therapies aimed at retarding tumor angiogenesis may be considered for stage I NSCLC patients with high VEGF levels.

Clinical trial of tacrolimus versus cyclosporine in lung transplantation

BACKGROUND A prospective clinical trial was undertaken to compare the efficacy of tacrolimus (FK 506) versus cyclosporine as the primary immunosuppressive agent after lung transplantation. METHODS Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease. RESULTS One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p = 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05). CONCLUSIONS This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.

Microbial Risk Indicators of Early Childhood Caries

ABSTRACT The aim of this study was to use molecular identification methods, such as 16S RNA gene sequence and reverse-capture checkerboard hybridization, for identification of the bacteria associated with dental caries and with dental health in a subset of 204 twins aged 1.5 to 7 years old. A total of 448 plaque samples (118 collected from caries-free subjects and 330 from caries-active subjects) were used for analysis. We compared the bacteria found in biofilms of children exhibiting severe dental caries, with different degrees of lesion severity, with those found in biofilms of caries-free children. A panel of 82 bacterial species was selected, and a PCR-based reverse-capture checkerboard method was used for detection. A simple univariate test was used to determine the overabundance and underabundance of bacterial species in the diseased and in the healthy groups. Features identified with this univariate test were used to construct a probabilistic disease prediction model. Furthermore, a method for the analysis of global patterns of gene expression was performed to permit simultaneous analysis of the abundance of significant species by allowing cross-bacterial comparisons of abundance profiles between caries-active and caries-free subjects. Our results suggested that global patterns of microbial abundance in this population are very distinctive. The top bacterial species found to be overabundant in the caries-active group were Actinomyces sp. strain B19SC, Streptococcus mutans, and Lactobacillus spp., which exhibited an inverse relationship to beneficial bacterial species, such as Streptococcus parasanguinis, Abiotrophia defectiva, Streptococcus mitis, Streptococcus oralis, and Streptococcus sanguinis.

The validation of the Peer Assessment Rating index for malocclusion severity and treatment difficulty

The Peer Assessment Rating (PAR) index is a British occlusal index that measures the severity of dental malocclusion and has been used in several investigations that have evaluated the effectiveness of orthodontic treatment provision in Europe. As part of its development, the PAR index was validated for malocclusion severity, by using the opinions of a panel of 74 dentists and orthodontists. The present investigation was carried out to validate the PAR index, by using the opinion of an American panel of orthodontists. Eleven orthodontists examined a sample of 200 sets of study casts and rated them for malocclusion severity and perceived treatment difficulty. Multiple regression techniques were used to evaluate the predictive power of the components of malocclusion on the panels scores. Weightings were calculated from the partial regression coefficients and, when these weightings were applied to the PAR index, the association between the panels opinion and the PAR index scores was increased.

An Assessment of Survival Rates and Within-patient Clustering of Failures for Endosseous Oral Implants

This study examined endosseous cylinder implant survival, defined as the unqualified presence of the implant in the mouth at the end of the observation period, in 598 consecutive VA patients, with a total of 2098 implants. Data were taken from the Department of Veterans Affairs (VA) Dental Implant Registry, which has maintained longitudinal data on the survival of individual dental implants in VA patients since 1987. The maximum time of observation in any one patient was 2040 days (5.6 yr). Survival analysis by use of life-table methods was carried out on both an implant- and a patient-specific basis. Implant cases were accrued randomly, and therefore a random censoring model was used. A correlated binomial model was used for assessment of the degree of within-patient clustering of implant removals. Results showed that the implant-specific survival rate during the longest time interval (5.6 yr) was 89.9%; the patient-specific implant survival rate during the same time was 78.2%. Among implants which were removed, the mean time to removal was 292 days. The hazard function, which describes the probability of implant loss as a function of time, decreased steadily throughout the observation period. The correlated binomial model suggested a clustering of removals within patients with multiple implants (p = 0.11, p = 0.0001). The odds of having a second implant removed were 1.3 times greater if the patient had already had one implant removed. This study suggests that when implants fail, they do so soon after placement, and the likelihood of failure decreases steadily from implantation through the first five years post-surgery. These findings also suggest the existence of systemic factors which affect the survival of all implants within a given patient and may lead to multiple implant failures. Identification of these systemic factors may lead to improvements in patient selection and increases in the success rates for oral implants. Finally, results show that pure titanium implants had better short-term survival rates, but worse long-term survival rates, when compared with implants that had some other form of surface coating.

Systemic inflammatory markers, periodontal diseases, and periodontal infections in an elderly population

Objectives: To study the levels of systemic markers for inflammation with parameters of periodontal diseases in older people.

Exploring the genetic basis of chronic periodontitis: a genome-wide association study

Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age—62 years, moderate CP—43% and severe CP—17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 × 10−6) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)—NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28–1.73, P = 3.5 × 10−7))]; moderate CP (n = 2293)—NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24–1.59, P = 7.5 × 10−8), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52–2.65, P = 8.2 × 10−7). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 × 10−9) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP.

Global Oral Health Inequalities Task Group—Implementation and Delivery of Oral Health Strategies

This paper reviews the shortcomings of present approaches to reduce oral diseases and inequalities, details the importance of social determinants, and links that to research needs and policies on implementation of strategies to reduce oral health inequalities. Inequalities in health are not narrowing. Attention is therefore being directed at determinants of major health conditions and the extent to which those common determinants vary within, between, and among groups, because if inequalities in health vary across groups, then so must underlying causes. Tackling inequalities in health requires strategies tailored to determinants and needs of each group along the social gradient. Approaches focusing mainly on downstream lifestyle and behavioral factors have limited success in reducing health inequalities. They fail to address social determinants, for changing people’s behaviors requires changing their environment. There is a dearth of oral health research on social determinants that cause health-compromising behaviors and on risk factors common to some chronic diseases. The gap between what is known and implemented by other health disciplines and the dental fraternity needs addressing. To re-orient oral health research, practice, and policy toward a ‘social determinants’ model, a closer collaboration between and integration of dental and general health research is needed. Here, we suggest a research agenda that should lead to reductions in global inequalities in oral health.

Acute and chronic morbidity differences between muscle-sparing and standard lateral thoracotomies ☆ ☆☆ ★ ★★ ♢

INTRODUCTION Opinions differ regarding differences between totally muscle-sparing thoracotomy and standard lateral thoracotomy approaches to pulmonary resection with respect to operative time, postoperative pain and morbidity, and occurrence of chronic postthoracotomy pain syndromes and subjective shoulder dysfunction. METHODS Three hundred thirty-five consecutive patients undergoing muscle-sparing thoracotomy (n = 148) or lateral thoracotomy (n = 187) to accomplish lobectomy for stage I lung cancer during a 40-month period were evaluated. Local rib resection was not employed, and two chest tubes were routinely used after operation in both thoracotomy groups. Epidural analgesia use was similar after operation in the two groups (muscle-sparing thoracotomy 38%, lateral thoracotomy 38%). The postoperative hospital courses and patient functional statuses at 1 year were examined. RESULTS Demographic analyses demonstrated no differences between groups in age, sex, or association of significant comorbid medical illness. Although the operative time required for muscle-sparing thoracotomy was shorter, there were no differences between thoracotomy approaches in any of the other primary acute postoperative variables analyzed (chest tube duration, length of hospital stay, postoperative narcotic requirements, and postoperative mortality). The frequencies of chronic pain and shoulder dysfunction assessed 1 year after operation were also similar between thoracotomy groups. CONCLUSIONS The relative efficacies and rates of occurrence of acute or chronic morbidity are equivalent after muscle-sparing thoracotomy and standard lateral thoracotomy. Although muscle-sparing thoracotomy may possibly be performed more expediently, it appears that the singular advantage of muscle-sparing thoracotomy over standard lateral thoracotomy involves the preservation of chest wall musculature in case rotational muscle flaps should be needed later.

Prognostic markers in pheochromocytoma

Clinical and histopathological features do not reliably distinguish between benign and malignant pheochromocytomas. Additional markers that might be useful prognostic indicators in the pathological assessment of these tumors are sought. Immunohistochemical expression of MIB-1, Bcl-2, cathepsin B, cathepsin D, basic fibroblast growth factor (bFGF), c-met, and type IV collagenase were studied on formalin-fixed tissue from 33 nonconsecutive cases of pheochromocytoma, selected on the basis of reliable long-term follow-up, to determine associations with malignancy. The study group included 33 patients, 19 men and 14 women, with a mean age of 45 years, including five cases of neurofibromatosis (NF), three familial, and one MEN IIb. Mean follow-up was 63.2 months. Ten patients were determined to have malignant pheochromocytomas by the presence of metastatic disease. Features found to be associated with malignancy included MIB-1 labeling index (5% vs 1%) (P = .0009), male gender (90% vs 43%) (P = .008), extra-adrenal location (40% vs 9%) (P = .03), tumor weight (481 g vs 124 g) (P = .05), and young age (38 years vs 49 years) (P = .05). None of the five cases with NF were malignant (P = .04). S-100 positivity showed a significant (P = .02) but nonlinear association with benign tumors. Absent S-100 correlated with greater tumor weight. Malignancy was not associated with right versus left side or bilaterality, although bilateral tumors were smaller. C-met, bFGF, cathepsin B, cathepsin D, and collagenase were strongly expressed in most tumors and were not predictive of outcome, nor was bcl-2, which was variably expressed. Using multiple logistic regression with malignancy as the dependent variable, MIB-1 continued to show a significant association with malignancy (P = .005) independent of any association with sex, age, or extra-adrenal location. Using a cutoff value of MIB-1 labeling of greater than 3% yielded a specificity of 100% and a sensitivity of 50% in predicting malignancy.