Novel Phase I dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416.

PURPOSE: To determine the biological modulatory dose of SU5416, we employed a novel trial design, where "dose de-escalation" was based on demonstrable biological changes observed at the maximum tolerated dose. If such an effect was shown, dose de-escalation to a predefined dose level would occur to determine if the lower dose exhibited the same amount of pharmacodynamic effect as the higher dose. EXPERIMENTAL DESIGN: Ten patients with advanced solid tumors were enrolled at each dose level. One of the following pharmacodynamic effects was considered significant: (a) a 35% decrease in microvessel density in sequential tumor biopsies and (b) a 35% decrease in blood flow within tumor as assessed by dynamic contrast-enhanced magnetic resonance imaging. In addition, soluble E-selectin, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule, and plasma vascular endothelial growth factor were measured sequentially. RESULTS: Nineteen patients were enrolled. Sequential tumor biopsies in all evaluable patients showed an increase in microvessel density. Only one patient met the intended pharmacodynamic end point of >35% reduction in blood flow. There was a significant increase in both soluble E-selectin and soluble intercellular adhesion molecule levels pretreatment versus levels at the time of removal of patients from study (P = 0.04 and P = 0.0007, respectively). Levels of serum fibrinogen rose with therapy. There was a trend toward increase in plasma vascular endothelial growth factor levels. CONCLUSION: SU5416 does not result in decreased blood flow in tumors or a decrease in microvessel density. This corresponds to the lack of clinical activity seen with this agent. Our clinical trial design termed dose de-escalation is a novel approach to determine the in vivo biological effects of targeted therapies in cancer patients.     

Brain stimulation and morphine reward deficits in dopamine D2 receptor-deficient mice

Rationale The rewarding effects of lateral hypothalamic brain stimulation, various natural rewards, and several drugs of abuse are attenuated by D1 or D2 dopamine receptor (D1R or D2R) antagonists. Much of the evidence for dopaminergic involvement in rewards is based on pharmacological agents with limited or “relative” selectivity for dopamine receptor subtypes. Genetically engineered animal models provide a complementary approach to pharmacological investigations. Objectives In the present study, we explored the contribution of dopamine D2Rs to (1) brain stimulation reward (BSR) and (2) the potentiation of this behavior by morphine and amphetamine using D2R-deficient mice. Methods Wild-type (D2Rwt), heterozygous (D2Rhet), and D2R knockout (D2Rko) mice were trained to turn a wheel for rewarding brain stimulation. Once equivalent rate–frequency curves were established, morphine-induced (0, 1.0, 3.0, and 5.6 mg/kg s.c.) and amphetamine-induced (0, 1.0, 2.0, and 4.0 mg/kg i.p.) potentiations of BSR were determined. Results The D2Rko mice required approximately 50% more stimulation than the D2Rwt mice did. With the equi-rewarding levels of stimulation current, amphetamine potentiated BSR equally across the three genotypes. In contrast, morphine potentiated rewarding stimulation in the D2Rwt, had no effect in the D2Rhet, and antagonized rewarding stimulation in the D2Rko mice. Conclusions D2R elimination decreases, but does not eliminate, the rewarding effects of lateral hypothalamic stimulation. After compensation for this deficit, amphetamine continues to potentiate BSR, while morphine does not.     

Calorie restriction increases cigarette use in adult smokers

Rationale Cigarette smokers weigh less than nonsmokers, and smokers often gain weight when they quit. This is a major barrier to smoking cessation, especially among women. However, strict dieting is not recommended during smoking cessation out of concern that it might promote relapse. This concern derives, in part, from the observation that calorie restriction increases self-administration of drugs of abuse in animals. This relationship has never been experimentally demonstrated in humans.Objectives To evaluate whether calorie restriction increases cigarette smoking in humans.Methods Seventeen (nine males, eight females) healthy, normal-weight smokers not attempting to quit were cycled in partially counterbalanced order, double-blind, through four diets—normal calorie (2,000–2,800 kcal/day), low calorie (700 kcal/day deficit), low-carbohydrate (CHO)/normal-calorie, and low-CHO/low-calorie—for 6 days per diet in an inpatient research ward. Smoking was assessed by cigarette counts, breath carbon monoxide (CO) levels, and cigarette craving.Results Compared with the normal-calorie diet, while on the low-calorie diet, subjects smoked 8% more cigarettes (P<0.02) and had 11% higher breath CO levels (P<0.01). The low-CHO/normal-calorie diet showed no significant effect on either variable, but there was a 15% increase in breath CO levels (P<0.05) on the low-CHO/low-calorie diet. There were no changes in self-reported cigarette craving or mood.Conclusions Consistent with animal studies, moderate calorie restriction was associated with a small but statistically significant increase in cigarette smoking, with no independent effect of CHO deprivation. These findings suggest that dieting may increase smoking behavior and could impede smoking-cessation attempts.     

Loss of E-cadherin and p27 expression is associated with head and neck squamous tumorigenesis

BACKGROUND: In neoplastic head and neck lesions, it has been found that the loss or reduction in E-cadherin expression is a late event and is associated with invasion. Low p27 levels have been associated with a poor prognosis in many different tumors, including laryngeal carcinoma. The authors investigated p27 and E-cadherin protein expression in the early stages of head and neck tumorigenesis and evaluated their predictive roles individually and in association with carcinogenesis. METHODS: Tissue biopsies from 46 patients who were participants in 3 chemoprevention trials were analyzed for E-cadherin expression, and 40 samples were analyzed for p27 expression using immunohistochemistry. RESULTS: The data suggested that loss of both E-cadherin expression and p27 expression occurred early during the preneoplastic steps of head and neck carcinogenesis, and loss of p27 protein expression alone (P=0.02) and in combination with loss of E-cadherin expression (P=0.04) was a significant predictor of the risk for head and neck carcinoma. CONCLUSIONS: The loss of p27 expression may be useful in the construction of a risk model for head and neck carcinogenesis and may represent a potential target for chemopreventive interventions. Longer follow-up of the high percentage of low-risk preneoplastic lesions in the current study and validation in a larger sample size may be required to establish the predictive role of these abnormalities.     

Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation

BACKGROUND: In patients with locoregional carcinoma of the esophagus or esophagogastric junction who underwent preoperative chemoradiation, it is unclear whether survival was better predicted by pretherapy clinical stage or by posttherapy pathologic stage. METHODS: The authors studied 235 consecutive patients with pretherapy clinical Stage II, III, or IVA (according to American Joint Committee on Cancer criteria) carcinoma of the esophagus or esophagogastric junction who were treated with chemoradiation followed by esophagectomy. Posttherapy cancer status was classified using pathologic stage and semiquantitative assessment of residual carcinoma. Clinicopathologic features, residual carcinoma status, and pretherapy and posttherapy stage were compared with disease-free and overall survival. RESULTS: Posttherapy pathologic stage was Stage 0 in 29% of patients, Stage I in 11% of patients, Stage II in 34% of patients, Stage III in 20% of patients, and Stage IV in 6% of patients. Cancer downstaging occurred in 56% of patients. In univariate analysis, disease-free and overall survival were predicted by posttherapy pathologic stage (both with P < 0.001), margin status (P = 0.002 and P = 0.01, respectively), extent of residual carcinoma (both with P < 0.001), and downstaging (both with P = 0.001), but not by age, gender, type of cancer, pretherapy clinical stage, or preoperative regimen. However, in multivariate analysis, disease-free and overall survival were independently predicted by posttherapy pathologic stage (both with P = 0.02). Extent of residual carcinoma was a marginally significant predictor of overall survival (P = 0.04). CONCLUSIONS: Posttherapy pathologic stage was the best available predictor of outcome for patients with locoregional carcinoma of the esophagus or esophagogastric junction who underwent chemoradiation therapy followed by esophagectomy. The findings in the current study supported the concept of downstaging by preoperative therapy.     

The first community health centers: a model of enduring value

Community health centers in the United States, first launched as a federal initiative in 1965, were rooted in models from South Africa, the American civil rights struggle, and a national commitment to address poverty. The first 2 centers, one serving a rural population in the Mississippi Delta and another a public housing project in Boston, incorporated such core principles as provision of primary care to a defined area or population; public health interventions addressing social determinants of health; emphasis on community participation; community empowerment leading to control of the new institutions; epidemiologic methods to identify problems and guide decisions; new combinations of clinical and public health personnel; and reduction of disparities in health and healthcare of the poor and minorities. The continuing relevance of these principles in today's greatly expanded health center network is reviewed.     

Assessment of personal qualities in relation to admission to medical school

BACKGROUND: Recently there has been much scrutiny of the medical school admissions process by universities, the General Medical Council and the public. Improved objectivity, fairness and effectiveness of selection procedures are desirable. The ultimate outcome sought is the graduation of competent doctors who reflect the values of and are in tune with the communities they serve. METHODS: Applicants to the Scottish medical schools sat a battery of psychometric tests to measure cognitive ability, personality traits and moral/ethical reasoning (Personal Qualities Assessment, PQA). Analysis determined the potential impact of the latter variables, and those of educational background and socioeconomic class (assessed by residential 'deprivation category'), upon success in gaining a place to study medicine. RESULTS: Cognitive ability did not vary significantly as a function of gender or educational background, although there was a trend for it to be lower in individuals from more deprived backgrounds. Women as a group were more empathic, with a greater communitarian orientation, than men. There was no significant difference between individuals attending independent and state-funded schools in respect of any of the qualities measured by the PQA. Applicants from deprived backgrounds and those attending state-funded schools would not be disadvantaged by an admissions process based on the PQA. CONCLUSION: The incorporation of an assessment tool such as the PQA may have positive implications for widening access and the objective selection of suitable medical students, resulting in the training of doctors who are more representative of the community at large. A longterm follow-up of the professional careers of those medical students who completed the PQA will be undertaken.