Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.     

A population-based study of the extent of surgical resection of potentially curable colon cancer

Background We attempted to determine factors contributing to the extent of initial curative resection for colon cancer in a population-based cohort. Total abdominal colectomy with ileorectal anastomosis (TAC-IR) may be considered for young patients or those with a colorectal cancer family history to prevent metachronous lesions and facilitate surveillance. Methods All Ontario patients newly diagnosed with colon cancer over 12 months beginning in July 1997 were staged at the time of surgery. The extent of resection was compared with variables, including familial risk obtained from the Ontario Familial Colon Cancer Registry. Results Complete staging was possible for 86% of patients. A total of 1223 patients had a potentially curative resection: 17%, 46%, and 36% were stage I, II, and III, respectively. Patients were more likely to receive a TAC-IR if they were ≤50 years old (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.8–6.6), if they had a synchronous lesion (OR, 28.37; 95% CI, 12.2–61.2), or if they were at a teaching hospital (OR, 2.8; 95% CI, 1.6–4.7), but not if they had a family history (OR, 7; 95% CI, 3–1.5). Conclusions Young age, teaching hospital, and multiple cancers but not family history were important factors for performing a TAC-IR.     

The east–west advancement flap (horizontal advancement flap) to repair a defect on the nose ala

Background The repair of an alar nasal defect is a frequent challenge for dermatologic surgeons for reasons of the high rate of non‐melanoma cancers in the area. Objective Our aim was to describe the use of an east–west cheek‐based flap (horizontal advancement flap) to repair a surgical defect on the nose ala. Methods Benefits and limits of this surgical procedure are evaluated. Result The resulting S‐shaped scar was well‐camouflaged among the natural skin lines (melolabial fold and melonasal junction). No architectural distortion of the nose resulted from the procedure. Conclusion In selected patients with small‐to‐medium‐size defects of the nasal ala, the horizontal advancement flap is a simple, reliable and aesthetic reconstruction option.     

The Protective Value of Parental Sex Education: A Clinic-Based Exploratory Study of Adolescent Females

Study ObjectiveThis exploratory study compared the impact of sex education provided by parents to female adolescents against the same education provided in formal settings to female adolescents.MethodsFemales, 16–24 years old, attending an adolescent medicine clinic in an urban area of the South were recruited prior to examination. Each patient completed an anonymous self-administered questionnaire. Data from 110 respondents were analyzed to compare those indicating they had learned about each of four topics from parents to those not indicating learning about all four topics from a parent. The same process was repeated relative to learning about the four topics in formal educational settings.ResultsIn controlled, multivariate, analyses, adolescents not communicating with parents on all four topics were nearly five times more likely to report having multiple sex partners in the past three months. Further, these adolescents were 3.5 times more likely to have low self-efficacy for condom negotiation, 2.7 times more likely to report ever using alcohol or drugs before sex, and about 70% less likely to have ever talked about HIV prevention with a partner before engaging in sex. Differences relative to learning about the four topics in formal settings were not found.ConclusionFindings suggest that teen females (attending teen clinics) may experience a protective benefit based on communication with parents. This protective effect was not observed for education delivered in formal settings.     

The assessment of prognosis of surgically resected oesophageal cancer is dependent on the number of lymph nodes examined pathologically

Aims:  The prognosis in surgically resected oesophageal carcinoma (OC) is dependent on the number of regional lymph nodes (LN) involved, but no guidance exists on how many LNs should be examined histopathologically to give a reliable pN status. The aim of this study was to determine whether the number of LNs examined after OC resection has a significant effect on the assessment of prognosis.
Methods and results:  Routinely generated pathology reports from 237 consecutive patients undergoing oesophagectomy for OC were examined and analysed in relation to survival. The main outcome measure was survival from date of diagnosis. Lymph node count (LNC) correlated strongly with survival; a plateau was reached after a count of 10. Median and 2-year survival was 30 months and 42%, respectively, if <10 nodes were examined ( n  = 88), compared with 51 months and 61% if >10 nodes were examined ( P  = 0.005). This effect was greatest in pN0 cases. The prognostic value of the absolute number of LN metastases (<4) and LN ratio (<0.4) was strongly dependent on a LNC of >10.
Conclusions:  These results demonstrate the importance of careful pathological examination and lymph node retrieval after OC resection. At least 10 nodes should be examined to designate an OC as pN0.     

Female Perceptions of Male Versus Female Intendedness at the Time of Teenage Pregnancy

Teen pregnancy is a major public health concern and the majority of these pregnancies are unintended. The study population included women whose first pregnancy occurred at age 19 or younger (n?=?2,142). Data from the 2002 National Survey of Family Growth was used to determine whether women??s reports of her own pregnancy intentions differed from her perception of her male partner??s pregnancy intentions at the time of conception. Chi-square tests and multinomial logistic regression were used to examine perceived discrepant pregnancy intent. Most (55.4%) reported that the pregnancy was unintended by both, 22.1% indicated only he intended the pregnancy, 5.6% indicated only she intended the pregnancy, and 16.9% reported both intended the pregnancy. Compared to adolescent pregnancies respondents recalled being unintended by both her and her partner, Black and Hispanic respondents were more likely than whites to indicate the pregnancy was intended and were more likely to indicate that she did not intend the pregnancy but believed her partner did. Respondents who were older at the time of conception were more likely to indicate that the pregnancy was intended by both her and her partner. There are differences in recall of pregnancy intentions as perceived by respondents. Female adolescents perceived that the male who fathered the pregnancy intended to get pregnant at that time more often than she did. Teen pregnancy prevention efforts should consider both females and males intentions to become pregnant.     

Theory development in health promotion: are we there yet?

Theory development has not proceeded at a pace commensurate with the evolution of health promotion practice. At least three examples of this disparity are apparent: (1) theory is developed in an evidence-based paradigm rather than a practice-based paradigm, (2) a substantial majority of health behavior theories exist at the individual level, thereby neglecting contextual realities that shape behavior, and (3) “accessibility” levels of theory to practitioners may be quite low in comparison to the growing demands to prevent disease through expanding health promotion practices. The challenges of health promotion demand a great deal more attention to developing theories that reflect the reality of broad influences on health behavior. One critical question that must be answered involves setting limits regarding the realistic role of behavioral interventions in public health practice. The evolution of theory should be practice-based, largely ecological in nature, and the resulting theories should be easily accessible to practitioners.