A Placebo-controlled Study of PF-06473871 (Anti-Connective Tissue Growth Factor Antisense Oligonucleotide) in Reducing Hypertrophic Skin Scarring.

BACKGROUND: Connective tissue growth factor (CTGF) is a matricellular protein that plays a key role in wound healing and scar formation. Inhibition of CTGF by a specific antisense oligonucleotide significantly reduced scarring and fibrosis in animal models. This study examined whether an antisense oligonucleotide that inhibits human CTGF expression could reduce the severity of hypertrophic scar formation in patients following surgical revision of preexisting breast scars. METHODS: This study was a 24-week multicenter, randomized, double-blind, within-subject, placebo-controlled phase 2b study evaluating the efficacy and safety of PF-06473871 in 2 regimens of either 3 or 4 intradermal injections (postsurgery weeks 2, 5, 8, and 11) of 5 mg/cm adjacent to the new surgical incision. One hundred subjects with bilateral hypertrophic scars resulting from prior breast surgery were randomized. Efficacy was determined by the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: The Physician/Observer POSAS overall opinion score at (week 24) for the 4-injection regimen demonstrated a statistically significant (P = 0.022) treatment difference from placebo of 0.68, and the treatment difference for the 3-injection regimen was nonsignificant (P = 0.4). Physician evaluation of scar severity at (week 24) with the photo-guide in the 4-injection regimen had a significant reduction (point estimate of treatment difference of 0.43 favoring PF-06473871). The surgical effect was approximately 2.0 at week 24 and was nearly 3 times greater than the treatment effect. Patient evaluations using the POSAS and photo-guide were not significantly improved with either dose regimen. PF-06473871 was generally well tolerated systemically and locally. CONCLUSION: The 4-dose regimen of PF-06473871 provided statistically significant improvement, inhibiting severity of hypertrophic scar formation based on physician assessment. However, the effect of revision surgery alone is significant and may dominate the treatment effect of PF-06473871.

Body contouring following massive weight loss.

The growing prevalence of obesity in America has led to an increase in bariatric surgery, which produces successful long-term weight loss and improves the multiple co-morbidities caused by obesity. A weight loss of 100+ pounds leaves patients with significant amounts of loose-hanging excess skin and tissue that can be addressed only with surgery. This article briefly describes many body contouring procedures developed by plastic surgeons to address the needs of massive weight loss patients.

Skincare science: update on topical retinoids.

According to the author, the single most effective component in a skincare regimen for reversal of photoaging is the use of retinoids. Here is a guide to the mechanism and application of various formulations of retinoids, and a comprehensive skin regimen incorporating tretinoin.

DMSO: applications in plastic surgery.

The authors point out that dimethyl sulfoxide (DMSO) increases tissue perfusion and may effectively treat or prevent ischemia in flaps. They recommend application of topical DMSO every 4 to 6 hours, until blood flow improves, to areas that show signs of ischemia or less than adequate perfusion. Other potential cosmetic surgery uses of DMSO include areas of skin care, pain relief, and treatment of keloids.

Initial results from an online breast augmentation survey.

BACKGROUND: Data have been lacking to answer many questions raised in the clinical literature and by the US Food and Drug Administration with regard to patient satisfaction with breast implants, informed consent, the impact of augmentation on quality of life, repeat operations, and other issues related to breast augmentation. OBJECTIVE: The authors conducted an online survey of women with and without breast implants to collect data on key issues related to breast augmentation. METHODS: A survey including 177 questions was posted on the Web site www.implantinfo.com for 6 months, from August 2001 to February 2002. The survey was aimed at women who had undergone augmentation and those who were considering augmentation but had not yet undergone surgery. The raw data were analyzed by Data Harbor (Chicago, IL), an independent data management and technology development company with experience in managing large, complex medical databases. RESULTS: The survey was completed by 4011 women, including 2273 who had received breast implants and 1738 who were considering augmentation. Among the key findings: More than half of the women who had undergone breast augmentation and those who were considering the procedure thought about the decision for at least 3 years before proceeding. Most women who underwent breast augmentation (88%) were satisfied with the results, and 93% said they would recommend the procedure to friends or family members. Nearly all women who received implants thought the surgery improved their overall appearance (92%) and self-confidence (82%) but said it did not result in significant changes in their marriage/dating activities, careers, or social lives. At least 92% said their surgeons had answered their questions and listened to their concerns, and more than 75% said they remembered being informed of the risks of surgery. The percentage of women with breast pain was greater among women with implants than among those without. However, other physical symptoms, such as those associated with rheumatologic diseases, were more common among women considering augmentation. Respondents with implants did not smoke at levels higher than comparable women in the general population and were not major consumers of alcohol. CONCLUSIONS: The Online Breast Augmentation Survey provides a wealth of previously unavailable data on women who have undergone or who are considering breast augmentation. The data indicate that women consider breast augmentation carefully, that they are well informed by their physicians before surgery, and that they are generally happy with the results.

Initial report from an online breast augmentation follow-up survey.

BACKGROUND: The first Online Breast Augmentation Survey (Aesthetic Surg J 2004;24:117-135) reported on women who had undergone or who were considering breast augmentation with regard to motivation for surgery, patient satisfaction with results, and other issues. The Food and Drug Administration and others have also raised questions concerning informed consent, follow-up, health insurance, and related issues dealing with breast augmentation. OBJECTIVE: An Online Breast Augmentation Follow-Up Survey was designed to collect data from women who had undergone breast augmentation with regard to informed consent, follow-up, complications and problems following breast augmentation, and health insurance. METHODS: The survey comprised 56 questions, many of which were presented in a multiple-part format. Women who visited the Web site www.implantinfo.com and who had undergone breast augmentation were invited to participate in the survey. An independent research firm, Industry Insights, Inc. (Columbus, OH), assisted with the final design and collected and analyzed the data. RESULTS: The survey was posted from April 8-June 30, 2003. Surveys were submitted by 1350 women. Ninety-two percent of respondents said that surgeons asked them to return for regular follow-up during the first postoperative year. Ninety percent said they would return to the original surgeon if a problem developed. Almost all respondents (94%) said that they had been informed by the surgeon, the surgeon's staff, or both of specific problems or complications that might be associated with breast implants and augmentation; 89% said that the information they received was adequate. Eighty percent said they complied with the surgeon's recommendations for follow-up visits, although compliance declined after the first postoperative year. The survey also showed that most women who undergo breast augmentation seek out information about the procedure before surgery from independent sources, in most cases from Web sites. Eighty-eight percent of respondents said they were involved in some way in deciding on implant size; 88% said they were satisfied with breast size after surgery. Fourteen percent of respondents reported additional implant-related surgery after the original augmentation. CONCLUSIONS: Our data indicate that almost all patients are advised to return for follow-up visits, that most comply with their surgeons' recommendations for follow-up in the first postoperative year, and that the main reason for noncompliance is an absence of problems with implants. The survey also indicates that patients receive adequate informed consent from the surgeon or the surgeon's staff and that they also seek out information on their own. Finally, the data suggest that women who have undergone augmentation have a realistic appreciation of the problems involved and are willing to tolerate minor complications.

Suppression of beta-catenin inhibits the neoplastic growth of APC-mutant colon cancer cells.

Mutations involving the adenomatous polyposis coli (APC) tumor suppressorgene/beta-catenin signaling pathway have been identified in the majority of colon carcinomas. However, the role of aberrant beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells has not been directly studied. To address this question, antisense oligonucleotides have been used to specifically down-regulate beta-catenin expression in APC-mutant human colon carcinoma cells. Antisense-mediated suppression of beta-catenin inhibits the in vitro proliferation, anchorage-independent growth, and cellular invasiveness of APC-mutant human colon carcinoma cells. The systemic administration of beta-catenin antisense oligonucleotides down-regulates beta-catenin expression in vivo in human colon cancer xenografts in nude mice. Such treatment inhibits the tumorigenic growth of colon cancer xenografts and can completely eradicate tumors in some treated animals. These studies formally demonstrate the critical role of beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells and suggest that strategies targeting beta-catenin may be of use in the therapy of colon cancer.

HER2/neu antisense targeting of human breast carcinoma.

Overexpression of the HER2/neu oncogene is observed in approximately 30% of human breast carcinoma specimens. HER2/neu overexpression is a negative prognostic factor in breast cancer patients. Cancer cells that overexpress HER2/neu may also be less sensitive to chemotherapy. In order to further define mechanisms by which HER2/neu overexpression drives neoplastic cell growth and chemoresistance, antisense oligonucleotides (ODNs) have been utilized to selectively down-regulate HER2/neu expression in human breast cancer cells. Such antisense ODNs suppress HER2/neu mRNA and protein levels in a dose-dependent, sequence-specific manner. Down-regulation of HER2/neu expression in HER2/neu overexpressing breast cancer cells inhibits cell cycle progression in G0/G1 and results in apoptotic cell death. In tissue culture studies, combined treatment of HER2/ neu overexpressing breast cancer cells with HER2/neu antisense ODNs and conventional chemotherapeutic agents results in synergistic inhibition of cancer cell growth and activation of apoptotic cell death mechanisms. These studies have been extended to demonstrate synergistic antitumor effects following systemic treatment with antisense ODNs plus doxorubicin in nude mice bearing human breast carcinoma xenografts. Collectively these findings demonstrate that HER2/neu overexpression stimulates anti-apoptotic cell survival mechanisms and suggest that HER2/neu antisense ODNs may be of use in cancer therapeutics.

Synergistic antitumor effects of HER2/neu antisense oligodeoxynucleotides and conventional chemotherapeutic agents.

BACKGROUND: The HER2/neu oncogene is overexpressed in a substantial fraction of human tumors. HER2/neu overexpressing tumors may be intrinsically resistant to chemotherapy. The present study examined the ability of antisense-mediated downregulation of HER2/neu expression to enhance the antitumor effects of conventional chemotherapeutic agents against human tumor cells that overexpress HER2/neu. METHODS: The effects of HER2/neu antisense oligodeoxynucleotides (ODNs) on the growth inhibitory and proapoptotic activity of several distinct chemotherapeutic agents were examined in vitro. In vivo effects of HER2/neu antisense ODNs in combination with doxorubicin hydrochloride were assessed by examining the growth of human tumor xenografts implanted into nude mice. RESULTS: The proliferation of tumor cell lines that overexpress HER2/neu was inhibited by antisense ODNs in combination with conventional chemotherapeutic agents in an additive or synergistic fashion. Such combination therapy also demonstrated synergistic activation of apoptosis. HER2/neu antisense ODNs in combination with doxorubicin hydrochloride demonstrated synergistic antitumor effects in vivo as well. CONCLUSIONS: Downregulation of HER2/neu expression can enhance the sensitivity of human cancer cells, which overexpress HER2/neu to the cytotoxic effects of chemotherapy. Antisense ODNs targeting the HER2/neu gene may play a role in cancer therapy.