Epidermal growth factor receptor inhibitors plus chemotherapy in non-small-cell lung cancer: biologic rationale for combination strategies

Chemotherapy continues to play an essential role in the treatment of most stages of non-small-cell lung cancer (NSCLC). In fact, within the past 5 years, this role has greatly expanded into adjuvant therapy for early-stage resected disease. Likewise, agents targeting the epidermal growth factor receptor (EGFR), particularly the tyrosine kinase inhibitors gefitinib and erlotinib, have proven to be clinically active in patients with advanced-stage NSCLC. Because of these findings, it is logical to expect that combinations of these 2 classes of antineoplastic agents would prove more efficacious than either one alone. Yet 4 large randomized phase III trials of chemotherapy with or without an EGFR tyrosine kinase inhibitor in unselected patients with advanced-stage NSCLC, altogether totaling > 4000 patients, did not demonstrate improvement in clinical outcomes with the combination. Whether these negative results will be reproduced in ongoing combination studies of chemotherapy plus monoclonal antibodies directed against EGFR remain to be determined. Herein, we review recent preclinical and clinical data addressing this topic and explore the biologic rationale for developing new combination strategies based on patient selection by molecular and clinical factors, or by pharmacodynamic parameters.

Early implant placement following single-tooth extraction in the esthetic zone: biologic rationale and surgical procedures

Early implant placement is one treatment option for implant therapy following single-tooth extraction in the anterior maxilla. The surgical technique presented here is characterized by tooth extraction without flap elevation, a 4- to 8-week soft tissue healing period, implant placement in a correct three-dimensional position, simultaneous contour augmentation on the facial aspect with guided bone regeneration using a bioabsorbable collagen membrane combined with autogenous bone chips and a low-substitution bone filler, and tension-free primary wound closure. The surgical step-by-step procedure is presented with a case report. In addition, the biologic rationale is discussed.

Correlates of periodontal decline and biologic markers in older adults

BACKGROUND: There is limited information on infectious and host responses distinguishing older people with or without active periodontitis. This study measured bacterial and serum cytokine and high-sensitivity C-reactive protein (hsCRP) levels in older persons. METHODS: Elders (mean age: 67 years), whose periodontal status had declined most or least (20% worst or 20% best) over 5 years, were enrolled. Two years later, they were classified as periodontally declining (active periodontitis [AP]), if they had at least five teeth with probing depth (PD) > or =5 mm, or stable (stable periodontally [SP]), if they did not. Groups were compared with respect to demographics, PD, clinical loss of attachment, subgingival bacteria, serum hsCRP, interleukin (IL)-1beta and -6, and chronic diseases. RESULTS: Ten AP and 24 SP subjects were identified; 13% of women and 44% of men from the original sample were in the AP group (P <0.05). Most Asians were SP; most whites and all African Americans were classified as having AP (P <0.01). More AP elders had osteoporosis (P <0.01), but the AP and SP groups did not differ with respect to IL-1beta and -6 or hsCRP. Bacterial counts were higher in the AP group for Parvimonas micra (previously Peptostreptococcus micros or Micromonas micros) (7.7 x 10(5) cells versus 3.8 x 10(5) cells; P <0.05), Prevotella intermedia (25.7 x 10(5) cells versus 9.8 x 10(5) cells; P <0.01), Tannerella forsythia (previously T. forsythensis) (16.2 x 10(5) cells versus 8.0 x 10(5) cells; P <0.05), and Streptococcus mutans (6.2 x 10(5) cells versus 2.0 x 10(5) cells; P <0.01). Three risk factors were most predictive of periodontal decline: PD, osteoporosis, and being white or African American. CONCLUSION: Periodontal decline was associated with osteoporosis, ethnicity, PD, gender, serum hsCRP, and levels of four bacterial species.

Influence of hemostatic agents upon the outcome of periapical surgery: dressings with anesthetic and vasoconstrictor or aluminum chloride

OBJECTIVE To evaluate the effects of different hemostatic agents upon the outcome of periapical surgery. DESIGN A retrospective study was made of patients subjected to periapical surgery between 2006-2009 with the ultrasound technique and using MTA as retrograde filler material. We included patients with a minimum follow-up of 12 months, divided into two groups according to the hemostatic agent used: A) dressings impregnated in anesthetic solution with adrenalin; or B) aluminum chloride paste (Expasyl). Radiological controls were made after 6 and 12 months, and on the last visit. The global evolution scale proposed by von Arx and Kurt (1999) was used to establish the outcome of periapical surgery. RESULTS A total of 96 patients (42 males and 54 females) with a mean age of 40.7 years were included. There were 50 patients in the aluminum chloride group and 46 patients in the anesthetic solution with vasoconstrictor group. No significant differences were observed between the two groups in terms of outcome after 12 months - the success rate being 58.6% and 61.7% in the anesthetic solution with vasoconstrictor and aluminum chloride groups, respectively (p > 0.05). CONCLUSION The outcome after 12 months of follow-up was better in the aluminum chloride group than in the anesthetic solution with vasoconstrictor group, though the difference was not significant.

Increased vascularization during early healing after biologic augmentation in repair of chronic rotator cuff tears using autologous leukocyte- and platelet-rich fibrin (L-PRF): a prospective randomized controlled pilot trial

HYPOTHESIS We hypothesized that arthroscopic rotator cuff repairs using leukocyte- and platelet-rich fibrin (L-PRF) in a standardized, modified protocol is technically feasible and results in a higher vascularization response and watertight healing rate during early healing. METHODS Twenty patients with chronic rotator cuff tears were randomly assigned to 2 treatment groups. In the test group (N = 10), L-PRF was added in between the tendon and the bone during arthroscopic rotator cuff repair. The second group served as control (N = 10). They received the same arthroscopic treatment without the use of L-PRF. We used a double-row tension band technique. Clinical examinations including subjective shoulder value, visual analog scale, Constant, and Simple Shoulder Test scores and measurement of the vascularization with power Doppler ultrasonography were made at 6 and 12 weeks. RESULTS There have been no postoperative complications. At 6 and 12 weeks, there was no significant difference in the clinical scores between the test and the control groups. The mean vascularization index of the surgical tendon-to-bone insertions was always significantly higher in the L-PRF group than in the contralateral healthy shoulders at 6 and 12 weeks (P = .0001). Whereas the L-PRF group showed a higher vascularization compared with the control group at 6 weeks (P = .001), there was no difference after 12 weeks of follow-up (P = .889). Watertight healing was obtained in 89% of the repaired cuffs. DISCUSSION/CONCLUSIONS Arthroscopic rotator cuff repair with the application of L-PRF is technically feasible and yields higher early vascularization. Increased vascularization may potentially predispose to an increased and earlier cellular response and an increased healing rate.

Biologic and molecular analysis of tumor suppressor loci in human glioblastoma multiforme

Molecular and cytogenetic analyses of human glioblastomas have revealed frequent genetic alterations, including major deletions in chromosomes 9, 10, and 17, suggesting the presence of glioma-associated tumor suppressor genes on these chromosomes. To examine this hypothesis, copies of chromosomes 2, 4, and 10 derived from a human fibroblast cell line were independently introduced into a human glioma cell line, U251, by microcell-mediated chromosomal transfer. Successful transfer of chromosomes in each case was confirmed by resistance to the drug G418, indicating the presence of the neomycin-resistance gene previously integrated into each transferred chromosome. The presence of novel chromosomes and or chromosomal fragments was also demonstrated by molecular and karyotypic analyses. The hybrid clones containing either a novel chromosome 4 or chromosome 10 displayed suppression of the tumorigenic phenotype in vivo and suppression of the transformed phenotype in vitro, while cells containing a transferred chromosome 2 failed to alter their tumorigenic phenotype. The hybrid cells containing chromosome 4 or 10 exhibited a significant decrease in their saturation density, altered cellular morphology at high cell density, but only a slight decrease in their exponential growth rate. A dramatic decrease was observed in growth of cells with chromosome 4 or 10 in soft agarose, with the number and size of the colonies being greatly reduced, compared to the parental or chromosome 2 containing cells. The introduction of chromosome 4 or 10 also completely suppressed tumor formation in nude mice. These studies indicate that chromosome 10, as hypothesized, and chromosome 4, a novel finding for gliomas, harbor tumor suppressor loci that may be directly involved in the initiation or progression of normal glial precursors to human glioblastoma multiforme. ^

Systematic review of the survival rate and incidence of biologic, technical, and esthetic complications of single implant abutments supporting fixed prostheses

Purpose: To assess the 5-year survival rate and number of technical, biologic, and esthetic complications involving implant abutments. Materials and Methods: Electronic (Medline) and hand searches were performed to assess studies on metal and ceramic implant abutments. Relevant data from a previous review were included. Two reviewers independently extracted the data. Failure and complication rates were analyzed, and estimates of 5-year survival proportions were calculated from the relationship between event rate and survival function. Multivariable robust Poisson regression was used to compare abutment characteristics. Results: The search yielded 1,558 titles and 274 abstracts. Twenty-four studies were selected for data analysis. The survival rate for ceramic abutments was 97.5% (95% confidence interval [CI]): 89.6% to 99.4%) and 97.6% (95% CI: 96.2% to 98.5%) for metal abutments. The overall 5-year rate for technical complications was 11.8% (95% CI: 8.5% to 16.3%), 8.9% (95% CI: 4.3% to 17.7%) for ceramic and 12.0% (95% CI: 8.5% to 16.8%) for metal abutments. Biologic complications occurred with an overall rate of 6.4% (95% CI: 3.3% to 12.0%), 10.4% (95% CI: 1.9% to 46.7%) for ceramic, and 6.1% (95% CI: 3.1% to 12.0%) for metal abutments. Conclusions: The present meta-analysis on single-implant prostheses presents high survival rates of single implants, abutments, and prostheses after 5 years of function. No differences were found for the survival and failure rates of ceramic and metal abutments. No significant differences were found for technical, biologic, and esthetic complications of internally and externally connected abutments.

The effects of anti-infective preventive measures on the occurrence of biologic implant complications and implant loss: a systematic review.

PURPOSE To systematically appraise whether anti-infective protocols are effective in preventing biologic implant complications and implant loss after a mean observation period ≥ 10 years after loading. MATERIALS AND METHODS An electronic search of Medline via PubMed and Embase via Ovid databases complemented by manual search was conducted up to October 31, 2012. Studies were included provided that they were published in English, German, French, or Italian, and conducted on ≥ 20 partially and fully edentulous patients with dental implants and regular (≥ 1×/year) supportive periodontal therapy (SPT) over a mean observation period ≥ 10 years. Assessment of the identified studies and data extraction were performed independently by two reviewers. Authors were contacted if required. Collected data were reported by descriptive methods. RESULTS The initial electronic search resulted in the identification of 994 titles from Medline via PubMed and 531 titles from Embase via Ovid databases, respectively. After elimination of duplicate titles and exclusion of 60 full-text articles, 143 articles were analyzed, resulting in 15 studies eligible for qualitative analysis. The implant survival rate ranged from 85.7% to 99.2% after a mean observation period ≥ 10 years. One comparative study assessed the effects of regular SPT on the occurrence of biologic complications and implant loss. Overall, regular diagnosis and implementation of anti-infective therapeutic protocols were effective in the management of biological complications and prevention of implant loss. Residual probing depths at the end of active periodontal therapy and development of reinfection during supportive periodontal therapy (SPT) represented a significant risk for the onset of peri-implantitis and implant loss. Comparative studies indicated that implant survival and success rates were lower in periodontally compromised vs noncompromised patients. CONCLUSIONS In order to achieve high long-term survival and success rates of dental implants and their restorations, enrollment in regular SPT including anti-infective preventive measures should be implemented. Therapy of peri-implant mucositis should be considered as a preventive measure for the onset of peri-implantitis. Completion of active periodontal therapy should precede implant placement in periodontally compromised patients.

EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders.

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1β, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions.

Wound models for periodontal and bone regeneration: the role of biologic research

The ultimate goals of periodontal therapy remain the complete regeneration of those periodontal tissues lost to the destructive inflammatory-immune response, or to trauma, with tissues that possess the same structure and function, and the re-establishment of a sustainable health-promoting biofilm from one characterized by dysbiosis. This volume of Periodontology 2000 discusses the multiple facets of a transition from therapeutic empiricism during the late 1960s, toward regenerative therapies, which is founded on a clearer understanding of the biophysiology of normal structure and function. This introductory article provides an overview on the requirements of appropriate in vitro laboratory models (e.g. cell culture), of preclinical (i.e. animal) models and of human studies for periodontal wound and bone repair. Laboratory studies may provide valuable fundamental insights into basic mechanisms involved in wound repair and regeneration but also suffer from a unidimensional and simplistic approach that does not account for the complexities of the in vivo situation, in which multiple cell types and interactions all contribute to definitive outcomes. Therefore, such laboratory studies require validatory research, employing preclinical models specifically designed to demonstrate proof-of-concept efficacy, preliminary safety and adaptation to human disease scenarios. Small animal models provide the most economic and logistically feasible preliminary approaches but the outcomes do not necessarily translate to larger animal or human models. The advantages and limitations of all periodontal-regeneration models need to be carefully considered when planning investigations to ensure that the optimal design is adopted to answer the specific research question posed. Future challenges lie in the areas of stem cell research, scaffold designs, cell delivery and choice of growth factors, along with research to ensure appropriate gingival coverage in order to prevent gingival recession during the healing phase.

The biologic and signaling effects of Tiam1 overexpression in colorectal carcinoma

Cellular migration is essential to many normal cellular processes. In tumor cells, aberrant activation of the normal pathways regulating migration is one of the critical steps in the development of metastasis. Previously, I demonstrated for the first time that overexpression of Tiam1, a guanine nucleotide exchange factor (GNEF) for small G proteins in the Rho family, could alter migration in colorectal tumor cells. ^ This dissertation focuses on the roles of Tiam1 in promoting cell migration, survival, and metastasis of colorectal carcinoma cells, utilizing the model system I developed. To determine the in vivo phenotype of the migratory cell lines, athymic nude mice were injected with cells into the orthotopic site. Several of the mice injected with cells of increased migratory potential had metastases. Thus, the in vitro selection for increased migration resulted in increased metastatic potential in vivo, and therefore, the Tiam1-overexpressing cells provide a model to examine signal transduction pathways important to this process. ^ To examine effects of Tiam1 signaling on small G proteins critical to cellular functions associated with migration, I examined the activation status of the small G proteins Rac, Rho, and Cdc42. The cells of increased migratory potential have increased GTP-bound Rac and Rho, compared to control SW480 cells. Cells that overexpress Tiam1 are more migratory and are resistant to detachment-induced death, or anoikis. To determine which effects and phenotypes were Tiam1-specific, we utilized siRNA to downregulate Tiam1 expression. These results demonstrate that Tiam1 is sufficient but not required for the migration of colorectal carcinoma cells in our model system, and that the biologically selected cells have additional changes that promote migration besides the increase in Tiam1. I also show that Tiam1 protects colorectal carcinoma cells from detachment-induced death, but is not required for anoikis resistance in the biologically selected migratory cells. ^ In summary, my studies demonstrate a heretofore-unknown regulator of phenotypes critical to the development of colorectal carcinoma metastases, overexpression of Tiam1. Understanding the mechanism by which Tiam1 contributes to cellular migration and metastasis is crucial to developing desperately needed new therapies for colorectal carcinoma. ^