Intramuscular cavernous malformation in the temporalis muscle: Diagnosis and treatment of a rare tumor in a rare site.

In this case report we present a very rare case of intramuscular cavernous hemangioma in the temporalis muscle which was successfully managed with surgical excision with no evidence of recurrence in follow-up.

TransCon IL-2 ß/γ: a novel long-acting prodrug with sustained release of an IL-2Rß/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer.

BACKGROUND: Recombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe toxicities including cytokine storm and vascular leak syndrome (VLS). IL-2 promotes antitumor function of IL-2Rß/γ+ natural killer (NK) cells and CD8+, CD4+ and gamma delta (γδ) T cells. However, IL-2 also potently activates immunosuppressive IL-2Rα+ regulatory T cells (Tregs) and IL-2Rα+ eosinophils and endothelial cells, which may promote VLS. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high Cmax likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2Rα+ cells and suboptimal pharmacokinetics with high Cmax and short half-life. METHODS: TransCon IL-2 ß/γ was designed to optimally address these drawbacks. To abolish IL-2Rα binding yet retain strong IL-2Rß/γ activity, IL-2 ß/γ was created by permanently attaching a small methoxy polyethylene glycol (mPEG) moiety in the IL-2Rα binding site. To improve pharmacokinetics, IL-2 ß/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 ß/γ, with sustained release of IL-2 ß/γ. IL-2 ß/γ was characterized in binding and primary cell assays while TransCon IL-2 ß/γ was studied in tumor-bearing mice and cynomolgus monkeys. RESULTS: IL-2 ß/γ demonstrated selective and potent human IL-2Rß/γ binding and activation without IL-2Rα interactions. TransCon IL-2 ß/γ showed slow-release pharmacokinetics with a low Cmax and a long (>30 hours) effective half-life for IL-2 ß/γ in monkeys. In mouse tumor models, TransCon IL-2 ß/γ promoted CD8+ T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 ß/γ induced robust activation and expansion of CD8+ T cells, NK cells and γδ T cells, relative to CD4+ T cells, Tregs and eosinophils, with no evidence of cytokine storm or VLS. Similarly, IL-2 ß/γ enhanced proliferation and cytotoxicity of primary human CD8+ T cells, NK cells and γδ T cells. SUMMARY: TransCon IL-2 ß/γ is a novel long-acting prodrug with sustained release of an IL-2Rß/γ-selective IL-2. It has remarkable and durable pharmacodynamic effects in monkeys and potential for improved clinical efficacy and tolerability compared with aldesleukin. TransCon IL-2 ß/γ is currently being evaluated in a Phase 1/2 clinical trial (NCT05081609).

Does P16 Protein Expression Affect Treatment Prognosis in Oral Squamous Cell Carcinoma - A Comparative Study.

INTRODUCTION: P16 is an independent and reliable surrogate for the detection of human papillomavirus (HPV) in oral squamous cell carcinoma (OSCC). The aim of this study was to assess the P16 expression as a marker for HPV infection in OSCC and its impact on the treatment outcome. METHODS AND MATERIALS: A cross-sectional study was conducted on patients with a definite diagnosis of OSCC. Patients were assigned into two groups with and without recurrence or metastasis. Tumour resection was performed in the same manner for all patients. P16 expression was evaluated by immunohistochemical staining. Independent t-test and Chi-square tests were used to find significant differences in age, gender, stage of the disease, tumour size, lymph node involvement, and P16 expression between the two groups. RESULTS: Of 50 patients, 37 did not show any recurrence or metastasis (group 1), while 13 had a relapse (group 2). There was no significant difference for age, gender distribution, stage of the disease, or lymph node involvement between the two groups (P > 0.05). A significant difference in tumour size was noted between the two groups (P = 0.001). The mean expression of P16 was 38.92 ± 24.36 in group 1 and 51.54 ± 33.63 in group 2. No significant difference was found between the two groups for the mean expression of P16 (P = 0.23). DISCUSSION: A review of the recent literature revealed that the HPV role in OSCC treatment is controversial. According to the results of this study, there was no significant difference in terms of P16 expression between OSCC patients with and without recurrence or metastasis.

Penetrating Orbital Injury; a Case Report and Treatment Algorithm.

Penetrating orbital trauma (POT) consists of high and low velocity penetrating injuries that may lead to severe consequences such as visual impairment and globe tearing. It has been reported to make up 30% to 50% of all orbital injuries. POT requires a multidisciplinary approach due to complex orbital injury, which involves eye function, brain injury, and facial aesthetics. In this report, we presented a case of POT due to knife injury in which the knife blade was removed and bleeding was controlled, the patient's general condition after surgery was good, but the vision of the right eye was lost.

Pharmacokinetic Properties of Humanized IgG1 and IgG4 Antibodies in Preclinical Species: Translational Evaluation.

Assessment of the factors that regulate antibody exposure-response relationships in the relevant animal models is critical for the design of successful translational strategies from discovery to the clinic. Depending on the specific clinical indication, preclinical development paradigms may require that the efficacy or dosing-related attributes for the existing antibody be assessed in various species when cross-reactivity of the lead antibody to the intended species is justified. Additionally, with the success of monoclonal antibodies for management of various human conditions, a parallel interest in therapeutic use of these novel modalities in various veterinary species has followed. The protective role of neonatal Fc receptor (FcRn) in regulation of IgG homeostasis and clearance is now well recognized and the "nonspecific clearance" of antibodies through bone marrow-derived phagocytic and vascular endothelial cells (via lysosomal processes) is modulated by interactions with FcRn receptors. In this study, we have attempted to examine the PK properties of human IgG antibodies in dog and monkey. These studies establish a translational framework for evaluation of IgG antibody PK properties across species.

Integrative Pharmacology: Advancing Development of Effective Immunotherapies.

With the recent advances in cancer immunotherapy, it is now evident that the antigen-specific activation of the patients' immune responses can be utilized for achieving significant therapeutic benefits. Novel molecules have been developed and promising advances have been achieved in cancer therapy. The recent success of cancer immunotherapy clearly reflects the novelty of the approach and importance of this class of therapeutics. Due to the nature of immunotherapy, i.e., harnessing the patient's immune system, it becomes critical to evaluate the important variables that can guide preclinical development, translational strategies, patient selection, and effective clinical dosing paradigms following single and combination therapies. To further boost the durability and efficacy profiles of IO (immuno-oncology) drugs following single agent therapy, novel combination therapies are being sought. Combination strategies have become critical for enhancing the anti-tumor immunity in broader cancer indications. Comprehensive methods are being developed to quantify the synergistic combination effect profiles at various development phases. Further evaluation of the signaling and pathway components can potentially establish a unique "signature" characteristic for specific combination therapies following modulation of various immunomodulatory pathways. In this article, critical topics related to preclinical, translational, and clinical development of IO agents are discussed.

Salivary Visfatin Concentration in Response to Non-surgical Periodontal Therapy.

INTRODUCTION: Visfatin is a pro-inflammatory cytokine that has been associated with several immunomodulating processes. The relationship between visfatin and periodontitis has been the subject of a few studies that have described visfatin as an inflammatory marker for periodontitis. However, studies on visfatin as a potential therapeutic target in periodontal diseases are scarce. In the present study, we evaluated the alterations in salivary visfatin levels in response to non-surgical periodontal treatment. MATERIALS AND METHODS: Twenty individuals with moderate to severe chronic periodontitis and twenty periodontally healthy individuals were selected for this study according to clinical parameters. Patients with chronic periodontitis were treated by non-surgical periodontal therapy. Clinical parameters were recorded and saliva samples were obtained from the control group and test group before (T1 group) and one month after periodontal treatment (T2 group). Salivary visfatin concentrations were measured by standard enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed with the statistical software SPSS, version 18. RESULTS: Visfatin was detectable in all samples. T1 and control groups were significantly different in terms of clinical parameters and visfatin levels. Visfatin concentrations were reduced significantly after non-surgical periodontal therapy. Periodontal treatment also resulted in significant reductions of all clinical parameters with the exception of clinical attachment level. CONCLUSION: The results demonstrated that salivary levels of visfatin are reduced after non-surgical periodontal therapy to the levels comparable with those found in healthy individuals. Therefore, the salivary visfatin level may have the potential to be a target marker for assessment of responses to non-surgical periodontal therapy. However, more studies with larger sample sizes are necessary to validate these findings.

Salivary soluble receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio in periodontal disease and health.

PURPOSE: The receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system plays a significant role in osteoclastogenesis, activation of osteoclasts, and regulation of bone resorption. This study aimed to evaluate the use of the salivary soluble RANKL (sRANKL)/OPG ratio as a diagnostic marker for periodontitis in nonsmokers. METHODS: Twenty-five patients with chronic periodontitis and 25 individuals with a healthy periodontium were enrolled in this study. Samples containing 5 mL of unstimulated saliva were obtained from each subject. Salivary sRANKL and OPG concentrations were determined using a standard enzyme-linked immunosorbent assay. Statistical analysis was performed using SPSS ver. 18.0. RESULTS: The levels of sRANKL and OPG were detectable in all of the samples. Positive relationships were found between the plaque index and clinical attachment level and both the salivary concentration of sRANKL and the salivary sRANKL/OPG ratio (P<0.05). The salivary concentration of sRANKL and the sRANKL/OPG ratio were significantly higher in the periodontitis group than in the healthy group (P=0.004 and P=0.001, respectively). In contrast, the OPG concentration showed no significant differences between the groups (P=0.455). CONCLUSIONS: These findings suggest that the salivary sRANKL/OPG ratio may be helpful in the screening and diagnosis of periodontitis. However, longitudinal studies with larger populations are needed to confirm these results.

Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth.

Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R-targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI-573 significantly inhibited the in vivo growth of IGF-I- or IGF-II-driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of (18)F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways.

Population pharmacokinetic evaluation of a fully human IgG monoclonal antibody in patients with inflammatory diseases.

ABX-IL8 is a fully human IgG2 monoclonal antibody generated using transgenic mouse technology (Xenomouse®) that binds to human Interleukin-8 with high affinity and specificity. The objective of this study was to evaluate the pharmacokinetic (PK) properties of ABX-IL8 in patients with active inflammatory diseases. Patients with psoriasis and rheumatoid arthritis received single or multiple short intravenous infusions of ABX-IL8 or placebo. Serum concentrations of ABX-IL8, baseline serum IgG and IgG2 concentrations and Anti-Drug Antibody (ADA) response to ABX-IL8 were determined using relevant immunoassays. Pharmacokinetic analyses of the serum ABX-IL8 concentration-time data were performed. Following single-dose administration of ABX-IL8, dose proportional increases in drug exposure were observed. Consistent with the disposition properties of the endogenous IgG antibodies, ABX-IL8 appeared to be primarily distributed into the plasma compartment and the extra-vascular fluid and the steady-sate volume of distribution (61 ± 14 to 71 ± 14 mL/kg) was comparable to that for the endogenous antibodies. Following the multiple-dose administration, PK properties of the antibody were linear with dose and time. Steady-state clearance (2.6 ± 1.1 to 2.7 ± 1.4 mL/day/kg) was similar to that observed following the single dose administration and no ADA response was detected throughout the study. PK variability and serum exposure to ABX-IL8 following administration of the fixed doses were comparable to those observed following administration of the weight-adjusted doses; the impact of body weight on clearance was minimal and this correlation did not translate into requirements for body weight-adjusted dosing. Additionally, age and disease type (psoriasis or RA) had no impact on ABX-IL8 pharmacokinetics.

Biomechanical stress distribution on fixation screws used in bilateral sagittal split ramus osteotomy: assessment of 9 methods via finite element method.

PURPOSE: The aim of this study was to assess the biomechanical stress tolerance of screws used in 9 fixation methods after bilateral sagittal split ramus osteotomy to determine which configuration leads to lesser force load on the cortical bone at fixation points. MATERIALS AND METHODS: A 3-dimensional computerized model of a human mandible with posterior teeth was generated. The bilateral sagittal split ramus osteotomy was virtually performed on this model. The separated model was assembled with 9 fixation methods: single screw, 2 screws one behind the other, 2 screws one below the other, 3 screws in an L configuration, 3 screws in an inverted backward L configuration, miniplate with 2 screws, miniplate with 4 screws, 2 parallel plates (upper + lower border), and square miniplate with 4 screws. Then, 75-, 135-, and 600-N vertical loads were applied on the posterior teeth of these models. The stress distribution on the screw sites on the buccal cortex was measured by the finite element method. RESULTS: In this model all the fixation methods withstood forces between 75 and 135 N. However, the single-screw and the 2-hole miniplate models showed that the stress distributions in the configurations were intolerable when 600 N of posterior force was applied. The results of this study indicated that the inverted backward L configuration with 3 bicortical screws was the most stable. CONCLUSION: Although this study indicated that the inverted backward L configuration with 3 bicortical screws was the most stable pattern, most of the patterns had adequate stability for clinical applications (mean, 125 N).

Application of quantitative pharmacology in development of therapeutic monoclonal antibodies.

The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose- and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

Trigeminocardiac reflex during Le Fort I osteotomy: a case-crossover study.

OBJECTIVE: The present study aimed to assess the occurrence of trigeminocardiac reflex (TCR) during Le Fort I osteotomies. STUDY DESIGN: This case-crossover study included 25 Le Fort I osteotomy candidates without systemically compromising conditions. Mean arterial blood pressure and pulse rate values were recorded before downfracture (DF) (MABP1, PR1), during DF (MABP2, PR2), and after DF (MABP3, PR3). The data were analyzed using repeated measure ANOVA tests (alpha = 0.05). RESULTS: PR1 and PR3 were significantly higher than PR2 (P < .001). MABP2 value was significantly lower compared with MABP1 and MABP3 values (P < .001). PR2 and MABP2 showed a mean decrease of 6.5% and 9.7% compared with PR1 and MABP1, respectively. CONCLUSION: Different values have been suggested for TCR. Considering the limitations, the present study may suggest a revision of the values or descriptions for TCR, at least in maxillofacial Le Fort I osteotomy.

A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models.

Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis, making it an attractive candidate for antiangiogenic therapy. A fully human monoclonal antibody (3.19.3) was developed, which may have significant pharmaceutical advantages over synthetic peptide-based approaches in terms of reduced immunogenicity and increased half-life to block Ang2 function. The 3.19.3 antibody potently binds Ang2 with an equilibrium dissociation constant of 86 pmol/L, leading to inhibition of Tie2 receptor phosphorylation in cell-based assays. In preclinical models, 3.19.3 treatment blocked blood vessel formation in Matrigel plug assays and in human tumor xenografts. In vivo studies with 3.19.3 consistently showed broad antitumor activity as a single agent across a panel of diverse subcutaneous and orthotopic xenograft models. Combination studies of 3.19.3 with cytotoxic drugs or anti-vascular endothelial growth factor agents showed significant improvements in antitumor activity over single-agent treatments alone with no apparent evidence of increased toxicity. Initial pharmacokinetic profiling studies in mice and nonhuman primates suggested that 3.19.3 has a predicted human half-life of 10 to 14 days. These studies provide preclinical data for 3.19.3 as a potential new antiangiogenic therapy as a single agent or in combination with chemotherapy or vascular endothelial growth factor inhibitors for the treatment of cancer.

Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies.

Despite the widespread use of rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop new agents with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 anti-CD20 monoclonal antibody was generated. This antibody, denoted mAb 1.5.3, evoked enhanced pro-apoptotic activity in vitro, as compared to rituximab, in the Ramos lymphoma cell line. Also, mAb 1.5.3 mediated both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) similar to rituximab in human B-lymphoma lines. Interestingly, mAb 1.5.3 demonstrated superior ADCC compared to rituiximab when FcgammaRIIIa F/F allotype donors were profiled and superior cytolytic activity across multiple human B-lymphoma and chronic B-cell leukemia lines in an in vitro whole blood assay. Furthermore, mAb 1.5.3 exhibited enhanced anti-tumor activity in Ramos, Daudi, and Namalwa tumour xenograft models. Lastly, mAb 1.5.3 produced a superior B-cell depletion profile in lymph node organs and bone marrow as compared to rituximab in a primate pharmacodynamic (PD) model. These findings underscore the potential of mAb 1.5.3 to exhibit improved clinical activity in the treatment of B-cell malignancies compared to rituximab.

Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease.

The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.

Surrogate approaches in development of monoclonal antibodies.

When cross-reactivity of a lead antibody across species is limited, antibody development programs require the generation of surrogate molecules or surrogate animal models necessary for the conduct of preclinical pharmacology and safety studies. When surrogate approaches are employed, the complexities and challenges for translation of preclinical safety and efficacy results to the clinic are undoubtedly enhanced. Because there are no currently established criteria or regulatory guidance regarding the application of surrogate approaches, a science-based strategy for translation of preclinical information to the clinic is vital for effective development of the lead antibody.

Translational strategies for development of monoclonal antibodies from discovery to the clinic.

Successful strategies for the development of monoclonal antibodies require integration of knowledge with respect to target antigen properties, antibody design criteria such as affinity, isotype selection, Fc domain engineering, PK/PD properties and antibody cross-reactivity across species from the early stages of antibody development. Biophysical measurements are one of the critical components necessary for the design of effective translational strategies for lead selection and evaluation of relevant animal species for preclinical safety and efficacy studies. Incorporation of effective translational strategies from the early stages of the antibody development process is a necessity; when considered it not only reduces development time and cost, but also fosters implementation of rational decision-making throughout all phases of antibody development.

Application of analytical detection concepts to immunogenicity testing.

The cut point and detection limit of any immunogenicity assay are two of the most important quantities that define the adequacy of an assay for detecting anti-drug antibodies against therapeutic proteins. To date in the immunogenicity testing literature, only the type I (alpha) error (i.e., the false positive) rate of the assay has been considered for establishing cut points. The "sensitivity" of an immunogenicity assay is usually reported as the concentration of a monoclonal or polyclonal anti-drug antibody standard corresponding to the signal at the cut point. We propose that a more traditional and rigorous analytical chemistry definition of the detection capability be utilized wherein both type I and type II (beta, false negative) error rates are considered. Specifically, the Hubaux-Vos technique of calculating cut points and limits of detection from predication intervals on calibration curves is recommended as a statistically rigorous approach. The utility of using receiver-operator characteristic curves for managing the type I and II error rates of an immunogenicity assay is also presented. In addition, we illustrate how a soluble receptor, sMUC18, for the therapeutic mAb ABX-MA1 can result in false positives by Biacore methodology. This result suggests that immunogenicity confirmatory experiments must be carefully designed, preferably with a smaller type I and II error rate than in the primary screening if an acceptable limit of detection can be maintained.