Evaluating Autologous Lipofilling for Parry-Romberg Syndrome-Associated Defects: A Systematic Literature Review and Case Report.

BACKGROUND: Parry-Romberg syndrome (PRS) is a rare craniofacial disease that causes progressive hemifacial atrophy of the soft tissue before spontaneously entering remission. Autologous fat grafting may provide a less invasive alternative, producing aesthetically pleasing results while avoiding the need for traditional microsurgical free flap coverage. METHODS: A systematic review of the literature was conducted. Inclusion and exclusion criteria were applied. The case report highlights the technique using two-dimensional and three-dimensional photography. RESULTS: Our review yielded 31 articles in addition to our case describing 147 cases of lipofilling to correct PRS soft-tissue defects. Patients underwent an average of 2.2 procedures, receiving on average 95 mL of grafted fat. Disease severity was classified into mild (41%), moderate (42%), and severe (17%) in the identified patients. Increasing disease severity correlated with an increasing number of procedures and fat-grafting volumes to achieve adequate aesthetic outcomes (mean, 1.5 and 38 mL; 2.3 and 81 mL; 3.7 and 129 mL, respectively). Reported benefits over flap-based reconstructions included reductions in cost (40%), operative time (50%), donor-site morbidity (52%), and rate of complications (33%). Aesthetic benefits cited included improved skin quality (65%), more natural contours (1%), and more natural facial expressions (10%). CONCLUSION: Fat grafting for correction of PRS-associated soft-tissue defects is receiving heightened acceptance for its ability to restore natural facial contours. While additional fat-grafting procedures may be required with increased disease severity, autologous fat grafting may be a beneficial option as a sole modality to correct PRS-associated soft-tissue atrophy.

Targeting c-Met in melanoma: mechanism of resistance and efficacy of novel combinatorial inhibitor therapy.

Numerous tyrosine kinase inhibitors (TKIs) targeting c-Met are currently in clinical trials for several cancers. Their efficacy is limited due to the development of resistance. The present study aims to elucidate this mechanism of c-Met TKI resistance by investigating key mTOR and Wnt signaling proteins in melanoma cell lines resistant to SU11274, a c-Met TKI. Xenografts from RU melanoma cells treated with c-Met TKIs SU11274 and JNJ38877605 showed a 7- and 6-fold reduction in tumor size, respectively. Resistant cells displayed upregulation of phosphorylated c-Met, mTOR, p70S6Kinase, 4E-BP1, ERK, LRP6, and active ß-catenin. In addition, GATA-6, a Wnt signaling regulator, was upregulated, and Axin, a negative regulator of the Wnt pathway, was downregulated in resistant cells. Modulation of these mTOR and Wnt pathway proteins was also prevented by combination treatment with SU11274, everolimus, an mTOR inhibitor, and XAV939, a Wnt inhibitor. Treatment with everolimus, resulted in 56% growth inhibition, and a triple combination of SU11274, everolimus and XAV939, resulted in 95% growth inhibition in RU cells. The V600E BRAF mutation was found to be positive only in MU cells. Combination treatment with a c-Met TKI and a BRAF inhibitor displayed a synergistic effect in reducing MU cell viability. These studies indicate activation of mTOR and Wnt signaling pathways in c-Met TKI resistant melanoma cells and suggest that concurrent targeting of c-Met, mTOR, and Wnt pathways and BRAF may improve efficacy over traditional TKI monotherapy in melanoma patients.

Advances in oncologic head and neck reconstruction: systematic review and future considerations of virtual surgical planning and computer aided design/computer aided modeling.

BACKGROUND: Mastery of craniomaxillofacial reconstruction has been traditionally considered to be learning curve dependent, often with inconsistent results during the skill acquisition phase. Until recently, the overall success in bony oncologic reconstruction of the craniomaxillofacial skeleton has relied mainly on the use of 2D imaging modalities, as well as surgical trial-and-error. Virtual surgical planning (VSP) and computer aided design (CAD)/computer aided modeling (CAM) are gaining traction in oncologic applications and offers opportunity for increased accuracy, improved efficiency, and enhanced outcomes. Its role in oncologic head and neck reconstruction has not been formally evaluated. METHODS: A systematic review of the current literature was conducted by three independent reviewers. Three separate search schemes were utilized to identify cases incorporating VSP-CAD/CAM technology in head and neck reconstruction for an oncologic indication. Inclusion and exclusion criteria were applied; articles that met criteria were evaluated for cohort demographics, osteocutaneous flap type and usage, oncologic indication, recipient bone reconstructed, flap survival, follow up, VSP technology usage, specific reported benefits of the technology, and qualitative and quantitative outcome assessments. RESULTS: The systematic literature review yielded 87 articles; of these, 33 met inclusion criteria describing a total of 220 cases of oncologic head and neck reconstruction incorporating virtual planning technology. Numerous qualitative benefits of VSP were reported including increased accuracy of the reconstruction (93%), decreased intraoperative time (80%), and ease of use (24%) among others. However, quantitative results using survey data or preoperative/postoperative CT scan comparisons were given for only 33% (3%, 30% respectively) of cases. CONCLUSION: VSP represents an evolving technology that ushers oncological craniomaxillofacial reconstruction into a modern era that holds potential to advance the field with increased reconstructive accuracy, expedition of the surgical phase, and improved outcomes. While qualitative improvements from the technology are delineated, specific quantifiable benefits and cost-benefit analysis are limited and need to be further investigated.

Alternative signaling pathways as potential therapeutic targets for overcoming EGFR and c-Met inhibitor resistance in non-small cell lung cancer.

The use of tyrosine kinase inhibitors (TKIs) against EGFR/c-Met in non-small cell lung cancer (NSCLC) has been shown to be effective in increasing patient progression free survival (PFS), but their efficacy is limited due to the development of resistance and tumor recurrence. Therefore, understanding the molecular mechanisms underlying development of drug resistance in NSCLC is necessary for developing novel and effective therapeutic approaches to improve patient outcome. This study aims to understand the mechanism of EGFR/c-Met tyrosine kinase inhibitor (TKI) resistance in NSCLC. H2170 and H358 cell lines were made resistant to SU11274, a c-Met inhibitor, and erlotinib, an EGFR inhibitor, through step-wise increases in TKI exposure. The IC50 concentrations of resistant lines exhibited a 4-5 and 11-22-fold increase for SU11274 and erlotinib, respectively, when compared to parental lines. Furthermore, mTOR and Wnt signaling was studied in both cell lines to determine their roles in mediating TKI resistance. We observed a 2-4-fold upregulation of mTOR signaling proteins and a 2- to 8-fold upregulation of Wnt signaling proteins in H2170 erlotinib and SU11274 resistant cells. H2170 and H358 cells were further treated with the mTOR inhibitor everolimus and the Wnt inhibitor XAV939. H358 resistant cells were inhibited by 95% by a triple combination of everolimus, erlotinib and SU11274 in comparison to 34% by a double combination of these drugs. Parental H2170 cells displayed no sensitivity to XAV939, while resistant cells were significantly inhibited (39%) by XAV939 as a single agent, as well as in combination with SU11274 and erlotinib. Similar results were obtained with H358 resistant cells. This study suggests a novel molecular mechanism of drug resistance in lung cancer.