Albert H. Park

A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.

Targeting DLL3 with an antibody-drug conjugate eliminates tumor-initiating cells in high-grade pulmonary neuroendocrine cancers. Not just another Notch Pulmonary neuroendocrine tumors, such as small cell lung cancer, are among the most difficult cancers to treat. Although standard chemotherapy regimens are available for this type of cancer, their effects are only transient, and the tumors typically acquire resistance to the drugs very quickly. Saunders et al. have discovered that DLL3, a ligand in the Notch signaling pathway, is associated with the neuroendocrine cancer phenotype. The authors targeted DLL3 with an antibody conjugated to a cytotoxic drug, which proved to be much more effective than standard chemotherapy for treating patient-derived tumor xenografts. Unlike chemotherapy, the anti-DLL3 treatment appeared to be particularly effective against tumor-initiating cells, which may account for its efficacy. The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.

Mitigation of tracheobronchomalacia with 3D-printed personalized medical devices in pediatric patients

Patient-specific, image-based design coupled with 3D biomaterial printing produced personalized implants for treatment of collapsed airways in patients with tracheobronchomalacia. Printing in 4D: Personalized implants The 3D printing revolution is in full swing, with frequent reports of printed kidneys and jaws, dolls and cars, food, and body armor. The new challenge is to make 3D materials evolve in the fourth dimension: time. Such “4D” materials could change in response to temperature, light, or even stress, making them adaptable and enduring. In pediatric medicine, 4D implants become particularly relevant; as the patient grows, so, too, should the material. Morrison et al. used 3D printing technology with a safe, bioresorbable polymer blend to create splints for three pediatric patients with tracheobronchomalacia (TBM)—a condition of excessive collapse of the airways during normal breathing. Currently available fixed-size implants can migrate and require frequent resizing. Thus, the authors used imaging and computational models to design the splints for each TBM patient’s individual geometries, structuring the implants to accommodate airway growth and prevent external compression over a period of time, before being resorbed by the body. In all three patients (one with two airways splinted), the 4D devices were implanted without issue. All four implants were stable and functional after 1 month, and one implant has remained in place, keeping the airway open for over 3 years. This pilot trial demonstrates that the fourth dimension is a reality for 3D-printed materials, and with continued human studies, 4D biomaterials promise to change the way we envision the next generation of regenerative medicine. Three-dimensional (3D) printing offers the potential for rapid customization of medical devices. The advent of 3D-printable biomaterials has created the potential for device control in the fourth dimension: 3D-printed objects that exhibit a designed shape change under tissue growth and resorption conditions over time. Tracheobronchomalacia (TBM) is a condition of excessive collapse of the airways during respiration that can lead to life-threatening cardiopulmonary arrests. We demonstrate the successful application of 3D printing technology to produce a personalized medical device for treatment of TBM, designed to accommodate airway growth while preventing external compression over a predetermined time period before bioresorption. We implanted patient-specific 3D-printed external airway splints in three infants with severe TBM. At the time of publication, these infants no longer exhibited life-threatening airway disease and had demonstrated resolution of both pulmonary and extrapulmonary complications of their TBM. Long-term data show continued growth of the primary airways. This process has broad application for medical manufacturing of patient-specific 3D-printed devices that adjust to tissue growth through designed mechanical and degradation behaviors over time.

Injectable synthetic extracellular matrices for tissue engineering and repair.

The development of novel biointeractive hydrogels for tissue engineering1, 2, 3, tissue repair, and release of drugs4 and growth factors5 has attracted considerable attention over the past decade. Our attention has focused on hydrogels based on the extracellular matrix (ECM), a heterogeneous collection of covalent and noncovalent molecular interactions comprised primary of proteins and glycosaminoglycans (GAGs)6. In the ECM, covalent interactions connect chondroitin sulfate (CS), heparan sulfate (HS) and other sulfated GAGs to core proteins forming proteoglycans (PGs). Noncovalent interactions include binding of link modules of PGs to hyaluronan (HA), electrostatic associations with ions, hydration of the polysaccharide chains, and triple helix formation to generate collagen fibrils.

Endoscopic versus traditional approaches to choanal atresia

With the introduction of endoscopic techniques and powered instrumentation for pediatric sinusitis, one would expect that the definitive treatment of congenital choanal atresia has been established. An international survey of pediatric otolaryngologists and the plethora of surgical approaches in the literature, however, indicate that there is still much controversy in its management. This article addresses this controversy between endoscopic and traditional approaches to neonatal bilateral bony choanal atresia and proposes guidelines for optional treatment.

Management of pediatric ranula.

OBJECTIVE: Many surgical techniques to manage ranulas have been described in the literature. These techniques include excision of the cyst with or without excision of the ipsilateral sublingual gland, marsupialization, cryosurgery, and CO2 laser excision. Few studies have described the approach toward management in pediatric patients. METHODS: Six patients were treated for intraoral ranulas. Two patients had spontaneous resolution of their lesions. Four patients required dissection of the submandibular duct and lingual nerve to completely excise an oral cavity ranula and an ipsilateral sublingual gland. RESULTS: There were no recurrent lesions. One patient developed a lingual nerve injury but no numbness. The 2 patients with spontaneous resolution did not develop a subsequent lesion. CONCLUSION: Optimal management of pediatric oral cavity ranulas may include observation for 5 months for spontaneous resolution. If the lesion does not resolve or recurs repeatedly, surgical treatment is recommended. Submandibular duct dissection with relocation appears to enhance exposure to the floor of mouth. The pseudocyst and entire sublingual gland should be removed. Identification of the lingual nerve is necessary to accomplish this goal.

Sleep Disordered Breathing and Obstructive Sleep Apnea in the Cleft Population

Objectives/Hypothesis: Children with cleft deformities have the tendency for multilevel airway obstruction. The incidence of sleep disordered breathing (SDB) in this population has not been well studied. This study attempts to describe the high incidence and the results of intervention.

Clinical Course of Pediatric Congenital Inner Ear Malformations

Objective To determine any factors that could improve the early detection and management of congenital inner ear malformations.

Should All Newborns Who Undergo Patent Ductus Arteriosus Ligation Be Examined for Vocal Fold Mobility

To determine the incidence of left vocal fold paralysis (LVFP) in premature infants who undergo patent ductus arteriosus (PDA) ligation.

Identification of hearing loss in pediatric patients with Down syndrome.

Objective. To determine the type of hearing loss, incidence of the lost to follow-up rate, and the time to diagnose sensorineural hearing loss (SNHL) in children with Down syndrome (DS) identified from a statewide database. Study Design. Case series with chart review. Setting. Pediatric referral center. Subjects and Methods. Three hundred forty-four patients with DS born in Utah between January 2002 and December 2006 were identified using the Utah Department of Health’s Newborn Hearing Screening database and birth defects registry. Results. Three hundred thirty-two patients were included in the study. Eighty-seven infants (26.2%) did not pass their newborn hearing screening (NBS). Thirty-three of these children (37.9%) had a conductive hearing loss attributed to serous otitis media. Five infants had SNHL; 3 children were diagnosed with a mixed hearing loss (MHL). The average time to diagnose a sensorineural hearing loss was 485 ± 601 days. One child who passed his NBS was subsequently found to have an SNHL. More than 43% of the newborns with DS who passed their NBS developed a conductive hearing loss requiring insertion of ventilation tubes. Eighty-four percent of newborns with DS who did not undergo NBS did not have any apparent subsequent audiologic testing. Conclusion. Patients with DS present with a relatively high incidence of conductive hearing loss, MHL, and SNHL and a higher lost to follow-up rate compared to patients without DS. The authors were not able to diagnose SNHL within the 90-day period recommended by the Joint Committee on Infant Hearing.

Odontogenic myxoma of the maxilla: a report of two pediatric cases

Myxomas are benign, slow growing neoplasms derived from mesenchyme. While these tumors most frequently occur in the myocardium, the other sites most commonly affected are the maxilla and mandible. Nevertheless, myxoma is a very uncommon lesion of the midface, particularly in the pediatric population. We present two reports of infant children with midfacial myxomas. The clinical features, radiographic evaluation and treatment of these cases will be presented.