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Journal of Clinical Oncology : Official... Apr 2023Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20 B cells....
PURPOSE
Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20 B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes.
PATIENTS AND METHODS
In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037), adults with relapsed or refractory CD20 large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee.
RESULTS
As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event.
CONCLUSION
Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.
Topics: Adult; Humans; Middle Aged; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Agents; T-Lymphocytes; Receptors, Chimeric Antigen
PubMed: 36548927
DOI: 10.1200/JCO.22.01725 -
Polymers Sep 2022This paper introduces a complex novel concept and methodology for the creation of personalized biomedical appliances 3D-printed from certified biocompatible photopolymer...
This paper introduces a complex novel concept and methodology for the creation of personalized biomedical appliances 3D-printed from certified biocompatible photopolymer resin Dental LT Clear (V2). The explained workflow includes intraoral and CT scanning, patient virtualization, digital appliance design, additive manufacturing, and clinical application with evaluation of the appliance intended for patients with cranio-facial syndromes. The presented concept defines virtual 3D fusion of intraoral optical scan and segmented CT as sufficient and accurate data defining the 3D surface of the face, intraoral and airway morphology necessary for the 3D design of complex personalized intraoral and extraoral parts of the orthopedic appliance. A central aspect of the concept is a feasible utilization of composite resin for biomedical prototyping of the sequence of marginally different appliances necessary to keep the pace with the patient rapid growth. Affordability, noninvasiveness, and practicality of the appliance update process shall be highlighted. The methodology is demonstrated on a particular case of two-year-old infant with Pierre Robin sequence. Materialization by additive manufacturing of this photopolymer provides a highly durable and resistant-to-fracture two-part appliance similar to a Tübingen palatal plate, for example. The paper concludes with the viability of the described method and material upon interdisciplinary clinical evaluation of experts from departments of orthodontics and cleft anomalies, pediatric pneumology and phthisiology, and pediatric otorhinolaryngology.
PubMed: 36146014
DOI: 10.3390/polym14183858 -
Cell Stem Cell Nov 2020Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS)....
Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.
Topics: Cell Differentiation; Humans; Mutation; Neural Crest; Pierre Robin Syndrome; Regulatory Sequences, Nucleic Acid; SOX9 Transcription Factor
PubMed: 32991838
DOI: 10.1016/j.stem.2020.09.001 -
Seminars in Plastic Surgery May 2012Pierre Robin sequence (PRS) is classically described as a triad of micrognathia, glossoptosis, and airway obstruction. Infants frequently present at birth with a...
Pierre Robin sequence (PRS) is classically described as a triad of micrognathia, glossoptosis, and airway obstruction. Infants frequently present at birth with a hypoplastic mandible and difficulty breathing. The smaller mandible displaces the tongue posteriorly, resulting in obstruction of the airway. Typically, a wide U-shaped cleft palate is also associated with this phenomenon. PRS is not a syndrome in itself, but rather a sequence of disorders, with one abnormality resulting in the next. However, it is related to several other craniofacial anomalies and may appear in conjunction with a syndromic diagnosis, such as velocardiofacial and Stickler syndromes. Infants with PRS should be evaluated by a multidisciplinary team to assess the anatomic findings, delineate the source of airway obstruction, and address airway and feeding issues. Positioning will resolve the airway obstruction in ~70% of cases. In the correct position, most children will also be able to feed normally. If the infant continues to show evidence of desaturation, then placement of a nasopharyngeal tube is indicated. Early feeding via a nasogastric tube may also reduce the amount of energy needed and allow for early weight gain. A proportion of PRS infants do not respond to conservative measures and will require further intervention. Prior to considering any surgical procedure, the clinician should first rule out any sources of obstruction below the base of the tongue that would necessitate a tracheostomy. The two most common procedures for treatment, tongue-lip adhesion and distraction osteogenesis of the mandible, are discussed.
PubMed: 23633934
DOI: 10.1055/s-0032-1320065 -
Plastic and Reconstructive Surgery.... Apr 2022The literature does not offer any review of the pathogenesis of the clinical features of syndromes with Pierre Robin sequence (PRS). The senior author (MMA) proposed a...
UNLABELLED
The literature does not offer any review of the pathogenesis of the clinical features of syndromes with Pierre Robin sequence (PRS). The senior author (MMA) proposed a hypothesis that SOX9 and its interactions may play a key role in this pathogenesis. The current review aims to test this hypothesis.
METHODS
Three literature searches were made: the first aimed to document the main syndromes associated with PRS; and the second was to document the main functions of SOX9 in development; and the third was to investigate if SOX9 and its interactions may play a role in the pathogenesis.
RESULTS
SOX9 is the main positive regulator in the development of the mandibular cartilage and it also enhances collagen type II (the main collagen type in cartilage) expression in the mandibular cartilage. Furthermore, SOX9 participates in neural crest development, binds to the exon junction complex, and participates in sex determination. The interactions of SOX9 could explain the pathogenesis of the clinical features of syndromic PRS. These included interactions with collagen type II (in Strickler syndrome), exon junction complex (in Richier-Costa-Periera syndrome), glucose (in Catel-Manzke syndrome), RNA-binding proteins (in TARP syndrome), and the spliceosome (in cerebra-costo-mandibular syndrome). Finally, SOX9 mutations cause campomelic dysplasia.
CONCLUSIONS
The review supports the hypothesis of the participation of SOX9 in the pathogenesis of the clinical features of syndromic and nonsyndromic PRS. This should guide future research on the topic.
PubMed: 35415063
DOI: 10.1097/GOX.0000000000004241