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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 -
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 -
Maturitas Sep 2022The aim of these recommendations is to set forth an individualized approach to the management of early postmenopausal women (i.e., within the first 10 years after... (Review)
Review
Management of postmenopausal women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d'Etude sur la Ménopause et le Vieillissement (GEMVi) Clinical Practice Guidelines.
AIM
The aim of these recommendations is to set forth an individualized approach to the management of early postmenopausal women (i.e., within the first 10 years after natural menopause) covering all aspects of lifestyle and therapeutic management, with or without menopause hormone therapy (MHT).
MATERIALS AND METHODS
Literature review and consensus of French expert opinion. Recommendations were graded according to the HAS methodology and levels of evidence derived from the international literature, except when there was no good-quality evidence.
SUMMARY RECOMMENDATIONS
The beginning of menopause is an ideal time for each woman to evaluate her health status by assessing her bone, cardiovascular, and cancer-related risk factors that may be amplified by postmenopausal estrogen deficiency and by reviewing her lifestyle habits. Improving lifestyle, including nutrition and physical activity, and avoiding risk factors (notably smoking), should be recommended to all women. MHT remains the most effective treatment for vasomotor symptoms but it could be also recommended as first-line treatment for the prevention of osteoporosis in early postmenopausal women at low to moderate risk for fracture. The risks of MHT differ depending on its type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. There is reasonable evidence that using transdermal estradiol in association with micronized progesterone or dydrogesterone may limit both the venous thromboembolic risk associated with oral estrogens and the risk of breast cancer associated with synthetic progestins. Treatment should be individualized to each woman, by using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of its benefit-risk balance. For bothersome genitourinary syndrome of menopause (GSM) symptoms, vaginal treatment with lubricants and moisturizers is recommended as first-line treatment together with low-dose vaginal estrogen therapy, depending on the clinical course. No recommendation of an optimal duration of MHT can be made, but it must take into consideration the initial indication for MHT as well as each woman's benefit-risk balance. Management of gynecological side-effects of MHT is also examined. These recommendations are endorsed by the Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVI) and the Collège National des Gynécologues-Obstétriciens Français (CNGOF).
Topics: Estrogen Replacement Therapy; Estrogens; Female; Humans; Menopause; Postmenopause; Practice Guidelines as Topic; Progestins
PubMed: 35717745
DOI: 10.1016/j.maturitas.2022.05.008 -
Current Topics in Developmental Biology 2015The tongue and mandible have common origins. They arise simultaneously from the mandibular arch and are coordinated in their development and growth, which is evident... (Review)
Review
The tongue and mandible have common origins. They arise simultaneously from the mandibular arch and are coordinated in their development and growth, which is evident from several clinical conditions such as Pierre Robin sequence. Here, we review in detail the molecular networks controlling both mandible and tongue development. We also discuss their mechanical relationship and evolution as well as the potential for stem cell-based therapies for disorders affecting these organs.
Topics: Animals; Gene Expression Regulation, Developmental; Humans; Mandible; Mesoderm; Neural Crest; Osteogenesis; Stem Cells; Tendons; Tongue
PubMed: 26589920
DOI: 10.1016/bs.ctdb.2015.07.023