Introduction: Obinutuzumab is hypothesized to improve progression-free survival (PFS) combined with bendamustine induction in mantle cell lymphoma (MCL). Measurable-residual disease (MRD) testing may predict benefit from maintenance therapy.
Methods: Adults (≥ 18 years) with untreated MCL ineligible for intensive therapies received 4 to 6 cycles of bendamustine + obinutuzumab (BO) followed by consolidation obinutuzumab (CO).
Purpose: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study.
Experimental Design: Plasma samples were collected for serial ctDNA profiling at baseline (cycle 1 day 1 prior to treatment) and multiple on-treatment time points (cycle 1 day 15 and cycle 3 day 1).
Results: KRAS G12C ctDNA was detectable from plasma samples in 72.
Lenalidomide (LEN) and rituximab (RTX) have independently improved progression-free survival (PFS) in CLL, leading to interest in use of LEN + RTX (R2) following induction chemoimmunotherapy. Patients with previously untreated CLL received bendamustine + RTX (BR) for 6 cycles, then 24 cycles of R2. LEN dosing was 5-10 mg daily; RTX was given odd cycles (12 doses).
View Article and Find Full Text PDFKRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC.
View Article and Find Full Text PDFPrimary bone diffuse large B-cell lymphoma is a rare variant of extranodal non-Hodgkin lymphoma historically treated with induction chemotherapy followed by consolidative radiation therapy (RT). It remains unknown whether RT confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction in patients with limited stage disease. We conducted a multicenter, retrospective analysis of patients treated between 2005 and 2019 using rituximab-based CIT regimens with or without consolidative RT to discern whether consolidative RT adds benefit in patients with stage I-II disease that could be encompassed in one radiation field.
View Article and Find Full Text PDFBackground: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity.
Methods: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed.
There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S.
View Article and Find Full Text PDFThe objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.
View Article and Find Full Text PDFJ Oral Maxillofac Surg
October 2022
Purpose: The geriatric population is a constantly growing population that is especially vulnerable to trauma. The primary purpose of this study was to determine what factors are associated with increased rates of hospital admission in geriatric patients who sustain craniomaxillofacial fractures secondary to falls.
Materials And Methods: This is a 5-year retrospective cross-sectional study that was conducted using the NEISS database.
In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.
View Article and Find Full Text PDFCell migration in confining microenvironments is limited by the ability of the stiff nucleus to deform through pores when migration paths are preexisting and elastic, but how cells generate these paths remains unclear. Here, we reveal a mechanism by which the nucleus mechanically generates migration paths for mesenchymal stem cells (MSCs) in confining microenvironments. MSCs migrate robustly in nanoporous, confining hydrogels that are viscoelastic and plastic but not in hydrogels that are more elastic.
View Article and Find Full Text PDFAn 87-year-old patient donated his body to the Institute of Anatomy and Cell Biology in gratefulness for the longevity of a Björk-Shiley convexo-concave (BSCC) prosthetic aortic valve, implanted 34 years ago. The dissection of the enlarged heart showed no major signs of thrombosis, malignant fibrosis, or any other relevant issue that could potentially lead to valve failure as in other patients. Despite the reported high mortality rate of the earlier designs, especially of the BSCC valves, some patients survived for longer than expected.
View Article and Find Full Text PDFCancer cells typically invade through basement membranes (BMs) at key points during metastasis, including primary tumor invasion, intravasation, and extravasation. Cells extend invadopodia protrusions to create channels in the nanoporous BM through which they can invade, either via proteolytic degradation or mechanical force. Increased matrix stiffness can promote cancer progression, and two-dimensional (2D) culture studies indicate that increased stiffness promotes invadopodia degradation activity.
View Article and Find Full Text PDFPurpose: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL).
Patients And Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683).
Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive subtype of non-Hodgkin lymphoma with a varied presentation and no pathognomonic findings. Early diagnosis is critical to altering the disease course as early treatment with chemoimmunotherapy is required to prevent a rapidly fatal outcome. Strategies including improved awareness of this clinical entity through publication of cases with unique presentations are essential to prompt consideration of IVLBCL early in the disease workup.
View Article and Find Full Text PDFDisulfide-linked bioconjugates allow the delivery of pharmacologically active or other cargo to specific tissues in a redox-sensitive fashion. However, an understanding of the kinetics, subcellular distribution, and mechanism of disulfide cleavage in such bioconjugates is generally lacking. Here, we report a modular disulfide-linked TAMRA-BODIPY based FRET probe that can be readily synthesized, modified, and conjugated to a cysteine-containing biomolecule to enable real-time monitoring of disulfide cleavage during receptor-mediated endocytosis in cells.
View Article and Find Full Text PDFIn epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and endothelial tissues, is primarily composed of laminin and collagen IV and serves as a structural barrier to cancer cell invasion, intravasation, and extravasation. BM invasion has been thought to require protease degradation since cells, which are typically on the order of 10 µm in size, are too large to squeeze through the nanometer-scale pores of the BM.
View Article and Find Full Text PDFIn breast cancer, the increased stiffness of the extracellular matrix is a key driver of malignancy. Yet little is known about the epigenomic changes that underlie the tumorigenic impact of extracellular matrix mechanics. Here, we show in a three-dimensional culture model of breast cancer that stiff extracellular matrix induces a tumorigenic phenotype through changes in chromatin state.
View Article and Find Full Text PDFDiffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL.
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