Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL.

ABSTRACT: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Regeneration of sedimentary manganese in coastal sediments deciphered by 224Ra/228Th disequilibria.

Manganese (Mn) is a vital micronutrient and participates in multiple biochemical reactions and enzyme catalytic activities. Its cycling is tightly connected with iron (Fe) and nitrogen (N). Although coastal sediments are recognized as an important source of dissolved Mn to marine waters, this contribution remains inadequately quantified. In the summer of 2019 and 2020, we investigated benthic fluxes of dissolved Mn, Fe and ammonia (NH4+) in the Changjiang Estuary and East China Sea shelf using the 224Ra/228Th disequilibrium approach. Our results showed that the availability of reactive Mn oxides (MnD) played a crucial role in sedimentary Mn regeneration, as revealed by the positive correlation (r = 0.75, P < 0.05) between Mn fluxes and MnD contents. In addition, the positive correlation (r = 0.80, P < 0.01) between the decomposition rates of sedimentary organic matter (NH4+ flux) and Mn fluxes suggested that the reduction of MnD was mainly driven by the organic carbon oxidation. Furthermore, NH4+ and Mn fluxes exhibited an exponential increase against the product of dissolved oxygen concentration (DO) and the amplification factor of sediment surface area (ξ). In this context, ξ represents the rate of bottom water DO pumped into the sediment via physical reworking and bio-irrigation. In contrast to the most efficient Fe released from sediment overlain by hypoxic waters (DO <62.5 µM), the maximum Mn flux (63.5 ± 9.4 mmol m-2 d-1) was observed at sediment with oxygenated bottom waters (DO = 158 µM). This implies that the regeneration of Mn was associated with a more permissive redox state compared to that of Fe. We further demonstrated that Mn flux was 1-2 orders of magnitude higher than those estimated through traditional methods. Therefore, coastal sediments may contribute more Mn to ocean waters than previously thought. The precise estimation of Mn release from coastal sediments holds critical significance for research on the global Mn budget.

The History of Classification Systems for Periprosthetic Femoral Fractures: A Literature Review.

Periprosthetic femoral fractures (PPFFs) following total hip arthroplasty (THA) present a significant clinical challenge due to their increasing incidence with an aging population and evolving surgical practices. Historically, classifications were primarily based on anatomical fracture location, the stability of the implant, and bone quality surrounding the implant. We critically analyzed 25 classification systems, highlighting the emergence and adaptations of key systems such as the Vancouver classification system (VCS) and the Unified classification system (UCS), which are lauded for their simplicity and effectiveness yet require further refinement. VCS, developed in 1995, categorizes fractures based on the site, implant stability, and bone quality, and remains widely used due to its robust applicability across different clinical settings. Introduced in 2014, UCS expands the VCS to encompass all periprosthetic fractures with additional fracture types, aiming for a universal application. Despite their widespread adoption, these systems exhibit shortcomings, including the incomplete inclusion of all PPFF types and the imprecise assessment of implant stability and surrounding bone loss. These gaps can result in misclassification and suboptimal treatment outcomes. This paper suggests the necessity for ongoing improvements in classification systems to include emerging fracture types and refined diagnostic criteria, ensuring that they remain relevant to contemporary orthopedic practices and continue to facilitate the precise tailoring of treatment to patient-specific circumstances. This comprehensive historical review serves as a foundation for future innovations in classification systems, ultimately aiming to standardize PPFF treatment and improve patient prognosis.

Bispecific CAR-T cells targeting CD19/20 in patients with relapsed or refractory B cell non-Hodgkin lymphoma: a phase I/II trial.

Non-Hodgkin lymphoma (NHL) is a common malignancy in the hematologic system, and traditional therapy has limited efficacy for people with recurrent/refractory NHL (R/R NHL), especially for patients with diffuse large B cell lymphoma (DLBCL). Chimeric antigen receptor (CAR) T-cell therapy is a novel and effective immunotherapy strategy for R/R hematopoietic malignancies, but relapses can occur due to the loss of CAR-T cells in vivo or the loss of antigen. One strategy to avoid antigen loss after CAR-T cell therapy is to target one more antigen simultaneously. Tandem CAR targeting CD19 and CD22 has demonstrated the reliability of tandem CAR-T cell therapy for R/R B-ALL. This study explores the therapeutic potential of tandem CD19/20 CAR-T in the treatment of R/R B cell NHL. The efficacy and safety of autologous CD19/20 CAR-T cells in eleven R/R B cell NHL adult patients were evaluated in an open-label, single-arm trial. Most patients achieved complete response, exhibiting the efficacy and safety of tandem CD19/20 CAR-T cells. The TCR repertoire diversity of CAR-T cells decreased after infusion. The expanded TCR clones in vivo were mainly derived from TCR clones that had increased expression of genes associated with immune-related signaling pathways from the infusion product (IP). The kinetics of CAR-T cells in vivo were linked to an increase in the expression of genes related to immune response and cytolysis/cytotoxicity.

Jellyfish-Inspired Artificial Spider Silk for Luminous Surgical Sutures.

The development of functional surgical sutures with excellent mechanical properties, good fluorescence, and high cytocompatibility is highly required in the field of medical surgeries. Achieving fibers that simultaneously exhibit high mechanical robustness, good spinnability, and durable fluorescence emission has remained challenging up to now. Taking inspiration from the spinning process of spider silk and the luminescence mechanism of jellyfish, this work reports a luminous artificial spider silk prepared with the aim of balancing the fiber spinnability and mechanical robustness. This is realized by employing highly hydrated segments with aggregation-induced luminescence for enhancing the fiber spinnability and polyhydroxyl segments for increasing the fiber mechanical robustness. Twist insertion during fiber spinning improves the fiber strength, toughness, and fluorescence emission. Furthermore, coating the fiber with an additional polymer layer results in a "sheath-core" architecture with improved mechanical properties and capacity to withstand water. This work provides a new design strategy for performing luminescent and robust surgical sutures.

Favorable response of a patient with primary B/myeloid mixed phenotype acute Leukemia to CD19-CAR-T: Case report and literature review.

RATIONALE: Mixed phenotype acute leukemia (MPAL) is a rare and heterogeneous type of leukemia known for its poor prognosis. The optimal treatment strategy for this condition currently lacks consensus, leaving uncertainty in its management. Nonetheless, a potential therapeutic option for patients with refractory MPAL who express target antigens is donor-derived chimeric antigen receptor T (CAR-T) cell therapy. PATIENT CONCERNS: We recently reported a 61-year-old woman with MPAL and elucidated its diagnosis and treatment. DIAGNOSIS: The diagnosis of MPAL was established based on the classification of World Health Organization in 2016. INTERVENTIONS: Despite undergoing 3 different acute lymphoblastic leukemia (ALL) regimens and 1 acute myelogenous leukemia (AML) regimen, the patient did not achieve remission. Subsequently, the patient received human CD19-targeted CAR-T cell therapy. OUTCOMES: The patient achieved a successful and complete remission after CAR-T cell therapy. Tragically, 8 months after CAR-T infusion, the patient experienced a relapse characterized by CD19-negative disease and ultimately passed away. LESSONS: This case underscores the potential efficacy and safety of human-derived CD19 CAR-T cell therapy in treating refractory MPAL. While this particular patient outcome was unfortunate, it suggests that CAR-T cell therapy may still hold promise as a viable treatment option for MPAL patients unresponsive to other therapies. Further research in this field is warranted to determine the most effective treatment strategies for managing this challenging disease.