Multiple myeloma has long been considered incurable; however, advances in therapy have markedly improved outcomes, with a growing proportion of patients achieving sustained remissions suggestive of cure. Minimal (or measurable) residual disease (MRD) has emerged as the most informative biomarker for assessing depth of response and predicting clinical outcomes. Evidence consistently demonstrates that MRD negativity surpasses conventional complete response in prognostic value across disease settings, treatment regimens, and risk groups. Furthermore, MRD has shown potential as a surrogate endpoint for clinical trials and as a tool to guide therapeutic decisions, including treatment intensification, de-escalation, and maintenance strategies. Emerging data also support its relevance in the context of immunotherapy and non-bone marrow-based assessment approaches. Collectively, these findings position MRD as a central component in the evolution toward more precise and individualized management of multiple myeloma.

Monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) have significantly expanded the therapeutic landscape of multiple myeloma (MM), contributing to deeper and more durable responses and meaningful survival benefits across the continuum of the disease. CD38-targeting mAbs are now integral to frontline regimens, while ADCs introduce a complementary strategy by enabling targeted delivery of cytotoxic payloads, most notably through B-cell maturation antigen (BCMA). However, the clinical integration of these agents has revealed new resistant mechanisms, including antigen loss, immune exhaustion, and the emergence of cross-resistance across BCMA-directed therapies. Furthermore, challenges in the sequencing of treatments have emerged, as novel immunotherapies have also become available in the early relapse setting. This contemporary review examines the evolving role of mAbs and ADCs in MM, addressing both current status and directions for future research in the field.

Multiple myeloma cells are uniquely dependent on proteostasis due to their exceptionally high immunoglobulin synthesis and protein turnover, rendering them hypersensitive to disruptions in protein degradation. Proteasome inhibitors targeting the 20 S catalytic core exploit this vulnerability and remain a therapeutic cornerstone in newly diagnosed and relapsed/refractory settings, anchoring both triplet and quadruplet regimens that incorporate anti-CD38 monoclonal antibodies, immunomodulatory agents, antibody-drug conjugates, and nuclear export inhibitors. Beyond the 20 S core, emerging targets, including the 19 S regulatory particle, deubiquitinating enzymes, and the E1-E2-E3 ubiquitination cascade, offer opportunities to intensify proteotoxic stress and overcome resistance. Targeted protein degradation platforms, including CELMoDs, proteolysis targeting chimeras, molecular glues, and proteasome cap-recruiting chimeras, further expand the therapeutic repertoire. Compensatory stress responses involving autophagy, the unfolded protein response, and the bone marrow microenvironment modulate therapeutic vulnerability. Collectively, these advances position proteostasis not as a single druggable target but as an integrated therapeutic network amenable to rational, biomarker-informed combination strategies in multiple myeloma.

Despite substantial improvements in survival over recent decades, multiple myeloma (MM) remains largely incurable, and most patients ultimately experience relapsed or refractory disease, highlighting the need for novel therapeutic strategies. Immunomodulatory drugs (IMiDs) have transformed MM treatment through direct antitumor and immune-enhancing effects mediated by cereblon modulation, while their ability to stimulate T-cell and NK-cell function has provided a strong rationale for combination with modern immunotherapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies. More recently, cereblon E3 ligase modulators (CELMoDs), such as iberdomide and mezigdomide, have emerged as next-generation cereblon-targeting agents with enhanced potency, deeper substrate degradation, and activity in lenalidomide- and pomalidomide-resistant settings. Clinical studies have demonstrated promising efficacy and manageable safety profiles across newly diagnosed and relapsed/refractory MM, including in heavily pretreated patients. In parallel, novel degraders such as cemsidomide have shown encouraging preliminary activity, further expanding the therapeutic potential of cereblon-directed approaches in MM. In this review, we aim to summarize the evolution of oral therapies in MM, focusing on the efficacy and safety of next-generation cereblon modulators and emerging cereblon-directed degraders.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor of multiple myeloma characterized by marked heterogeneity in the risk of progression. Current management relies on clinical risk stratification to identify patients who might benefit from early intervention. Models such as the 20/2/20 score and its International Myeloma Working Group refinement incorporate tumor burden and cytogenetic abnormalities, whereas emerging approaches integrating dynamic biomarkers, circulating tumor cells, genomic alterations, and immune signatures could further improve the prediction of progression if validated in larger cohorts. Randomized trials suggest that early treatment with lenalidomide-based regimens or anti-CD38 monoclonal antibodies delays progression and possibly improves survival in high-risk SMM, and daratumumab has been approved as an early intervention in high-risk SMM. More intensive immunotherapy-based strategies can achieve high rates of sustained measurable residual disease negativity, which might translate into durable disease control or even a cure. Future management will likely depend on biologically informed, risk-adapted strategies to balance early treatment benefits against overtreatment, together with safety profile and patients' preferences.

A 17-year-old adolescent boy with primary osteosarcoma of the proximal femur underwent cement-augmented internal fixation with a femoral neck system for a pathologic hip fracture, allowing for pain control, neoadjuvant chemotherapy, and diagnostic work-up to be completed before resection and endoprosthetic reconstruction. No hardware complications or local recurrences were noted at 3 years postoperatively.

Cement-augmented internal fixation with a femoral neck system is an option for certain patients with pathologic hip fractures. This approach allows for diagnostic work-up, patient optimization, logistical planning, and neoadjuvant chemotherapy to be completed before definitive resection.

This study examined dynamic resting-state functional connectivity and graph-theoretic measures in 71 patients with left intra-axial tumors (40 left frontal lobe tumors and 31 left temporal lobe tumors) and 53 age- and sex-matched healthy controls. Dynamic functional connectivity was estimated across 8 80-s sliding windows, region of interest-to-region of interest Fisher-z connectivity values from 132 atlas regions were harmonized using ComBat, and graph metrics were calculated at a 20% proportional density. The primary within-study comparison was restricted to left frontal lobe tumors and left temporal lobe tumors to avoid the confounding between diagnosis and the public healthy control datasets. In restricted maximum likelihood mixed-effects models with AR(1) within-subject covariance, adjusted for z-scored age, categorical TR, and window, none of the 11 graph metrics showed an overall tumor-location effect (P = 0.219 to 0.928; partial eta-squared < 0.001 to 0.019). However, tumor location-by-window interactions survived correction across 11 metrics for clustering coefficient, transitivity, modularity, and assortativity, at T8, adjusted values were higher in left temporal lobe tumors than left frontal lobe tumors for all 4 metrics. Grade-stratified analyses provided no corrected evidence that grade moderated these temporal location effects, while adjustment for peritumoral edema or standardized log lesion volume did not materially alter the primary tumor-location findings. Secondary comparisons indicated lower integration and altered path-based and centrality measures in tumor groups relative to healthy controls, but diagnosis was partially confounded with acquisition protocol; healthy control-only models identified residual acquisition-batch effects for betweenness centrality and eccentricity after correction. Global connectivity laterality index differences did not survive multiple-comparison correction (minimum q = 0.334) and are interpreted descriptively. These findings distinguish temporally specific topology differences from generalized tumor-location effects and require confirmation in uniformly acquired, clinically characterized cohorts.

Niosomes are promising nanocarriers for improving the stability, bioavailability, and delivery of plant-derived bioactive compounds. This study aimed to prepare and physicochemically characterize niosomes loaded with Ocimum basilicum L. extract and evaluate their anticancer and metastasis-related effects in human ovarian cancer SKOV3 cells. The niosomes were characterized using DLS, SEM, FTIR, and in vitro release analysis, showing a mean particle size of 256.2 ± 0.21 nm, PDI of 0.265 ± 0.007, zeta potential of -35.4 ± 0.3 mV, and encapsulation efficiency of 85.2 ± 0.6%. Cytotoxicity was assessed by MTT assay after 24, 48, and 72 h, and the 72 h IC₅₀ (398.24 µg/mL) was used for subsequent analyses. The extract-loaded niosomes exhibited significantly greater cytotoxicity than the free extract and empty niosomes, particularly after 72 h. qRT-PCR revealed significant upregulation of Bax (3.46-fold) and downregulation of Bcl2 (0.67-fold), MMP2 (0.63-fold), and MMP9 (0.64-fold) (p < 0.001). Flow cytometry confirmed enhanced apoptosis, with 27.8% apoptotic and 5.87% necrotic cells. Overall, O. basilicum extract-loaded niosomes increased apoptosis and modulated apoptosis- and metastasis-associated genes, supporting their potential as nanocarriers for plant-derived anticancer compounds.

Cholangiocarcinoma (CCA) is a highly aggressive biliary malignancy with limited responses to existing treatments. Gemcitabine plus cisplatin (GC) remains the standard first-line chemotherapy for advanced disease, but its clinical efficacy is suboptimal, and drug resistance frequently emerges in patients. Through high-throughput synergistic drug screening, we identified PKMYT1 as a key synthetic lethal target regulating the chemosensitivity of cholangiocarcinoma cells. Functional validation confirmed that the PKMYT1 small-molecule inhibitor RP6306 exerts robust synthetic lethal effects when used in combination with gemcitabine or cisplatin. Data from colony formation assays and a series of cellular functional experiments showed that genetic or pharmacological inhibition of PKMYT1 substantially compromises DNA damage repair (DDR) and induces massive DNA double-strand breaks. Further mechanistic investigations revealed that PKMYT1 binds to Aldolase A (encoded by the ALDOA gene) and enhances its enzymatic activity, thereby upregulating CCA glycolysis levels and inducing lactate accumulation, which ultimately elevates the lactylation level of MRE11, accelerates DDR and consequently drives chemoresistance in CCA. Both cell-derived and patient-derived xenograft models verified that combined treatment with RP6306 and GC markedly inhibits tumor growth in vivo. Taken together, this work reveals that the PKMYT1-ALDOA-mediated protein lactylation pathway acts as a critical regulator of chemoresistance in CCA. Targeting PKMYT1 could reverse chemotherapy resistance and enhance therapeutic outcomes for advanced CCA, offering a promising combination strategy for clinical application.

The aim of this study was to develop an overall survival (OS) prediction model integrating key somatic driver gene mutations in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative-intent pancreatectomy.

Patients with resected PDAC from a prospectively maintained pancreatectomy database from 2018 to 2023 were identified. Somatic mutations in KRAS, TP53, SMAD4, and CDKN2A were assessed using in-house or commercial sequencing panels. Restricted cubic spline analyses were used to assess non-linear effects. An integrated Cox proportional hazards model incorporating genomic and clinicopathological variables was developed to predict OS and validated using 1000 bootstrap resamples.

In total, 885 patients were identified, of whom 663 met the inclusion criteria. After a median follow-up of 40.8 months, 387 deaths occurred (median OS of 28.4 months). The 1-, 2-, and 3-year OS rates were 80.0%, 56.2%, and 41.5% respectively. In univariable analysis, mutations in KRAS, TP53, SMAD4, and CDKN2A were each associated with inferior OS. Mortality risk increased with the cumulative number of mutated driver genes and remained independently significant in multivariable analysis (0-4; HR per mutation 1.27; P < 0.001). Other independent OS predictors included advanced age, resectability status, elevated pretreatment carbohydrate antigen 19-9 (CA19-9), larger tumour size, positive nodal stage, lymphovascular invasion, poor differentiation, neoadjuvant response classification, and receipt of adjuvant chemotherapy. The integrated model showed moderate discrimination (C-index 0.690 (95% c.i. 0.669 to 0.723); optimism-corrected C-index 0.676), which was significantly higher than AJCC eighth edition pathological staging alone (C-index 0.568 (95% c.i. 0.545 to 0.599); ΔC = 0.122; P < 0.001), with reasonable calibration.

The cumulative burden of driver gene mutations provided independent and incremental prognostic information after PDAC resection. External validation is required before clinical application.