Ospedale Niguarda Ca' Granda, best known simply as Ospedale Niguarda or Niguarda Hospital is largest and one of the most important hospitals in Milan, Italy..
Screw stripping is a common complication in orthopaedic surgery that can compromise fixation stability. This study evaluates the relationship between stripping torque (ST) and infill density in 3D-printed bone surrogates, establishes a conversion factor between surrogates and ASTM F-1839-08 foam, and tests the hypothesis that screw insertion angle up to 45 °C does not affect ST. PLA surrogates with 3D Honeycomb or Gyroid infill patterns were printed at densities ranging from 5 to 27
Although the Woven EndoBridge (WEB) device is increasingly used for the treatment of wide-neck intracranial aneurysms, including in the acute rupture setting, comparative evidence assessing the impact of rupture status remains limited. This study compared angiographic, safety, and clinical outcomes between ruptured and unruptured intracranial aneurysms treated with WEB. We conducted a retrospective analysis of prospectively collected data from the multicenter cohort registry WorldWideWEB, including consecutive adult patients with intracranial aneurysms treated with the WEB. Patients were stratified into groups of ruptured and unruptured aneurysms. Propensity score matching was used to balance baseline characteristics between both groups. Retreatment rate was the primary outcome. Secondary outcomes included mRS, safety events (thromboembolic complications) and angiographic outcomes (periprocedurally and last follow-up). Among 1,220 patients, 342 (28.0
The combination of 5-fluorouracil and irinotecan (FOLFIRI) remains a standard-of-care treatment for metastatic colorectal cancer (mCRC) yet benefits only about half of patients. Using patient-derived xenografts, we investigated the biological underpinnings of this heterogeneous response. FOLFIRI-resistant models showed transcriptional upregulation of innate immunity and mitochondrial metabolism genes, together with reduced expression of the DNA polymerase POLD1. Sensitive counterparts exhibited a BRCAness-like phenotype with genomic scars of homologous recombination (HR) deficiency, not caused by genetic or epigenetic loss of HR genes but by low abundance of the RAD51 recombinase. In tumoroids, forced RAD51 overexpression attenuated HR deficiency-related scars and chemotherapy-induced damage, whereas HR inhibition through ATM blockade enhanced drug sensitivity. The predictive relevance of key response determinants was validated in clinical samples. This work illuminates functional, nongenetic facets of BRCAness in mCRC and introduces actionable biomarkers and targets, offering prospects to improve clinical decision-making and broaden therapeutic options for chemorefractory patients. SIGNIFICANCE:FOLFIRI response biomarkers in mCRC are lacking. Evidence in patient-derived xenografts, tumoroids, and patients shows that chemosensitivity arises from functional relaxation, rather than (epi)genetic inactivation, of the HR DNA repair pathway. Integrative analyses yield a chemopredictive algorithm centered on the expression of the RAD51 recombinase, with potential to refine patient stratification.
ABSTRACT:Bruton tyrosine kinase inhibitors (BTKis) have dramatically changed the therapeutic landscape of chronic lymphocytic leukemia (CLL), with ibrutinib, first-in-class, demonstrating durable efficacy even in high-risk patients. However, off-target adverse events (AEs) have raised concerns, prompting the development of more selective second-generation BTKis, such as zanubrutinib, designed to improve tolerability while maintaining efficacy. Despite encouraging results from clinical trials, real-world data comparing zanubrutinib with ibrutinib remain limited. In this multicenter, retrospective study, we analyzed 934 patients with CLL treated outside clinical trials, including 393 receiving zanubrutinib and 541 receiving ibrutinib. We evaluated time to treatment discontinuation (TTD) and time to next treatment or death (TTNTD) in both the overall cohort and a propensity score-matched population. Patients who were treated with zanubrutinib experienced lower 12-month discontinuation rates (overall: 12.6% vs 21.4%; matched: 12.4% vs 20.2%) and higher 12-month TTNTD rates (overall: 91.9% vs 83.0%; matched: 93.2% vs 83.4%). Multivariable analyses confirmed zanubrutinib as an independent predictor of longer TTD and TTNTD, whereas high-risk features, including age, relapsed/refractory disease, Binet stage C, TP53 disruption, Eastern Cooperative Oncology Group 2 to 3, and congestive heart failure, were consistently associated with poorer outcomes. AEs leading to discontinuation, particularly atrial fibrillation, bleeding, and infections, were less frequent with zanubrutinib, reflecting its favorable safety profile. These findings provide real-world evidence that zanubrutinib offers more durable disease control and improved persistence compared with ibrutinib, reinforcing its clinical value as a preferred second-generation BTKi. Nevertheless, the relatively short follow-up for zanubrutinib warrants cautious interpretation of long-term outcomes, and underscores the need for ongoing observation to fully characterize its durability and safety.
ABSTRACT:Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who harbor del(17p) and/or tumor protein p53 (TP53) mutations represent a high-risk population with a historically poor prognosis. To assess zanubrutinib efficacy and safety outcomes in patients with CLL/SLL with del(17p) and/or TP53 mutations (N = 301; n = 132, treatment-naive [TN]; n = 169, relapsed/refractory [R/R]), data from SEQUOIA (phase 3; TN; zanubrutinib; NCT03336333), ALPINE (phase 3; R/R; zanubrutinib vs ibrutinib; NCT03734016), and AU-003 (NCT02343120) (phase 1/2; zanubrutinib) were evaluated. In SEQUOIA (n = 127; median follow-up, 64.8 months), median progression-free survival (PFS) and overall survival (OS) were not reached; estimated 60-month PFS and OS were 70.7% and 82.3%, respectively. In ALPINE (n = 75, each treatment arm; median follow-up, 39.0 months), 36-month PFS rates were 59.2% among patients treated with zanubrutinib and 38.5% among those treated with ibrutinib, and OS rates were 73.6% and 72.5%, respectively. In AU-003 (n = 24; median follow-up, 69.6 months), 10 of 24 patients experienced progressive disease. Rate of response with zanubrutinib in SEQUOIA was 96.9% (95% confidence interval [CI], 95.2-98.8), and in ALPINE was 89.3% (95% CI, 80.1-95.3) with zanubrutinib vs 76.0% (95% CI, 64.7-85.1) with ibrutinib. Responses deepened over time in both TN and R/R populations. The most frequent nonhematologic treatment-emergent adverse events occurring in >20% of patients treated with zanubrutinib with del(17p) and/or TP53 mutations in SEQUOIA and ALPINE were COVID-19, upper respiratory tract infection, arthralgia, diarrhea, and contusion. In conclusion, zanubrutinib demonstrated strong efficacy in high-risk del(17p) and/or TP53 CLL/SLL, with a tolerable safety profile, further supporting use of zanubrutinib in both frontline and R/R settings.
