Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience.

ABSTRACT: Bendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicenter observational study evaluating bendamustine toxicity in real-world practice. Patients receiving at least 1 dose of bendamustine with/without rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details, and grade 3 to 5 adverse events (AEs) were analyzed and correlated. In total, 323 patients were enrolled from 9 National Health Service hospitals. Most patients (96%) received bendamustine-R, and 46%, R maintenance. Overall, 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%) and the relative risk highest during maintenance (54%), induction (34%), and follow-up (28%). Toxicity led to permanent treatment discontinuation for 13% of patients, and 2.8% died of bendamustine-related infections (n = 5), myelodysplastic syndrome (n = 3), and cardiac disease (n = 1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor preinduction performance status (PS), poor premaintenance PS, and abnormal preinduction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3 of 10 opportunistic infections occurred despite prophylaxis. In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to those of trial populations of younger, fitter patients. Poor PS, mantle cell histology, and maintenance R were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death, warranting extended antimicrobial prophylaxis and infectious surveillance, especially for maintenance-treated patients.

Non-Invasive Ventilation for Community-Acquired Pneumonia: Outcomes and Predictors of Failure from an ICU Cohort.

Background and Objectives: The use of non-invasive ventilation (NIV) for community-acquired pneumonia (CAP) remains controversial. NIV failure in the setting of acute hypoxemic respiratory failure is associated with increased mortality, highlighting the need for careful patient selection. Methods and Methods: This is a retrospective observational cohort study. We included 140 patients with severe CAP, treated with either NIV or invasive mechanical ventilation (IMV) as their primary oxygenation strategy. Results: The median PaO2/FiO2 ratio and SOFA score upon ICU admission were 151 mmHg and 6, respectively. We managed 76% of patients with NIV initially and report an NIV success rate of 59%. Overall, the 28-day mortality was 25%, whilst for patients with NIV success, the mortality was significantly lower at 13%. In the univariate analysis, NIV failure was associated with the SOFA score (OR 1.33), the HACOR score (OR 1.14) and the presence of septic shock (OR 3.99). The SOFA score has an AUC of 0.75 for NIV failure upon ICU admission, whilst HACOR has an AUC of 0.76 after 2 h of NIV. Conclusions: Our results suggest that a SOFA ≤ 4 and an HACOR ≤ 5 are reasonable thresholds to identify patients with severe CAP likely to benefit from NIV.

Endoscopic management of intentional foreign body ingestion: experience from a UK centre.

Objective: We report on the increasing incidence and outcomes from intentional foreign body ingestion (iFoBI) presenting to our hospital over a 5-year period. The aim was to assess the impact on services and to identify ways to safely mitigate against this clinical challenge. Design/method: We performed a retrospective observational study of all patients presenting to a university hospital between January 2015 and April 2020 with iFoBI with a focus on objects swallowed, timing of endoscopy and clinical outcomes. Results: 239 episodes of iFoBI in 51 individuals were recorded with a significant increase in incidence throughout the study period (Welch (5, 17.3)=15.1, p<0.001), imposing a high burden on staff and resources. Items lodged in the oesophagus were more likely to lead to mucosal injury (p=0.009) compared with elsewhere. Ingested item type and timing of endoscopy were not related to complications (p=0.78) or length of stay (p=0.8). In 12% of cases, no objects were seen at endoscopy. Conclusion: In all except those patients with oesophageal impaction of the object on radiograph, there is no need to perform endoscopic extraction out of hours. A subset of cases can avoid endoscopy with an X-ray immediately prior to the procedure as a significant proportion have passed already. We discuss more holistic approaches to deal with recurrent attendances.

USP7 inhibition alters homologous recombination repair and targets CLL cells independently of ATM/p53 functional status.

The role of deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whereas previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we recently showed that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome. We demonstrate that USP7 is upregulated in CLL cells, and its loss or inhibition disrupts homologous recombination repair (HRR). Consequently, USP7 inhibition induces significant tumor-cell killing independently of ATM and p53 through the accumulation of genotoxic levels of DNA damage. Moreover, USP7 inhibition sensitized p53-defective, chemotherapy-resistant CLL cells to clinically achievable doses of HRR-inducing chemotherapeutic agents in vitro and in vivo in a murine xenograft model. Together, these results identify USP7 as a promising therapeutic target for the treatment of hematological malignancies with DDR defects, where ATM/p53-dependent apoptosis is compromised.