Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.     

A Multidisciplinary Approach to Evaluate the Efficiency of a Clean-Up Technology to Remove Mercury from Water

A microporous material denoted ETS-4 was used as the decontaminant agent to treat water with a low level of Hg contamination. The effectiveness of the treatment was evaluated by assessment of the efficiency of Hg removal and ecotoxicological responses. The results showed that under highly competitive conditions the removal of Hg ranged between 58 % and 73 % depending upon the initial Hg concentration, and that Hg removal was reflected in decreased toxicity to some organisms. The ecotoxicological data indicated that the bacterium Vibrio fischeri was the least sensitive organism tested, as no toxicity was observed in either pre- or post-treatment waters. Daphnia magna was highly sensitive to Hg. Mercury removal by ETS-4 was not sufficient to completely remove the toxicity of Hg to D. magna. However, it was effective in the complete reduction of toxicity for the green alga, Pseudokirchneriella subcapitata.     

Cost analysis and effectiveness comparing the routine use of intraoperative fluorescent cholangiography with fluoroscopic cholangiogram in patients undergoing laparoscopic cholecystectomy

Background

Despite the standardization of laparoscopic cholecystectomy (LC), the rate of bile duct injury (BDI) has risen from 0.2 to 0.5 %. Routine use of intraoperative cholangiography (IOC) has not been widely accepted because of its cost and a lack of evidence concerning its use in preventing BDI. Fluorescent cholangiography (FC), which has recently been advocated as an alternative to IOC, is a novel intraoperative procedure involving infrared visualization of the biliary structures. This study evaluated costs and effectiveness of routinely implemented FC and IOC during LC.

Materials and methods

Between February and June 2013, the authors prospectively collected the data of all patients undergoing laparoscopic cholecystectomy. We retrospectively reviewed and compared the use of FC and IOC. Procedure time, procedure cost, and effectiveness of the two methods were analyzed and compared. The surgeons involved in the cases completed a survey on the usefulness of each method.

Results

A total of 43 patients (21 males and 22 females) were analyzed during the study period. Mean age was 49.53 ± 14.35 years and mean body mass index was 28.35 ± 8 kg/m². Overall mean operative time was 64.95 ± 17.43 min. FC was faster than IOC (0.71 ± 0.26 vs. 7.15 ± 3.76 min; p < 0.0001). FC was successfully performed in 43 of 43 cases (100 %) and IOC in 40 of 43 cases (93.02 %). FC was less expensive than IOC (US$14.10 ± 4.31 vs. US$778.43 ± 0.40; p < 0.0001). According to the survey, all surgeons found routine use of FC useful.

Conclusion

In this study, FC was effective in delineating important anatomic structures. It required less time and expense than IOC, and was perceived by the surgeons to be easier to perform, and at least as useful as IOC. Further prospective studies are warranted to evaluate the effectiveness of FC in decreasing BDI.     

SARS-CoV-2-mediated inflammatory response in lungs: should we look at RAGE?

Inflammation Research -     

Validación de la técnica de dihidrorodamina 123 para el diagnóstico de la enfermedad granulomatosa crónica en Colombia

Introduction

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in the respiratory burst of phagocytes. Affected patients often suffer from granulomas and recurrent infections, mainly due to encapsulated bacteria.

Aim

To standardize the dihydrorhodamine test (DHR) in Colombia used for the diagnosis of CGD by evaluating the respiratory burst in human blood neutrophils and monocytes after in vitro activation.

Methods

Phagocyte respiratory burst in peripheral blood samples from 10 healthy controls was evaluated by flow cytometry after leukocyte activation with several concentrations of phorbol myristate acetate (PMA). The different oxidation patterns of DHR in X-linked or autosomal recessive CGD were also obtained.

Results

The most suitable concentrations of PMA for the evaluation of the respiratory burst in peripheral blood were 0.2 to 5 μg/ml. Reference values for this test in neutrophils from our population were established. It was shown that the oxidation patterns of DHR in monocytes were not always identical to those observed in neutrophils.

Conclusion

The evaluation of DHR oxidation by flow cytometry is a screening method that easily identifies the different phenotypes of CGD, with good sensitivity and at a lower cost. However, it is crucial that every laboratory establishes its own normal range for this test, in order to achieve the accurate characterization of this condition. DHR oxidation patterns may be also evaluated in different blood cells, since cell type-specific defects have also been reported.     

High pressure extraction of bioactive diterpenes from the macroalgae Bifurcaria bifurcata: an efficient and environmentally friendly approach

The brown macroalgae Bifurcaria bifurcata have gained special attention due to their ability to biosynthesize linear diterpenes (rarely found in other species). However, the conventional extraction methods normally used to extract these compounds involve organic solvents and often high temperatures, leading to the degradation of thermo-labile compounds. In this context, the main objective of this work was to study and optimize for the first time the extraction of diterpenes from B. bifurcata through an environmentally friendly methodology, namely, high pressure extraction (HPE) using ethanol : water. This was compared with conventional Soxhlet extraction, using dichloromethane. Box–Behnken design was employed to evaluate the linear, quadratic, and interaction effects of 3 independent variables (pressure (X₁), ethanol percentage (X₂), and time of extraction (X₃)) on response variables (extraction yield and diterpenes content (mg g⁻¹ of extract and mg kg⁻¹ of dry weight)) and the optimal extraction conditions (X₁: 600 MPa; X₂: 80%; X₃: 5 min) were estimated by response surface methodology (RSM). B. bifurcata extract obtained under HPE optimal conditions showed a diterpenes content (612.2 mg g⁻¹ of extract) 12.2 fold higher than that obtained by conventional extraction (50.1 mg g⁻¹ of extract). The HPE extract, obtained under optimal conditions, showed antioxidant and antibacterial (against Staphylococcus aureus) activities considerably higher than the Soxhlet extract, and also presented a promising synergic effect with antibiotics, improving the antibiotic efficacy against S. aureus. In conclusion, these results indicate that HPE is a promising methodology, compared to conventional methodologies to obtain linear diterpene rich extracts from B. bifurcata with great potential to be exploited in pharmaceutical or biomedical applications.

Bioactive linear diterpenes were selectively extracted from the macroalga Bifurcaria bifurcata through optimized high-pressure extraction.