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Fulltext Immune Checkpoint Inhibitors in Urothelial Carcinoma: Recommendations for Practical Approaches to PD-L1 and Other Potential Predictive Biomarker Testing

Lopez-Beltran A, López-Rios F, Montironi R, Wildsmith S, Eckstein M

Cancers (Basel), 2021 Mar 20;13(6).
PMID: 33804698 DOI: 10.3390/cancers13061424

Immuno-oncology (IO) agents (anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1)) are approved as first- and second-line treatments for metastatic UC. PD-L1 expression levels in UC tumors help clinicians determine which patients are more likely to respond to IO therapies. Assays for approved IO agents use different antibodies, immunohistochemical protocols, cutoffs (defining "high" vs. "low" PD-L1 expression), and scoring algorithms. The robust control of pre-analytical and analytical standards is needed to obtain high-quality PD-L1 results. To better understand the status and perspectives of biomarker-guided patient selection for anti-PD-1 and anti-PD-L1 agents in UC, three workshops were held from December 2018 to December 2019 in Italy, Malaysia, and Spain. The primary goal was to develop recommendations for best practice approaches to PD-L1 testing in UC. Recommendations pertaining to the interpretation and reporting of the results of PD-L1 assays from experienced pathologists and oncologists from around the globe are included. A test request form for pathology laboratories was developed as a critical first step for oncologists/urologists to encourage communication between clinicians and pathologists, ensuring fast and high-quality test results. In this era of personalized medicine, we briefly discuss novel biomarkers being evaluated for IO agents in UC.
Fulltext Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial

Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, Laranjeira LN, Paisani DM, Damiani LP, et al.

JAMA, 2017 10 10;318(14):1335-1345.
PMID: 28973363 DOI: 10.1001/jama.2017.14171

Importance: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain.
Objective: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy.
Design, Setting, and Participants: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS.
Interventions: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning.
Main Outcomes and Measures: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality.
Results: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality.
Conclusions and Relevance: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients.
Trial Registration: clinicaltrials.gov Identifier: NCT01374022.

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