Meghan J. Mooradian

BACKGROUND: Lung cancer is made up of distinct subtypes, including non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although overall mortality from lung cancer has been declining in the United States, little is known about mortality trends according to cancer subtype at the population level because death certificates do not record subtype information. METHODS: Using data from Surveillance, Epidemiology, and End Results (SEER) areas, we assessed lung-cancer mortality and linked deaths from lung cancer to incident cases in SEER cancer registries. This allowed us to evaluate population-level mortality trends attributed to specific subtypes (incidence-based mortality). We also evaluated lung-cancer incidence and survival according to cancer subtype, sex, and calendar year. Joinpoint software was used to assess changes in incidence and trends in incidence-based mortality. RESULTS: Mortality from NSCLC decreased even faster than the incidence of this subtype, and this decrease was associated with a substantial improvement in survival over time that corresponded to the timing of approval of targeted therapy. Among men, incidence-based mortality from NSCLC decreased 6.3% annually from 2013 through 2016, whereas the incidence decreased 3.1% annually from 2008 through 2016. Corresponding lung cancer-specific survival improved from 26% among men with NSCLC that was diagnosed in 2001 to 35% among those in whom it was diagnosed in 2014. This improvement in survival was found across all races and ethnic groups. Similar patterns were found among women with NSCLC. In contrast, mortality from SCLC declined almost entirely as a result of declining incidence, with no improvement in survival. This result correlates with limited treatment advances for SCLC in the time frame we examined. CONCLUSIONS: Population-level mortality from NSCLC in the United States fell sharply from 2013 to 2016, and survival after diagnosis improved substantially. Our analysis suggests that a reduction in incidence along with treatment advances - particularly approvals for and use of targeted therapies - is likely to explain the reduction in mortality observed during this period.

BACKGROUND AND OBJECTIVES: Immune checkpoint inhibitor use in oncology is increasing rapidly. We sought to determine the frequency, severity, cause, and predictors of AKI in a real-world population receiving checkpoint inhibitors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included all patients who received checkpoint inhibitor therapy from May 2011 to December 2016 at Massachusetts General Hospital. Baseline serum creatinine, averaged 6 months before checkpoint inhibitor start date, was compared with all subsequent creatinine values within 12 months of starting therapy. AKI was defined by Kidney Disease: Improving Global Outcomes criteria for fold changes in creatinine from baseline. Sustained AKI events lasted at least 3 days and was our primary outcome. The cause of sustained AKI was determined by chart review. Cumulative incidence and subdistribution hazard models were used to assess the relationship between baseline demographics, comorbidities, and medications, and sustained AKI and potential checkpoint inhibitor-related AKI. RESULTS: ) at baseline. A total of 169 patients (17%) experienced AKI, defined by an increase in creatinine at least 1.5 times the baseline within 12 months; 82 patients (8%) experienced sustained AKI and 30 patients (3%) had potential checkpoint inhibitor-related AKI. The first episode of sustained AKI occurred, on average, 106 days (SD 85) after checkpoint inhibitor initiation. Sixteen (2%) patients experienced stage 3 sustained AKI and four patients required dialysis. Proton pump inhibitor use at baseline was associated with sustained AKI. CONCLUSIONS: AKI is common in patients receiving checkpoint inhibitor therapy. The causes of sustained AKI in this population are heterogenous and merit thorough evaluation. The role of PPI and other nephritis-inducing drugs in the development of sustained AKI needs to be better defined.

Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined. ANN NEUROL 2020;87:659-669.

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.