Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.

BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded. RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS. CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

Characteristics of Real-World Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval.

BACKGROUND: Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. MATERIALS AND METHODS: We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real-world metastatic non-small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting (n = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort. RESULTS: Median age at PD-1 inhibitor initiation was 69 years (interquartile range 61-75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death-ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015. CONCLUSION: During the year following U.S. regulatory approval of PD-1 inhibitors for treatment of NSCLC, real-world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real-world treatment decisions. IMPLICATIONS FOR PRACTICE: Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real-world patients receiving these drugs following regulatory approval. Real-world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor-treated metastatic non-small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real-world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies.

Diabetes mellitus concurrent with hepatic haemosiderosis in two macaws (Ara severa, Ara militaris).

Diabetes mellitus was diagnosed in a 5-year-old male chestnut-fronted macaw (Ara severa) and an 8-year-old female Military macaw (Ara militaris) based on persistent hyperglycaemia and glucosuria. Hepatic biopsies showed marked hepatic haemosiderosis, while pancreatic biopsies showed no inflammatory lesions. Repeatable and titratable responses to bovine or porcine protamine zinc insulin were recorded in both patients, who were followed up for more than 2 years. In addition, iron-elimination therapy was initiated by chelation or phlebotomy, and the birds' diet was changed to low-iron content pellets. Both birds responded favourably to this therapy, showing a decreased demand for extrinsic insulin. Follow-up biopsies demonstrated marked reduction in hepatic haemosiderin. Plasma fructosamine and beta-hydroxybutyric acid levels were measured periodically in both birds and compared with euglycaemic psittacines. Both tests appeared useful for monitoring treatment success. The potential association between diabetes mellitus and excessive iron storage in birds should be further investigated.

Red cell morphologic alterations in cats with hepatic disease.

Medical records from 39 cats with hepatic disease, examined at the Veterinary Medical Teaching Hospital, University of Florida, between 1987 and 1992 were retrospectively evaluated for alterations in red blood cell (RBC) morphology. Diagnoses included: hepatic lipidosis, neoplasia, cholangiohepatitis, hepatitis/hepatopathy, systemic histoplasmosis, and portocaval shunt. A total of 56 laboratory data sets were studied which included complete blood counts and serum chemistry results. Stained blood smears were evaluated from 51 of the data sets. Twenty-two cats (56%) were determined to have poikilocytosis on the basis of blood smear evaluation. Eleven (28%) cats had moderate to marked poikilocytosis (2+ to 4+). Acanthocytes accounted for 62.6 -/+ 22.1% of morphologically abnormal RBC and were observed in blood smears from 100% of cats with poikilocytosis. Elliptocytes (ovalocytes) comprised 19.5 -/+ 15.8% of poikilocytes and were found in smears from 82% of cats with poikilocytosis. Keratocytes (7.0 -/+ 6.8%), schistocytes (3.6 -/+ 4.4%), and blister cells (2.6 -/+ 6.4%) were present in lower numbers and in fewer cats. Serum total cholesterol values were significantly greater (p < 0.05) in cats with moderate to marked alterations in RBC morphology. Cats with hepatic lipidosis were significantly (p < 0.04) more likely to have poikilocytosis than cats with other types of hepatic disease.

Gene fishing: the use of a simple protocol to isolate multiple homeodomain classes from diverse invertebrate taxa.

Comparison of relevant gene sequence and functional data is central to understanding the evolution of metazoan development. The conservation of portions of regulatory genes, such as homeoboxes, allows for the design of PCR-based sequence isolation and amplification strategies. Here we describe a simple protocol that uses a degenerate primer pair to isolate a variety of homeobox-containing genes from diverse metazoan taxa. In a nonexhaustive survey, we have isolated 28 gene sequence fragments from 15 taxa, representing eight invertebrate phyla (Mollusca, Echiura, Annelida, Platyhelminth, Acoela, Ctenophora, Cnidaria, and Porifera). Based on BLAST and parsimony analyses, these gene fragments affiliate with several gene groups (PAIRED-like, HOX, and ParaHOX) and several single genes, including pancreas/duodenum homeoboxes (Pdx), empty spiracles (ems/Emx), gastrulation brain homeoboxes (Gbx), hematopoietically expressed homeoboxes (HEX), brain specific homeobox (bsh/BarH1/BarH2), NK-1 (NK-1/s59/slouch), and ladybird (Lbl/Lbe/Lbx). In several cases, these fragments represent the first reported orthologue for the phylum or superphyletic group (i.e., Lophotrochozoa).