Representativeness of Patients With Lung Cancer in an Integrated Health Care Delivery System.

INTRODUCTION: Observational research is important for understanding the real-world benefits of advancements in lung cancer care. Integrated health care systems, such as Kaiser Permanente Northern California, have extensive electronic health records suitable for such research, but the generalizability of their populations is often questioned. METHODS: Leveraging data from the California Cancer Registry, the authors compared distributions of demographic and clinical characteristics, in addition to neighborhood and environmental conditions, between patients diagnosed with lung cancer from 2015 through 2019 at Kaiser Permanente Northern California, National Cancer Institute-designated cancer centers (NCICCs), and all other non-NCICC hospitals within the same catchment area. RESULTS: Of 20,178 included patients, 30% were from Kaiser Permanente Northern California, 8% from NCICCs, and 62% from other non-NCICC hospitals. Compared to NCICC patients, Kaiser Permanente Northern California patients were more similar to other non-NCICC patients on most characteristics. Compared to other non-NCICC patients, Kaiser Permanente Northern California patients were slightly older, more likely to be female, and less likely to be Hispanic or Asian/Pacific Islander and to reside in lower socioeconomic status (SES) neighborhoods. In contrast, NCICC patients were younger, less likely to be female or from non-Asian/Pacific Islander minoritized racial groups, and more likely to present with early-stage disease and adenocarcinoma and to reside in neighborhoods with higher SES and lower air pollution than Kaiser Permanente Northern California or other non-NCICC patients. DISCUSSION: Patients from Kaiser Permanente Northern California, compared to NCICCs, are more broadly representative of the underlying patient population with lung cancer. CONCLUSION: Research using electronic health record data from integrated health care systems can contribute generalizable real-world evidence to benchmark and improve lung cancer care.

A retrospective population-based analysis of wait times for cataract surgery in Ontario, Canada.

BACKGROUND: Current methods used to estimate surgical wait times in Ontario may be subject to inconsistencies and inaccuracies. In this population-level study, we aimed to estimate cataract surgery wait times in Ontario using a novel, objective and data-driven method. METHODS: We identified adults who underwent cataract surgery between 2005 and 2019 in Ontario, using administrative records. Wait time 1 represented the number of days from referral to initial visit with the surgeon, and wait time 2 represented the number of days from the decision for surgery until the first eye surgery date. In the primary analysis, a ranking method prioritized referrals from optometrists, followed by ophthalmologists and family physicians. RESULTS: The cohort consisted of 1 138 532 people with mostly female patients (57.4%) and those aged 65 years and older (79.0%). In the primary analysis, the median was 67 days for wait time 1 (interquartile range [IQR] 29-147). There was a median of 77 days for wait time 2 (IQR 37-155). Overall, the following proportions of patients waited less than 3, 6 and 12 months: 54.1%, 78.5% and 91.7%, respectively. For wait time 2, the proportions of patients who waited less than 3, 6 and 12 months were 49.5%, 77.1% and 93.3%, respectively. In total, 19.3% of patients did not meet the provincial target for wait time 1, 20.5% did not meet the target for wait time 2 and 35.0% did not meet the target for wait times 1 or 2. INTERPRETATION: Administrative health services data can be used to estimate cataract surgery wait times. With this method, 35.0% of patients in 2005-2019 did not receive initial consultation or surgery within the provincial wait time target.

Risk Factors for Immune Checkpoint Inhibitor Immunotherapy Toxicity Among Older Adults with Cancer.

OBJECTIVES: Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults. MATERIALS AND METHODS: This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians. For patients aged ≥70 years, frequency, type, and grade of irAEs and their association with baseline patient demographics, comorbidities, mobility, and functional status were characterized using bivariate analysis. Based on those results, multivariable logistic regressions were constructed to model the association between these characteristics with any grade and grade 3 or higher irAEs. RESULTS: Data were analyzed for 238 patients aged ≥70 years who received IO for mostly (≥90%) advanced cancer between 2011 and 2018. Thirty-nine percent of older adults experienced an irAE and 13% experienced one that was grade 3 or higher. In the multivariable analysis, depression was associated with an increased incidence of any grade irAE, while decreased life-space mobility was associated with an increased incidence of grade ≥3 irAEs. CONCLUSION: Most characteristics of special interest among older adults, include fall risk, weight loss, cognitive limitations, and hearing loss, were not associated with irAEs in our study. However, decreased life-space mobility and depression are potential risk factors for IO toxicity among older adults with advanced cancer. Interventions designed to evaluate and mitigate modifiable risk factors for treatment-related toxicity are needed, and the results of this study may be useful for guiding those efforts.

Association of medical comorbidities and cardiovascular disease with toxicity and survival among patients receiving checkpoint inhibitor immunotherapy.

BACKGROUND AND OBJECTIVES: Medical comorbidities (MC) are highly prevalent among patients with cancer and predict worse outcomes for traditional therapies. This association is poorly understood for checkpoint inhibitor immunotherapy (IO). We aimed to explore the relationship between common MC including cardiovascular disease (CVD), immune-related adverse events (irAEs), and overall survival (OS) among patients receiving IO for advanced cancer. METHODS: This is a retrospective cohort study of 671 patients with any cancer who received IO at our institution from 2011 to 2018. Clinical data were abstracted via chart review and query of ICD-10 codes and used to calculate modified Charlson comorbidity index (mCCI) scores. The primary outcomes were the association of individual MC with irAEs and OS using bivariate and multivariable analyses. Secondary outcomes included association of mCCI score with irAEs and OS. RESULTS: Among 671 patients, 62.1% had a mCCI score ≥ 1. No individual MC were associated with irAEs or OS. Increased CCI score was associated with decreased OS (p < 0.01) but not with irAEs. Grade ≥ 3 irAEs were associated with increased OS among patients without CVD (HR 0.37 [95% CI: 0.25, 0.55], p < 0.01), but not among patients with CVD. CONCLUSIONS: No specific MC predicted risk of irAEs or OS for patients receiving IO. Increased CCI score did not predict risk of irAEs but was associated with shorter OS. This suggests IO is safe for patients with MC, but MC may limit survival benefits of IO. CVD may predict shorter OS in patients with irAEs and should be evaluated among patients receiving IO.

Clinical and Visual Field Outcomes Following Minimally Invasive Glaucoma Surgery Combined with Cataract Surgery.

Purpose: To determine the change in Humphrey visual field and clinical parameters after minimally invasive glaucoma surgery combined with cataract surgery. Patients and Methods: Patients undergoing minimally invasive glaucoma surgery combined with cataract surgery in a multicenter retrospective case series between 2013 and 2021 with reliable preoperative and 12 to 18 month postoperative visual field measurements were included. Devices included iStent, XEN, and Hydrus. Clinical parameters were compared with a generalized linear model with generalized estimating equations between preoperative and postoperative visits including best corrected visual acuity, intraocular pressure, number of glaucoma medications and visual fields. Visual field metrics included mean deviation (MD), pattern standard deviation (PSD), visual field index (VFI), and Collaborative Initial Glaucoma Treatment Study (CIGTS) score of total deviation probability and pattern deviation probability. Results: Forty-four eyes from 39 patients were included. During the follow up period, visual acuity improved from 0.23±0.17 to 0.10±0.14 logMAR (mean ± standard deviation, p<0.001), number of glaucoma medications was reduced from 2.68±1.06 to 1.46±1.32 (p<0.001), and intraocular pressure decreased from 17.08±4.23 mmHg to 14.92±3.13 mmHg (p=0.003). Differences across devices were negligible. The only significant difference was a greater reduction in number of glaucoma medications in the XEN group (p<0.001). There were no significant changes in the global parameters of VFI, MD, PSD, or CIGTS. Conclusion: Overall, minimally invasive glaucoma surgery combined with cataract surgery appears to be effective at stabilizing visual field function, reducing intraocular pressure, reducing number of glaucoma medications, and improving visual acuity over a 12 to 18 month follow-up period across MIGS devices.

Accelerated hypofractionated radiation for elderly or frail patients with a newly diagnosed glioblastoma: A pooled analysis of patient-level data from 4 prospective trials.

BACKGROUND: The standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) is safe and efficacious. METHODS: Elderly or frail patients with GBM treated with 52.5 Gy in 15 fractions were pooled from 3 phase 1/2 studies and a prospective observational study. Overall survival (OS) and progression-free survival (PFS) were defined time elapsing between surgery/biopsy and death from any cause or progression of disease. RESULTS: Sixty-two newly diagnosed patients were eligible for this pooled analysis of individual patient data. The majority (66%) had a Karnofsky performance status (KPS) score <70. The median age was 73 years. The median OS and PFS were 10.3 and 6.9 months, respectively. Patients with KPS scores ≥70 and <70 had a median OS of 15.3 and 9.5 months, respectively. Concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). There was no grade 4/5 toxicity. CONCLUSIONS: This is the only analysis of elderly/frail patients with GBM prospectively treated with a hypofractionated radiation regimen that is isoeffective to the Stupp regimen. Treatment was well tolerated and demonstrated excellent OS and PFS compared with historical studies. This regimen gives the elderly/frail population an alternative to regimens with a lower BED. Randomized trials are needed to validate these results.

Accuracy of Hemolyzed Potassium Levels in the Emergency Department.

INTRODUCTION: In the emergency department (ED), pseudohyperkalemia from hemolysis may indirectly harm patients by exposing them to increased length of stay, cost, and repeat blood draws. The need to repeat hemolyzed potassium specimens in low-risk patients has not been well studied. Our objective was to determine the rate of true hyperkalemia among low-risk, adult ED patients with hemolyzed potassium specimens. METHODS: We conducted this prospective observational study at two large (129,000 annual visits) academic EDs in the mid-Atlantic. Data were collected from June 2017-November 2017 as baseline data for planned departmental quality improvement and again from June 2018-November 2018. Inclusion criteria were an initial basic metabolic panel in the ED with a hemolyzed potassium level > 5.1 milliequivalents per liter that was repeated within 12 hours, age (≥18, and bicarbonate (HCO3) > 20. Exclusion criteria were age > 65, glomerular filtration rate (GFR) < 60, creatine phosphokinase > 500, hematologic malignancy, taking potassium-sparing or angiotensin-acting agents, or treatment with potassium-lowering agents (albuterol, insulin, HCO3, sodium polystyrene sulfonate, or potassium-excreting diuretic) prior to the repeat lab draw. RESULTS: Of 399 encounters with a hemolyzed, elevated potassium level in patients with GFR ≥ 60 and age > 18 that were repeated, we excluded 333 patients for age > 64, lab repeat > 12 hours, invalid identifiers, potassium-elevating or lowering medicines or hematologic malignancies.This left 66 encounters for review. There were no instances of hyperkalemia on the repeated, non-hemolyzed potassium levels, correlating to a true positive rate of 0% (95% confidence interval 0-6%). Median patient age was 46 (interquartile range [IQR] 34 - 56) years. Median hemolyzed potassium level was 5.8 (IQR 5.6 - 6.15) millimoles per liter (mmol/L), and median repeated potassium level was 3.9 (IQR 3.6 - 4.3) mmol/L. Median time between lab draws was 145 (IQR 87 - 262) minutes. CONCLUSION: Of 66 patients who met our criteria, all had repeat non-hemolyzed potassiums within normal limits. The median of 145 minutes between lab draws suggests an opportunity to decrease the length of stay for these patients. Our results suggest that in adult patients < 65 with normal renal function, no hematologic malignancy, and not on a potassium-elevating medication, there is little to no risk of true hyperkalemia. Further studies should be done with a larger patient population and multicenter trials.

PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice.

BACKGROUND & AIMS: Hyperactivation of the RAS-RAF signaling pathway in colorectal tumors is associated with metastasis and poor outcomes of patients. Little is known about how RAS-RAF signaling is turned off once activated. We investigated how the pH domain and leucine-rich repeat protein phosphatases (PHLPPs) control RAS-RAF signaling and colorectal cancer (CRC) development. METHODS: We used co-immunoprecipitation assays to identify substrates of PHLPP1 and PHLPP2. We studied phosphorylation of RAF1 in CRC cells that express exogenous PHLPP1 or PHLPP2, or lentiviral-based small hairpin RNAs against their transcripts; we measured effects on cell motility, migration, and invasion in vitro. Tumor progression and survival were analyzed in Phlpp1(-/-) Apc(Min) and Apc(Min)/Phlpp1(-/-) mice. Microarray datasets of colorectal tumor and nontumor tissues were analyzed for PHLPP gene expression. RESULTS: PHLPP1 and 2 were found to dephosphorylate RAF1 at S338, inhibiting its kinase activity in vitro and in CRC cells. In cells, knockdown of PHLPP1 or PHLPP2 increased the amplitude and duration of RAF-MEK-ERK signaling downstream of epidermal growth factor receptor and KRAS, whereas overexpression had the opposite effect. In addition, knockdown of PHLPP1 or PHLPP2 caused CRC cells to express markers of the epithelial-mesenchymal transition, and increased cell migration and invasion. Apc(Min)/Phlpp1(-/-) mice had decreased survival and developed larger intestinal and colon tumors compared to Apc(Min) mice. Whereas Apc(Min) mice developed mostly low-grade adenomas, 20% of the tumors that developed in Apc(Min)/Phlpp1(-/-) mice were invasive adenocarcinomas. Normal villi and adenomas of Apc(Min)/Phlpp1(-/-) mice had significantly fewer apoptotic cells than Apc(Min) mice. Human CRC patient microarray data revealed that the expression of PHLPP1 or PHLPP2 is positively correlated with CDH1. CONCLUSIONS: PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression.