A Prospective Observational Cohort Study of Language Preference and Preoperative Cognitive Screening in Older Adults: Do Language Disparities Exist in Cognitive Screening and Does the Association Between Test Results and Postoperative Delirium Differ Based on Language Preference?

BACKGROUND: A greater percentage of surgical procedures are being performed each year on patients 65 years of age or older. Concurrently, a growing proportion of patients in English-speaking countries such as the United States, United Kingdom, Australia, and Canada have a language other than English (LOE) preference. We aimed to measure whether patients with LOE underwent cognitive screening at the same rates as their English-speaking counterparts when routine screening was instituted. We also aimed to measure the association between preoperative Mini-Cog and postoperative delirium (POD) in both English-speaking and LOE patients. METHODS: We conducted a single-center, observational cohort study in patients 65 years old or older, scheduled for surgery and evaluated in the preoperative clinic. Cognitive screening of older adults was recommended as an institutional program for all patients 65 and older presenting to the preoperative clinic. We measured program adherence for cognitive screening. We also assessed the association of preoperative impairment on Mini-Cog and POD in both English-speaking and LOE patients, and whether the association differed for the 2 groups. A Mini-Cog score ≤2 was considered impaired. Postoperatively, patients were assessed for POD using the Confusion Assessment Method (CAM) and by systematic chart review. RESULTS: Over a 3-year period (February 2019-January 2022), 2446 patients 65 years old or older were assessed in the preoperative clinic prior. Of those 1956 patients underwent cognitive screening. Eighty-nine percent of English-speaking patients underwent preoperative cognitive screening, compared to 58% of LOE patients. The odds of having a Mini-Cog assessment were 5.6 times higher (95% confidence interval [CI], 4.6-7.0) P < .001 for English-speaking patients compared to LOE patients. In English-speaking patients with a positive Mini-Cog screen, the odds of having postop delirium were 3.5 times higher (95% CI, 2.6-4.8) P < .001 when compared to negative Mini-Cog. In LOE patients, the odds of having postop delirium were 3.9 times higher (95% CI, 2.1-7.3) P < .001 for those with a positive Mini-Cog compared to a negative Mini-Cog. The difference between these 2 odds ratios was not significant (P = .753). CONCLUSIONS: We observed a disparity in the rates LOE patients were cognitively screened before surgery, despite the Mini-Cog being associated with POD in both English-speaking and LOE patients. Efforts should be made to identify barriers to cognitive screening in limited English-proficient older adults.

Impact of Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography on Prostate Cancer Salvage Radiotherapy Management: Results from a Prospective Multicenter Randomized Phase 3 Trial (PSMA-SRT NCT03582774).

BACKGROUND: Both imaging and several prognostic factors inform the planning of salvage radiotherapy (SRT). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can localize disease unseen by other imaging modalities. OBJECTIVE: To evaluate the impact of PSMA-PET on biochemical recurrence-free survival rate after SRT. DESIGN, SETTING, AND PARTICIPANTS: This prospective randomized, controlled, phase 3 clinical trial randomized 193 patients with biochemical recurrence of prostate cancer after radical prostatectomy to proceed with SRT (control arm, n = 90) or undergo a PSMA-PET/computed tomography (CT) scan prior to SRT planning (investigational arm, n = 103) from June 2018 to August 2020. Any other approved imaging modalities were allowed in both arms (including fluciclovine-PET). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: This is a secondary endpoint analysis: impact of PSMA-PET on SRT planning. Case-report forms were sent to referring radiation oncologists to collect the management plans before randomization and after completion of SRT. The relative frequency (%) of management changes within each arm were compared using chi-square and Fisher's exact tests. RESULTS AND LIMITATIONS: The delivered SRT plan was available in 178/193 patients (92.2%; 76/90 control [84.4%] and 102/103 PSMA-PET [99%]). Median prostate-specific antigen levels at enrollment was 0.30 ng/ml (interquartile range [IQR] 0.19-0.91) in the control arm and 0.23 ng/ml (IQR 0.15-0.54) in the PSMA-PET arm. Fluciclovine-PET was used in 33/76 (43%) in the control arm. PSMA-PET localized recurrence(s) in 38/102 (37%): nine of 102 (9%) outside of the pelvis (M1), 16/102 (16%) in the pelvic LNs (N1, with or without local recurrence), and 13/102 (13%) in the prostate fossa only. There was a 23% difference (95% confidence interval [CI] 9-35%, p = 0.002) of frequency of major changes between the control arm (22% [17/76]) and the PSMA-PET intervention arm (45% [46/102]). Of the major changes in the intervention group, 33/46 (72%) were deemed related to PSMA-PET. There was a 17.6% difference (95% CI 5.4-28.5%, p = 0.005) of treatment escalation frequency between the control arm (nine of 76 [12%]) and the intervention arm (30/102 [29%]). Treatment de-escalation occurred in the control and intervention arms in eight of 76 (10.5%) and 12/102 (11.8%) patients, and mixed changes in zero of 76 (0%) and four of 102 (3.9%) patients, respectively. CONCLUSIONS: In this prospective randomized phase 3 study, PSMA-PET findings provided information that initiated major management changes to SRT planning in 33/102 (33%) patients. The final readout of the primary endpoint planned in 2025 may provide evidence on whether these changes result in improved outcomes. PATIENT SUMMARY: Prostate-specific membrane antigen positron emission tomography leads to management changes in one-third of patients receiving salvage radiotherapy for post-radical prostatectomy biochemical recurrence of prostate cancer.

Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma.

Increased utilization of glucose is a hallmark of cancer. Sodium-glucose transporter 2 (SGLT2) is a critical player in glucose uptake in early-stage and well-differentiated lung adenocarcinoma (LUAD). SGLT2 inhibitors, which are FDA approved for diabetes, heart failure, and kidney disease, have been shown to significantly delay LUAD development and prolong survival in murine models and in retrospective studies in diabetic patients, suggesting that they may be repurposed for lung cancer. Despite the antitumor effects of SGLT2 inhibition, tumors eventually escape treatment. Here, we studied the mechanisms of resistance to glucose metabolism-targeting treatments. Glucose restriction in LUAD and other tumors induced cancer cell dedifferentiation, leading to a more aggressive phenotype. Glucose deprivation caused a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. The dedifferentiated phenotype depended on unbalanced EZH2 activity that suppressed prolyl-hydroxylase PHD3 and increased expression of hypoxia-inducible factor 1α (HIF1α), triggering epithelial-to-mesenchymal transition. Finally, a HIF1α-dependent transcriptional signature of genes upregulated by low glucose correlated with prognosis in human LUAD. Overall, this study furthers current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying targets to prevent the development of resistance to therapies targeting glucose metabolism. SIGNIFICANCE: Epigenetic adaptation allows cancer cells to overcome the tumor-suppressive effects of glucose restriction by inducing dedifferentiation and an aggressive phenotype, which could help design better metabolic treatments.

Evaluating the Impact of Race and Ethnicity on Health-Related Quality of Life Disparities in Patients with Esophageal Cancer: A SEER-MHOS National Database Study.

BACKGROUND: It is unclear whether health-related quality of life (HRQOL) disparities exist between racial/ethnic groups in older patients with esophageal cancer, pre- and post-diagnosis. METHODS: Using the SEER-MHOS (Surveillance, Epidemiology, and End Results and Medicare Health Outcomes Survey) national database, we included patients ages 65-years-old or greater with esophageal cancer diagnosed from 1996 to 2017. HRQOL data within 36 months before and after diagnosis were measured by the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores from the SF-36 and VR-12 instruments. Total combined score (TCS) was reflected by both PCS and MCS. RESULTS: We identified 1,312 patients, with evaluable data on 873 patients pre-diagnosis and 439 post-diagnosis. On pre-diagnosis cohort MVA, the MCS was better for White over Hispanic patients (54.1 vs. 48.6, P = 0.012). On post-diagnosis cohort MVA, PCS was better for Hispanic compared with White (39.8 vs. 34.5, P = 0.036) patients, MCS was better for Asian compared with White (48.9 vs. 40.9, P = 0.034) patients, and TCS better for Asian compared with White (92.6 vs. 76.7, P = 0.003) patients. CONCLUSIONS: In older patients with esophageal cancer, White patients had better mental HRQOL as compared with Hispanic patients pre-diagnosis. However, post-diagnosis, White patients had worse mental and physical HRQOL compared with Asian and Hispanic patients, respectively, suggesting a greater negative impact on self-reported HRQOL in White patients with esophageal cancer. IMPACT: To our knowledge, this study is the first to explore HRQOL differences in patients with esophageal cancer of various racial and ethnic groups and warrants further validation in future studies.

External validation of a predictive model for reintubation after cardiac surgery: A retrospective, observational study.

STUDY OBJECTIVE: Explore validation of a model to predict patients' risk of failing extubation, to help providers make informed, data-driven decisions regarding the optimal timing of extubation. DESIGN: We performed temporal, geographic, and domain validations of a model for the risk of reintubation after cardiac surgery by assessing its performance on data sets from three academic medical centers, with temporal validation using data from the institution where the model was developed. SETTING: Three academic medical centers in the United States. PATIENTS: Adult patients arriving in the cardiac intensive care unit with an endotracheal tube in place after cardiac surgery. INTERVENTIONS: Receiver operating characteristic (ROC) curves and concordance statistics were used as measures of discriminative ability, and calibration curves and Brier scores were used to assess the model's predictive ability. MEASUREMENTS: Temporal validation was performed in 1642 patients with a reintubation rate of 4.8%, with the model demonstrating strong discrimination (optimism-corrected c-statistic 0.77) and low predictive error (Brier score 0.044) but poor model precision and recall (Optimal F1 score 0.29). Combined domain and geographic validation were performed in 2041 patients with a reintubation rate of 1.5%. The model displayed solid discriminative ability (optimism-corrected c-statistic = 0.73) and low predictive error (Brier score = 0.0149) but low precision and recall (Optimal F1 score = 0.13). Geographic validation was performed in 2489 patients with a reintubation rate of 1.6%, with the model displaying good discrimination (optimism-corrected c-statistic = 0.71) and predictive error (Brier score = 0.0152) but poor precision and recall (Optimal F1 score = 0.13). MAIN RESULTS: The reintubation model displayed strong discriminative ability and low predictive error within each validation cohort. CONCLUSIONS: Future work is needed to explore how to optimize models before local implementation.

Interplay of Cortisol, Testosterone, and Abdominal Fat Mass in Normal-weight Women With Polycystic Ovary Syndrome.

Context: Ovarian and adrenal steroidogenesis underlie endocrine-metabolic dysfunction in polycystic ovary syndrome (PCOS). Adipocytes express aldo-keto reductase 1C3 and type 1 11ß-hydroxysteroid dehydrogenase, which modulate peripheral androgen and cortisol production. Objectives: To compare serum adrenal steroids, including 11-oxygenated androgens (11-oxyandrogens), cortisol, and cortisone between normal-weight women with PCOS and body mass index- and age-matched ovulatory women with normal-androgenic profiles (controls), and assess whether adrenal steroids associate with abdominal adipose deposition. Design: Prospective, cross-sectional, cohort study. Setting: Academic medical center. Patients: Twenty normal-weight women with PCOS and 20 body mass index-/age-matched controls. Interventions: Blood sampling, IV glucose tolerance testing, and total-body dual-energy x-ray absorptiometry. Main Outcome Measures: Clinical characteristics, hormonal concentrations, and body fat distribution. Results: Women with PCOS had higher serum total/free testosterone (T) and androstenedione (A4) levels and a greater android/gynoid fat mass than controls (androgens P < .001; android/gynoid fat mass ratio, P = .026). Serum total/free T and A4 levels correlated positively with android/gynoid fat mass ratio in all women combined (P < .025, all values). Serum 11ß-hydroxyA4, 11-ketoA4, 11ß-hydroxyT, 11-ketoT, cortisol, and cortisone levels were comparable between female types and unrelated to body fat distribution. Serum 11-oxyandrogens correlated negatively with % total body fat, but lost significance adjusting for cortisol. Serum cortisol levels, however, correlated inversely with android fat mass (P = .021), with a trend toward reduced serum cortisol to cortisone ratio in women with PCOS vs controls (P = .075), suggesting diminished 11ß-hydroxysteroid dehydrogenase activity. Conclusion: Reduced cortisol may protect against preferential abdominal fat mass in normal-weight PCOS women with normal serum 11-oxyandrogens.

Presurgical 68Ga-PSMA-11 Positron Emission Tomography for Biochemical Recurrence Risk Assessment: A Follow-up Analysis of a Multicenter Prospective Phase 3 Imaging Trial.

BACKGROUND: In the initial staging of patients with high-risk prostate cancer (PCa), prostate-specific membrane antigen positron emission tomography (PSMA-PET) has been established as a front-line imaging modality. The increasing number of PSMA-PET scans performed in the primary staging setting might be associated with decreases in biochemical recurrence (BCR)-free survival (BCR-FS). OBJECTIVE: To assess the added prognostic value of presurgical PSMA-PET for BCR-FS compared with the presurgical Cancer of the Prostate Risk Assessment (CAPRA) and postsurgical CAPRA-Surgery (CAPRA-S) scores in patients with intermediate- to high-risk PCa treated with radical prostatectomy (RP) and pelvic lymph node dissection. DESIGN, SETTING, AND PARTICIPANTS: This is a follow-up study of the surgical cohort evaluated in the multicenter prospective phase 3 imaging trial (n = 277; NCT03368547, NCT02611882, and NCT02919111). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Each 68Ga-PSMA-11-PET scan was read by three blinded independent readers. PSMA-PET prostate uptake (low vs high), PSMA-PET extraprostatic disease (N1/M1), and CAPRA and CAPRA-S scores were used to assess the risk of BCR. Patients were followed after RP by local investigators using electronic medical records. BCR was defined by a prostate-specific antigen (PSA) level increasing to ≥0.2 ng/ml after RP or initiation of PCa-specific secondary treatment (>6 mo after surgery). Univariate and multivariable Cox models, and c-statistic index were performed to assess the prognostic value of PSMA-PET and for a comparison with the CAPRA and CAPRA-S scores. RESULTS AND LIMITATIONS: From December 2015 to December 2019, 277 patients underwent surgery after PSMA-PET. Clinical follow-up was obtained in 240/277 (87%) patients. The median follow-up after surgery was 32.4 (interquartile range 23.3-42.9) mo. Of 240 BCR events, 91 (38%) were observed. PSMA-PET N1/M1 was found in 41/240 (17%) patients. PSMA-PET prostate uptake, PSMA-PET N1/M1, and CAPRA and CAPRA-S scores were significant univariate predictors of BCR. The addition of PSMA-PET N1/M1 status to the presurgical CAPRA score improved the risk assessment for BCR significantly in comparison with the presurgical CAPRA score alone (c-statistic 0.70 [0.64-0.75] vs 0.63 [0.57-0.69]; p < 0.001). The C-index of the postsurgical model utilizing the postsurgical CAPRA-S score alone was not significantly different from the presurgical model combining the presurgical CAPRA score and PSMA-PET N1/M1 status (p = 0.19). CONCLUSIONS: Presurgical PSMA-PET was a strong prognostic biomarker improving BCR-FS risk assessment. Its implementation in the presurgical risk assessment with the CAPRA score improved the performance and reduced the difference with the reference standard (postsurgical CAPRA-S score). PATIENT SUMMARY: The use prostate-specific membrane antigen positron emission tomography improved the assessment of biochemical recurrence risk in patients with intermediate- and high-risk prostate cancer who were treated with radical prostatectomy and pelvic lymph node dissection.

Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma.

Increased utilization of glucose is a hallmark of cancer. Several studies are investigating the efficacy of glucose restriction by glucose transporter blockade or glycolysis inhibition. However, the adaptations of cancer cells to glucose restriction are unknown. Here, we report the discovery that glucose restriction in lung adenocarcinoma (LUAD) induces cancer cell de-differentiation, leading to a more aggressive phenotype. Glucose deprivation causes a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. We further show that this de-differentiated phenotype depends on unbalanced EZH2 activity, causing inhibition of prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1α (HIF1α), triggering epithelial to mesenchymal transition. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying novel targets to prevent the development of resistance to therapies targeting glucose metabolism.

Impact of Prediagnosis Risk of Major Depressive Disorder and Health-Related Quality of Life on Treatment Choice for Stage II-III Rectal Cancer.

PURPOSE: We hypothesized that depressive symptoms and health-related quality of life (HRQOL) reported by patients before their cancer diagnoses would be associated with treatment choice for stage II and III rectal cancer, specifically whether patients underwent surgery. METHODS: The Surveillance, Epidemiology, and End Results and Medicare Health Outcomes Survey linked data set was used to identify patients with stage II-III rectal adenocarcinoma diagnosed between 2004 and 2013 who had completed the health outcomes survey within 36 months before their cancer diagnoses. Risk for major depressive disorder (MDD) was determined on the basis of responses to screening questions for depressive disorders. HRQOL was assessed using the Mental Component Summary and Physical Component Summary of the 36-Item Short Form Survey and Veterans RAND 12-Item Health Survey. Using univariable and multivariable analyses, we assessed for associations between health survey responses and ultimate treatment modality. RESULTS: We identified 142 evaluable patients, of whom 109 (76.8%) underwent surgery. Thirty patients (21.1%) met criteria for being at risk for MDD before their cancer diagnoses. Patients at risk for MDD underwent surgery less often than those not at risk (P = .0499), and this association strengthened after adjusting for patient characteristics (odds ratio, 0.17; 95% CI, 0.04 to 0.82; P = .027). There was a nonsignificant trend between higher Mental Component Summary scores (indicating higher self-reported mental HRQOL) and increased frequency of undergoing surgery (P = .081). There were no significant associations between the Physical Component Summary and treatment modality. CONCLUSION: In Medicare beneficiaries with stage II-III rectal cancer, those at risk for MDD underwent standard-of-care treatment with surgery less frequently. Further studies are warranted to assess the effect of mental health on clinical decision making in this patient population.

Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight women with polycystic ovary syndrome.

OBJECTIVE: To examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates accelerated lipid accumulation in newly formed adipocytes derived from subcutaneous (SC) abdominal adipose stem cells (ASCs), and/or alters glucose-lipid metabolism. DESIGN: A double-blind, placebo-controlled randomized clinical trial. SETTING: An academic medical center. PATIENT(S): Twelve normal-weight women with PCOS and 12 age- and body mass index-matched controls. INTERVENTION(S): Women underwent circulating hormonal and metabolic determinations, intravenous glucose tolerance testing, total body dual-energy roentgenogram absorptiometry, and SC abdominal fat biopsy. Interventions were repeated in women with PCOS after 6-month administration of flutamide (125 mg orally daily) vs. placebo. MAIN OUTCOME MEASURE(S): Clinical parameters and lipid accumulation in newly formed adipocytes derived from SC abdominal ASCs in vitro were compared between controls and the women with PCOS receiving flutamide vs. placebo. RESULTS: Serum luteinizing hormone and androgen levels as well as lipid accumulation in newly formed SC abdominal adipocytes were greater in the women with PCOS than controls. Flutamide vs. placebo reduced percent android fat, lowered serum log low-density lipoprotein and log non-high-density lipoprotein levels, and increased fasting circulating glucose levels. In all women with PCOS, changes in percent android fat positively correlated with serum log non-high-density lipoprotein and log low-density lipoprotein levels, with correlations influenced by serum free testosterone levels. Flutamide vs. placebo also attenuated lipid accumulation in newly-formed PCOS SC abdominal adipocytes in vitro relative to controls, which was unrelated to serum lipid levels. CONCLUSION: Low-dose flutamide administration to normal-weight PCOS women reduces preferential abdominal fat deposition, attenuates accelerated lipid accumulation in newly-formed adipocytes derived from SC abdominal ASCs in vitro, and alters glucose-lipid homeostasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT01889199 (URL, clinicaltrials.gov; date of registration, 6/28/2013; enrollment date of first subject, 6/28/2013).

Early Postoperative Opioid Requirement Is Associated With Later Pain Control Needs After Supratentorial Craniotomies.

BACKGROUND: Despite a renewed focus in recent years on pain management in the inpatient hospital setting, postoperative pain after elective craniotomy remains under investigated. This study aims to identify which perioperative factors associate most strongly with postoperative pain and opioid medication requirements after inpatient craniotomy. MATERIALS AND METHODS: Using an existing dataset, we selected a restricted cohort of patients who underwent elective craniotomy surgery requiring an inpatient postoperative stay during a 7-year period at our institution (n=1832). We examined pain scores and opioid medication usage and analyzed the relative contribution of specific perioperative risk factors to postoperative pain and opioid medication intake (morphine milligram equivalents). RESULTS: Postoperative pain was found to be highest on postoperative day 1 and decreased thereafter (up to day 5). Factors associated with greater postoperative opioid medication requirement were preoperative opioid medication use, duration of anesthesia, degree of pain in the preoperative setting, and patient age. Notably, the most significant factor associated with a higher postoperative pain score and Morphine milligram equivalents requirement was the time elapsed between the end of general anesthesia and a patient's first intravenous opioid medication. CONCLUSION: Postcraniotomy patients are at higher risk for requiring opioid pain medications if they have a history of preoperative opioid use, are of younger age, or undergo a longer surgery. Moreover, early requirement of intravenous opioid medications in the postoperative period should alert treating physicians that a patient's pain may require additional or alternative methods of pain control than routinely administered, to avoid over-reliance on opioid medications.

Phase 2 of extracellular RNA communication consortium charts next-generation approaches for extracellular RNA research.

The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database. ERCC2 has established several Working Groups (Resource Sharing, Reagent Development, Data Analysis and Coordination, Technology Development, nomenclature, and Scientific Outreach) to promote collaboration between ERCC2 members and the broader scientific community. We expect that ERCC2's current and future achievements will significantly improve our understanding of exRNA biology and the development of accurate and efficient exRNA-based diagnostic, prognostic, and theranostic biomarker assays.

Performance of Salivary Extracellular RNA Biomarker Panels for Gastric Cancer Differs between Distinct Populations.

Gastric cancer (GC) has the fifth highest incidence among cancers and is the fourth leading cause of cancer-related death GC has predominantly a higher number of cases in certain ethnic groups such as the Korean population. GC found at an early stage is more treatable and has a higher survival rate as compared with GC found at a late stage. However, a diagnosis of GC is often delayed due to the lack of early symptoms and available screening programs in United States. Extracellular RNA (exRNA) is an emerging paradigm; exRNAs have the potential to serve as biomarkers in panels aimed at early detection of cancer. We previously reported the successful use of a panel of salivary exRNA for detecting GC in a high-prevalence Korean cohort, and that genetic changes reflected cancer-associated salivary exRNA changes. The current study is a case-control study of salivary exRNA biomarkers for detecting GC in an ethnically distinct U.S. cohort. A model constructed for the U.S. cohort combined demographic characteristics and salivary miRNA and mRNA biomarkers for GC and yielded an area under the receiver operating characteristic (ROC) curve (AUC) of 0.78. However, the constituents of this model differed from that constructed for the Korean cohort, thus, emphasizing the importance of population-specific biomarker development and validation.

Needlestick injuries among anesthesia providers from a large US academic center: A 10-year retrospective analysis.

STUDY OBJECTIVE: Anesthesiologists are at high risk for needlestick injury. Such injuries pose a serious health threat from exposure to bloodborne pathogens. This retrospective analysis aimed to examine needlestick injury rate among anesthesia providers between 2010 and 2020 at the University of California Los Angeles, Department of Anesthesiology and Perioperative Medicine to determine specialty-specific factors associated with these injuries. DESIGN: Retrospective analysis. SETTING: Academic Anesthesiology Department. PATIENTS AND INTERVENTIONS: None. MEASUREMENTS: All reported incidents of needlestick injuries to employees are sent to the Injury and Illness Prevention Committee. We included all anesthesia residents, fellows, nurse anesthetists, solo anesthesiologists, and supervising anesthesiologists. MAIN RESULTS: The overall rate of reported needlestick injuries was 5.3%. The rates for anesthesia residents were 2.1%, 13.5%, 7.9%, and 6.7% for post graduate year 1-4 (PGY 1-4) residents. The rates were 14.3%, 4.7%, 2.1%, and 6.9% for fellows, nurse anesthetists, supervising anesthesiologists, and solo anesthesiologists, respectively. We found that PGY2 residents had a higher injury rate than PGY1 residents (p-value<0.001). When grouping PGY2, PGY3, and PGY4 residents together, they had a collective rate of 9.4%. Furthermore, residents had a higher needlestick injury rate than supervising anesthesiologists (p-value <0.001). CONCLUSIONS: PGY2 residents and fellows had the highest rate of needlestick injury. Our study highlights the trend of increasing sharps injuries after PGY1 while supervising anesthesiologists had the lowest rate. Proposed mechanisms for the increased sharps injuries include residents' transition from medicine-based internship to the operating room environment with increased exposure to potentially injurious equipment, overnight call, and increased work-related and cognitive stress. Improving understanding of institution-specific prevention programs, raising awareness during their initial high-intensity training period with one-to-one supervision when habits are formed, and reducing exposure to sharps using a needleless system are some steps toward reducing the incidence of sharps injuries in a field where the risk remains high.

Relationship Between the Anion Gap and Serum Lactate in Hypovolemic Shock.

Background and objectives: Previous studies evaluating patients in the Intensive Care Unit with established lactic acidosis determined that the anion gap is an insensitive screening tool for elevated blood lactate. No prior study has examined the relationship between anion gap and serum lactate within the first hours of the development of lactic acidosis. Design, setting, participants, & measurements: Data were obtained prospectively from a convenience sample of adult trauma patients at a single level 1 trauma center. Venous samples were drawn prior to initiation of intravenous fluid resuscitation. A linear regression model was constructed to assess the relationship between serum lactate and anion gap, and 95% prediction intervals were computed. Logistic regression models were constructed to determine the sensitivity and specificity for several different anion gap and lactate cutpoints. Results: 128 patients with elevated serum lactate levels (>2.1 mmol/L) and 63 patients with normal serum lactate levels (< 2.1 mmol/L) were included. The sensitivity of an elevated anion gap (> 10) to reveal hyperlactatemia was only 43% whereas specificity was 84%. Sensitivity improved if the upper limit of normal anion gap was lowered and with increasing levels of serum lactate. The coefficient of determination between serum lactate level and AG yielded an R2 of 0.30 (p < 0.001) and the slope of this relationship was 2.185 with a 95% confidence interval of 2.011-2.359. The mean 95% prediction interval was + 8.9. Conclusions: Within the first hour of the development of lactic acidosis due to hypovolemic shock, the anion gap was not a sensitive indicator of an elevated serum lactate level, but it was fairly specific. The anion gap increased to a greater extent than the serum lactate, the 95% mean prediction interval was wide and approximately 70% of the change in anion gap could not be explained by increases in serum lactate, suggesting that other anions contribute to the anion gap in lactic acidosis.

Novel Framework for Treatment Response Evaluation Using PSMA PET/CT in Patients with Metastatic Castration-Resistant Prostate Cancer (RECIP 1.0): An International Multicenter Study.

Our objective was to develop version 1.0 of a novel framework for response evaluation criteria in prostate-specific membrane antigen (PSMA) PET/CT (RECIP) and a composite response classification that combines responses by prostate-specific antigen (PSA) measurements and by RECIP 1.0 (PSA + RECIP). Methods: This was an international multicenter, retrospective study. One hundred twenty-four men with metastatic castration-specific prostate cancer (mCRPC) who underwent 177Lu-PSMA therapy and received PSMA PET/CT at baseline and at an interim time point of 12 wk were included. Pairs of baseline interim PET/CT scans were interpreted by consensus among 3 masked readers for appearance of new lesions. Tumor lesions were segmented, and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP 1.0, which included classifications of complete response (RECIP-CR: absence of any PSMA-ligand uptake on interim PET/CT), partial response (RECIP-PR: decline ≥ 30% in PSMA-VOL and no appearance of new lesions), progressive disease (RECIP-PD: increase ≥ 20% in PSMA-VOL and appearance of new lesions), and stable disease (RECIP-SD: any condition but RECIP-PR or RECIP-PD). Changes in PSA levels at 12 wk by Prostate Cancer Working Group Criteria 3 were recorded. PSA + RECIP results were defined as response (PSA decline ≥ 50% or RECIP-PR/CR) or progression (PSA increase ≥ 25% or RECIP-PD). The study's primary outcome measure was the prognostic value of RECIP 1.0 for overall survival (OS). The secondary outcome measure was the prognostic accuracy (C-index) of PSA + RECIP versus PSA responses. Results: Patients with RECIP-PD (n = 39; 8.3 mo) had a shorter OS than patients with stable disease (RECIP-SD) (n = 47; 13.1 mo; P < 0.001) or RECIP-PR (n = 38; 21.7 mo; P < 0.001). In identifying responders and progressors, PSA + RECIP had C-indices superior to those of PSA only: 0.65 versus 0.62 (P = 0.028) and 0.66 versus 0.63 (P = 0.044), respectively. Conclusion: PSMA PET/CT by RECIP 1.0 is prognostic for OS and can be used as a response biomarker to monitor early efficacy of 177Lu-PSMA in men with mCRPC. PSA + RECIP may be used as a novel composite endpoint in mCRPC clinical trial design.

Correlation of 68Ga-FAPi-46 PET Biodistribution with FAP Expression by Immunohistochemistry in Patients with Solid Cancers: Interim Analysis of a Prospective Translational Exploratory Study.

Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts confer treatment resistance and promote metastasis and immunosuppression. Because FAP is overexpressed in many cancers, radiolabeled molecules targeting FAP are studied for their use as pancancer theranostic agents. This study aimed to establish the spectrum of FAP expression across various cancers by immunohistochemistry and to explore whether 68Ga FAP inhibitor (FAPi)-46 PET biodistribution faithfully reflects FAP expression from resected cancer and non-cancer specimens. Methods: We conducted a FAP expression screening using immunohistochemistry on a pancancer human tissue microarray (141 patients, 14 different types of cancer) and an interim analysis of a prospective exploratory imaging trial in cancer patients. Volunteer patients underwent 1 whole-body 68Ga-FAPi-46 PET/CT scan and, subsequently, surgical resection of their primary tumor or metastasis. 68Ga-FAPi-46 PET SUVmax and SUVmean was correlated with FAP immunohistochemistry score in cancer and tumor-adjacent non-cancer tissues for each patient. Results: FAP was expressed across all 14 cancer types on tissue microarray with variable intensity and frequency, ranging from 25% to 100% (mean, 76.6% ± 25.3%). Strong FAP expression was observed in 50%-100% of cancers of the bile duct, bladder, colon, esophagus, stomach, lung, oropharynx, ovary, and pancreas. Fifteen patients with various cancer types (colorectal [n = 4], head and neck [n = 3], pancreas [n = 2], breast [n = 2], stomach [n = 1], esophagus [n = 2], and uterus [n = 1]) underwent surgery after their 68Ga-FAPi-46 PET/CT scan within a mean interval of 16.1 ± 14.4 d. 68Ga-FAPi-46 SUVs and immunohistochemistry scores were higher in cancer than in tumor-adjacent non-cancer tissue: mean SUVmax 7.7 versus 1.6 (P < 0.001), mean SUVmean 6.2 versus 1.0 (P < 0.001), and mean FAP immunohistochemistry score 2.8 versus 0.9 (P < 0.001). FAP immunohistochemistry scores strongly correlated with 68Ga-FAPi 46 SUVmax and SUVmean: r = 0.781 (95% CI, 0.376-0.936; P < 0.001) and r = 0.783 (95% CI, 0.379-0.936; P < 0.001), respectively. Conclusion: In this interim analysis of a prospective exploratory imaging trial, 68Ga-FAPi-46 PET biodistribution across multiple cancers strongly correlated with FAP tissue expression. These findings support further exploration of FAPi PET as a pancancer imaging biomarker for FAP expression and as a stratification tool for FAP-targeted therapies.

Tumor Sink Effect in 68Ga-PSMA-11 PET: Myth or Reality?

We aimed to systematically determine the impact of tumor burden on 68Ga-prostate-specific membrane antigen-11 (68Ga-PSMA) PET biodistribution by the use of quantitative measurements. Methods: This international multicenter, retrospective analysis included 406 men with prostate cancer who underwent 68Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into a very low (quintile 1, ≤25 cm3), low (quintile 2, 25-189 cm3), moderate (quintile 3, 189-532 cm3), high (quintile 4, 532-1,355 cm3), or very high (quintile 5, ≥1,355 cm3) total PSMA-positive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semiautomatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as a control group. Normal organs, which included salivary glands, liver, spleen, and kidneys, were semiautomatically segmented using 68Ga-PSMA PET images, and SUVmean was obtained. Correlations between the SUVmean of normal organs and PSMA-VOL as continuous and categoric variables by quintiles were evaluated. Results: The median PSMA-VOL was 302 cm3 (interquartile range [IQR], 47-1,076 cm3). The median SUVmean of salivary glands, kidneys, liver, and spleen was 10.0 (IQR, 7.7-11.8), 26.0 (IQR, 20.0-33.4), 3.7 (IQR, 3.0-4.7), and 5.3 (IQR, 4.0-7.2), respectively. PSMA-VOL showed a moderate negative correlation with the SUVmean of the salivary glands (r = -0.44, P < 0.001), kidneys (r = -0.34, P < 0.001), and liver (r = -0.30, P < 0.001) and a weak negative correlation with the spleen SUVmean (r = -0.16, P = 0.002). Patients with a very high PSMA-VOL (quintile 5, ≥1,355 cm3) had a significantly lower PSMA uptake in the salivary glands, kidneys, liver, and spleen than did the control group, with an average difference of -38.1%, -40.0%, -43.2%, and -34.9%, respectively (P < 0.001). Conclusion: Tumor sequestration affects 68Ga-PSMA biodistribution in normal organs. Patients with a very high tumor load showed a significantly lower uptake of 68Ga-PSMA in normal organs, confirming a tumor sink effect. As similar effects might occur with PSMA-targeted radioligand therapy, these patients might benefit from increased therapeutic activity without exceeding the radiation dose limit for organs at risk.