Therapeutic drug monitoring of osimertinib in EGFR mutant non-small cell lung cancer by dried blood spot and plasma collection: A pilot study.

AIMS: Therapeutic drug monitoring (TDM) has led to significant improvements in individualized medical care, although its implementation in oncology has been limited to date. Tyrosine kinase inhibitors (TKIs) are a group of therapies for which TDM has been suggested. Osimertinib is one such therapy used in the treatment of epidermal growth factor receptor (EGFR) mutation-driven lung cancer. Herein, we describe a prospective pilot study involving 21 patients on osimertinib primarily as a preliminary evaluation of drug levels in a real-world setting. METHODS: Concentrations of the drug and its primary metabolites were measured with a validated liquid chromatography-mass spectrometry (LC-MS) assay across serial timepoints. As part of this study, inter-individual variability by dose and ethnicity as well as intra-individual variability across timepoints are explored. Furthermore, we attempted to validate dried blood spot (DBS)-based quantitation as an accurate alternative to plasma quantitation. RESULTS: Successful quantitation of osimertinib and primary metabolites was achieved for our subjects. Compound plasma levels were highly correlated to DBS levels. There was no significant difference in concentrations with ethnicity or dosing or intra-individual variability across timepoints. CONCLUSIONS: As such, we demonstrate that TDM for osimertinib is practical for future trials. We also validated the use of DBS as an alternative to conventional quantitation for exploration of TDM for osimertinib in larger trials and for other targeted therapies.

Outcomes of minimally invasive isolated tricuspid valve repair and replacement through right mini-thoracotomy.

Objective: Isolated tricuspid valve surgery is uncommon and associated with high perioperative morbidity and mortality. We aimed to study the overall outcomes of patients who underwent minimally invasive right thoracotomy tricuspid valve surgery (Mini-TVS), consisting of either tricuspid valve repair (TVre) or replacement (TVR). Methods: We performed a retrospective analysis of all Mini-TVS procedures (2017-2022), through which we identified isolated tricuspid valve surgeries. We examined in-hospital outcomes, survival analysis over a 4-year period, and competing risk analysis for reoperative surgery. Results: Among a total of 51 patients, the average age was 60 ± 16 years, and 67% (n = 34) were female. Severe tricuspid regurgitation was present in all cases. Infective endocarditis was noted in 7.8% (n = 4), and 24% (n = 12) had preexisting pacemakers. Mini-TVS included TVre in 18 patients (35%) and TVR in 33 patients (65%). The in-hospital and 30-day mortality rates were 4% (n = 2) and 6% (n = 3), respectively. At 4 years, the overall TVS survival was 76% (confidence interval, 62-93%), with no significant difference between TVre and TVR (91% vs 69%, P = .16). At follow-up, 3 patients required repeat surgery for recurrent regurgitation after 2.6, 3.3, and 11 months, with a reoperation rate of 7.3% (confidence interval, 2.4-22%) at 2 years. Factors associated with worse overall survival included nonelective surgery, right ventricular dysfunction, serum creatinine >2 g/dL, and concomitant left-sided valve disease. Conclusions: A nonsternotomy minimally invasive approach is a feasible option for high-risk patients. Midterm outcomes were similar in repair or replacement. Patients with right ventricular dysfunction and left-sided disease had worse outcomes.

First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study.

Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

Brief Report: Real-World Toxicity and Survival of Combination Immunotherapy in Pleural Mesothelioma-RIOMeso.

BACKGROUND: Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-year overall survival of 10%. First-line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate 743 trial, with supportive data from the later line single-arm MAPS2 trial. RIOMeso evaluates survival and toxicity of this regimen in real-world practice. METHODS: Demographic and clinicopathologic data of Australian patients treated with ipilimumab and nivolumab in first- and subsequent-line settings for pleural mesothelioma were collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log-rank test. Toxicity was investigator assessed using Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 119 patients were identified from 11 centers. The median age was 72 years, 83% were male, 92% had Eastern Cooperative Oncology Group less than or equal to 1, 50% were past or current smokers, and 78% had known asbestos exposure. In addition, 50% were epithelioid, 19% sarcomatoid, 14% biphasic, and 17% unavailable. Ipilimumab and nivolumab were used first line in 75% of patients. Median overall survival (mOS) was 14.5 months (95% confidence interval [CI]: 13.0-not reached [NR]) for the entire cohort. For patients treated first line, mOS was 14.5 months (95% CI: 12.5-NR) and in second- or later-line patients was 15.4 months (95% CI: 11.2-NR). There was no statistically significant difference in mOS for epithelioid patients compared with nonepithelioid (19.1 mo [95% CI: 15.4-NR] versus 13.0 mo [95% CI: 9.7-NR], respectively, p = 0.064). Furthermore, 24% of the patients had a Common Terminology Criteria for Adverse Events grade greater than or equal to 3 adverse events, including three treatment-related deaths. Colitis was the most frequent adverse event. CONCLUSIONS: Combination immunotherapy in real-world practice has poorer survival outcomes and seems more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma.

Impact of Transfer of Maternal Care for Fetal Anomalies on Maternal Depression and Anxiety Screening: A Prospective Cohort at a Tertiary Care Center.

INTRODUCTION: Perinatal depression and anxiety are major causes of maternal morbidity, and are more common in high-risk pregnancies compared to low-risk pregnancies. This study used validated screening tools to assess the prevalence of depression and anxiety symptoms in pregnant patients who transferred their obstetric care to a specialized fetal center for fetal anomaly. METHODS: This is a prospective cohort of patients with a fetal anomaly prompting transfer of obstetric care to Texas Children's Hospital Fetal Center between January 2021 and February 2022. The primary outcome was a self-assessed Edinburgh Postnatal Depression Scale score of 13 or higher, either antepartum or postpartum ("ever-positive EPDS"). Secondary outcomes included self-assessed Perinatal Anxiety Screening Scale (PASS) scores of 21 or higher ("ever-positive PASS"), obstetric outcomes, and neonatal outcomes. A frequentist analysis was performed. RESULTS: Of 149 women who transferred to Texas Children's Hospital during the study period, 94 enrolled in this study. Twenty-six percent of women had an ever-positive EPDS; 20% of patients had an ever-positive PASS. Patients were more likely to have an ever-positive EPDS if they were single (46% compared to 20%, p = 0.025). Women who had an ever-positive EPDS were more likely to be referred to psychiatry (46% compared to 14%, p = 0.004) and psychotherapy (29% compared to 1%, p < 0.001). Surprisingly, patients were more likely to have an ever-positive PASS if they reported good social support (p = 0.03). Antepartum EPDS and PASS scores had no relationship with postpartum EPDS scores. CONCLUSION: Women who transfer care to a tertiary setting have positive EPDS scores at double the rate of the general population, but tend to experience this either antepartum or postpartum (not both). Fetal centers should be prepared to screen for mental health symptoms before and after delivery and provide appropriate referral or treatment.

Digital exclusion as a potential cause of inequalities in access to care: a survey in people with inflammatory rheumatic diseases.

Objectives: COVID-19 led to rapid uptake of digital health care. We sought to examine digital access, health and digital literacy, and impact on confidence and satisfaction with remote consultations in people with inflammatory rheumatic diseases (IRDs). Methods: People with IRDs (n = 2024) were identified from their electronic health record and invited to participate in a cross-sectional survey, using short message service (SMS) and postal approaches. Data were collected on demographics, self-reported diagnosis, access to and use of internet-enabled devices, health and digital literacy, together with confidence and satisfaction with remote consultations. Ethical approval was obtained (Ref 21/PR/0867). Results: Six hundred and thirty-nine (639) people completed the survey [mean (s.d.) age 64.5 (13.1) years, 384 (60.1%) female]. Two hundred and eighty-seven (44.9%) completed it online. One hundred and twenty-six (19.7%) people reported not having access to an internet-enabled device. Ninety-three (14.6%) reported never accessing the internet; this proportion was highest (23%) in people with RA. One hundred and seventeen (18%) reported limited health literacy. Even in those reporting internet use, digital literacy was only moderate. People with limited health or digital literacy or without internet access were less likely to report confidence or satisfaction with remote consultations. Conclusion: Limited health and digital literacy, lack of digital access and low reported internet use were common, especially in older people with RA. People with limited health literacy or limited digital access reported lower confidence and satisfaction with remote consultations. Digital implementation roll-out needs to take account of people requiring extra support to enable them to access care digitally or risks exacerbating health inequalities.

The ASCC2 CUE domain in the ALKBH3-ASCC DNA repair complex recognizes adjacent ubiquitins in K63-linked polyubiquitin.

Alkylation of DNA and RNA is a potentially toxic lesion that can result in mutations and even cell death. In response to alkylation damage, K63-linked polyubiquitin chains are assembled that localize the Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3-Activating Signal Cointegrator 1 Complex Subunit (ASCC) repair complex to damage sites in the nucleus. The protein ASCC2, a subunit of the ASCC complex, selectively binds K63-linked polyubiquitin chains via its coupling of ubiquitin conjugation to ER degradation (CUE) domain. The basis for polyubiquitin-binding specificity was unclear, because CUE domains in other proteins typically bind a single ubiquitin and do not discriminate among different polyubiquitin linkage types. We report here that the ASCC2 CUE domain selectively binds K63-linked diubiquitin by contacting both the distal and proximal ubiquitin. The ASCC2 CUE domain binds the distal ubiquitin in a manner similar to that reported for other CUE domains bound to a single ubiquitin, whereas the contacts with the proximal ubiquitin are unique to ASCC2. Residues in the N-terminal portion of the ASCC2 α1 helix contribute to the binding interaction with the proximal ubiquitin of K63-linked diubiquitin. Mutation of residues within the N-terminal portion of the ASCC2 α1 helix decreases ASCC2 recruitment in response to DNA alkylation, supporting the functional significance of these interactions during the alkylation damage response. Our study reveals the versatility of CUE domains in ubiquitin recognition.

Employment disruption among women with gynecologic cancers.

BACKGROUND: Adverse employment outcomes pose significant challenges for cancer patients, though data patients with gynecologic cancers are sparse. We evaluated the decrease in employment among patients in the year following the diagnosis of a gynecologic cancer compared with population-based controls. METHODS: Patients aged 18 to 63 years old, who were diagnosed with cervical, ovarian, endometrial, or vulvar cancer between January 2009 and December 2017, were identified in Truven MarketScan, an insurance claims database of commercially insured patients in the USA. Patients working full- or part-time at diagnosis were matched to population-based controls in a 1:4 ratio via propensity score. Multivariable Cox proportional hazards models were used to evaluate the risk of employment disruption in patients versus controls. RESULTS: We identified 7446 women with gynecologic cancers (191 vulvar, 941 cervical, 1839 ovarian, and 4475 endometrial). Although most continued working following diagnosis, 1579 (21.2%) changed from full- or part-time employment to long-term disability, retirement, or work cessation. In an adjusted model, older age, the presence of comorbidities, and treatment with surgery plus adjuvant therapy versus surgery alone were associated with an increased risk of employment disruption (p<0.0003, p=0.01, and p<0.0001, respectively) among patients with gynecologic cancer. In the propensity-matched cohort, patients with gynecologic cancers had over a threefold increased risk of employment disruption relative to controls (HR 3.67, 95% CI 3.44 to 3.95). CONCLUSION: Approximately 21% of patients with gynecologic cancer experienced a decrease in employment in the year after diagnosis. These patients had over a threefold increased risk of employment disruption compared with controls.

Adaptation and Validation of the Dynamic Imaging Grade of Swallowing Toxicity for Flexible Endoscopic Evaluation of Swallowing: DIGEST-FEES.

Purpose While flexible endoscopic evaluation of swallowing (FEES) is a common clinical procedure used in the head and neck cancer (HNC) population, extant outcome measures for FEES such as bolus-level penetration-aspiration and residue scores are not well suited as global patient-level endpoint measures of dysphagia severity in cooperative group trials or clinical outcomes research. The Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) was initially developed and validated for use during videofluoroscopic evaluations as a way to grade safety, efficiency, and overall pharyngeal swallowing impairment. The purpose of this study was to adapt and validate DIGEST for use with FEES. Method A modified Delphi exercise was conducted for content validation, expert consensus, adaptation, and operationalization of DIGEST-FEES. Three blinded, expert raters then evaluated 100 de-identified post-HNC treatment FEES examinations. Intra- and interrater reliability were tested with quadratic weighted kappa. Criterion validity against the MD Anderson Dysphagia Inventory, Functional Oral Intake Scale, Secretion Severity Scale, and Yale Residue Rating Scale was assessed with Spearman correlation coefficients. Results Interrater reliability was almost perfect for overall DIGEST-FEES grade (κw = 0.83) and safety grade (κw = 0.86) and substantial for efficiency grade (κw = 0.74). Intrarater reliability was excellent for all raters (0.9-0.91). Overall DIGEST-FEES grade correlated with MD Anderson Dysphagia Inventory (r = -.43, p < .0001), Functional Oral Intake Scale (r = -.43, p < .0001), Secretion Severity Scale (r = .47, p < .0001), Yale Vallecular Residue (r = .73, p < .0001), and Yale Pyriform Sinus Residue (r = .65, p < .0001). Conclusion DIGEST-FEES is a valid and reliable scale to describe the severity of pharyngeal dysphagia in patients with HNC. Supplemental Material https://doi.org/10.23641/asha.14642787.

A Synthetic CardioCel Tube for Minimally Invasive Superior Vena Cava Bypass.

Superior vena cava occlusion is a condition in which the venous flow of blood to the right atrium is obstructed, requiring a recanalization or bypass procedure. These procedures are traditionally performed by endovascular repair surgery or a sternotomy, typically with a covered stent or spiral vein graft. However, these conduits have several limitations. This case report describes a minimally invasive right thoracotomy approach with the use of a synthetic tube to bypass an occluded superior vena cava in a 52-year-old woman.

Reduced pharyngeal constriction is associated with impaired swallowing efficiency in Amyotrophic Lateral Sclerosis (ALS).

BACKGROUND: Swallowing inefficiency is a prevalent but understudied problem in individuals with Amyotrophic Lateral Sclerosis (ALS). Although reduced pharyngeal constriction has been identified as a mechanism contributing to swallowing inefficiency following stroke, this relationship has not been empirically tested in the ALS population. This study sought to characterize profiles of swallowing efficiency in a sample of ALS patients and investigate relationships between pharyngeal constriction and swallowing efficiency. METHODS: Twenty-six adults with ALS underwent videofluoroscopic swallowing studies, involving 3 mL-thin, 20 mL-thin, and 3 mL-pudding boluses. Full-length recordings were segmented into bolus clips and randomized for analysis. We recorded the total number of swallows per bolus and obtained normalized pixel-based measures of pharyngeal constriction area and post-swallow residue in the vallecular and pyriform sinuses. Linear mixed models with Spearman's correlations were used to determine relationships between pharyngeal constriction and swallowing efficiency, with added factors of bolus volume and thickness. KEY RESULTS: Individuals with ALS demonstrated reduced pharyngeal constriction and increased vallecular and pyriform sinus residue, compared to norms. Reduced pharyngeal constriction had a significant effect on the presence of vallecular and pyriform sinus residue as well as the number of swallows per bolus. Increased bolus thickness was associated with increased vallecular residue, while increased bolus volume was associated with reduced pharyngeal constriction. Results were significant at P < 0.05. CONCLUSIONS & INFERENCES: Our results suggest that reduced pharyngeal constriction is a significant physiological parameter related to swallow inefficiency in ALS. Future work is needed to corroborate these preliminary results and investigate factors to mitigate such impairments.

Awareness of and reactions to mammography controversy among immigrant women.

BACKGROUND: There is substantial expert disagreement about the use of mammography to screen for breast cancer, and this disagreement routinely plays out in the media. Evidence suggests that some women are aware of the controversy over mammography, but less is known about whether immigrant and other underserved women have heard about it and, if so, how they react to it. OBJECTIVE: To explore immigrant women's awareness of and reactions to mammography controversy. DESIGN: Community-engaged qualitative study: we conducted six focus groups with 53 women aged 35-55 from three immigrant communities (Somali, Latina and Hmong) in a major US metropolitan area. A grounded theory approach was used to identify themes; NVivo 10 was used to enhance analyses. RESULTS: Several themes emerged: (i) low awareness of mammography controversy across groups, despite self-reported attention to health information; (ii) high intentions to be screened, even after being told about the controversy; (iii) few reported discussions of mammography's risks and benefits with clinicians; (iv) substantial interest in learning more about mammography and breast cancer, but some low self-efficacy to obtain such information; and (v) questions about whether health recommendations matter and what qualifies as evidence. CONCLUSION: Given on-going expert disagreement about mammography screening, it is important for clinicians to help women understand mammography's risks and benefits so they can make an informed choice. This is particularly critical for immigrant and other underserved women, who may be less able to access, attend to, process, retain and act on health information (a phenomenon known as communication inequality).

Detection of protective antibody titers against feline panleukopenia virus, feline herpesvirus-1, and feline calicivirus in shelter cats using a point-of-care ELISA.

Serum antibody titers are a useful measurement of protection against infection (feline panleukopenia virus [FPV]) or clinical disease (feline herpesvirus-1 [FHV] and feline calicivirus [FCV]), and their determination has been recommended as part of disease outbreak management in animal shelters. The objective of this study was to determine the sensitivity, specificity, and inter-observer and inter-assay agreement of two semi-quantitative point-of-care assays for the detection of protective antibody titers (PAT) against FPV, FHV and FCV in shelter cats. Low sensitivity for FPV antibodies (28%) rendered a canine point-of-care assay inappropriate for use in cats. The feline point-of-care assay also had low sensitivity (49%) and low negative predictive value (74%) for FPV PAT detection, but was highly accurate in the assessment of FHV and FCV PAT. Improvements in accuracy and repeatability of FPV PAT determination could make this tool a valuable component of a disease outbreak response in animal shelters.