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.

Characterizing the Validity of Using VASES to Derive DIGEST-FEES Grades.

INTRODUCTION: Visual Analysis of Swallowing Efficiency and Safety (VASES) and Dynamic Imaging Grade of Swallowing Toxicity for Flexible Endoscopic Evaluation of Swallowing (DIGEST-FEES) are two complimentary methods for assessing swallowing during FEES. Whereas VASES is intended to facilitate trial-level ratings of pharyngeal residue, penetration, and aspiration, DIGEST-FEES is intended to facilitate protocol-level impairment grades of swallowing safety and efficiency. The aim of this study was to assess the validity of using VASES to derive DIGEST-FEES impairment grades. METHODS: DIGEST-FEES grades were blindly analyzed from 50 FEES - first using the original DIGEST-FEES grading method (n = 50) and then again using a VASES-derived DIGEST-FEES grading method (n = 50). Weighted Kappa (κw) and absolute agreement (%) were used to assess the relationship between the original DIGEST-FEES grades and VASES-derived DIGEST-FEES grades. Spearman's correlations assessed the relationship between VASES-derived DIGEST-FEES grades with measures of construct validity. RESULTS: Substantial agreement (κw = 0.76-0.83) was observed between the original and VASES-derived grading methods, with 60-62% of all DIGEST-FEES grades matching exactly, and 92-100% of DIGEST-FEES grades within one grade of each other. Furthermore, the strength of the relationships between VASES-derived DIGEST-FEES grades and measures of construct validity (r = 0.34-0.78) were similar to the strength of the relationships between original DIGEST-FEES grades and the same measures of construct validity (r = 0.34-0.83). CONCLUSION: Findings from this study demonstrate substantial agreement between original and VASES-derived DIGEST-FEES grades. Using VASES to derive DIGEST-FEES also appears to maintain the same level of construct validity established with the original DIGEST-FEES. Therefore, clinicians and researchers may consider using VASES to increase the transparency and standardization of DIGEST-FEES ratings. Future research should seek to replicate these findings and explore the simultaneous use of VASES and DIGEST-FEES in a greater sampling of raters and across other patient populations.

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.

Sensitivity and specificity of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised to detect dysarthria in individuals with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Given the widespread use of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) to measure disease progression in ALS and recent reports demonstrating its poor sensitivity, we aimed to determine the sensitivity and specificity of the ALSFRS-R bulbar subscale and speech item to detect validated clinical ratings of dysarthria in individuals with ALS. METHODS: Paired ALSFRS-R and validated Speech Intelligibility Test (SIT) data from individuals with ALS were analyzed. Trained raters completed duplicate, independent, and blinded ratings of audio recordings to obtain speech intelligibility (%) and speaking rate (words per minute, WPM). Binary dysarthria profiles were derived (dysarthria ≤96% intelligible and/or <150 WPM). Data were obtained using the Kruskal-Wallis test, receiver-operating characteristic (ROC) curve, area under the curve (AUC), sensitivity and specificity percentages, and positive/negative predictive values (PPV/NPV). RESULTS: A total of 250 paired SIT and ALSFRS-R data points were analyzed. Dysarthria was confirmed in 72.4% (n = 181). Dysarthric speakers demonstrated lower ALSFRS-R bulbar subscale (8.9 vs. 11.2) and speech item (2.7 vs. 3.7) scores (P < .0001). The ALSFRS-R bulbar subscale score had an AUC of 0.81 (95% confidence interval [CI] 0.75 to 0.86). A subscale score of ≤11 yielded a sensitivity of 86%, specificity of 57%, PPV of 84%, and NPV of 60% to correctly identify dysarthria status. The ALSFRS-R speech item score demonstrated an AUC of 0.81 to detect dysarthria (95% CI 0.76 to 0.85), with sensitivity of 79%, specificity of 75%, PPV of 89%, and NPV of 58% for a speech item cutpoint of ≤3. DISCUSSION: The ALSFRS-R bulbar and speech item subscale scores may be useful, inexpensive, and quick tools for monitoring dysarthria status in ALS.

Experiences of dysmenorrhea and its treatment among allistic and autistic menstruators: a thematic analysis.

BACKGROUND: Dysmenorrhea (i.e., period pain) is common and debilitating. Autistic people are known to experience pain differently, yet little is known about the menstrual pain experiences of autistic menstruators relative to non-autistic peers. This study aimed to explore the experience of period pain and treatment uptake for period pain among allistic and autistic populations. METHODS: This study used a qualitative design and opportunity sampling approach. Thirty-seven participants (of whom 17 were autistic) were interviewed via video-conferencing software using a semi-structured topic guide. Transcriptions of interviews were analysed using Braun and Clarke's Reflexive Thematic Analysis. Data were initially analysed together for common themes. Autistic menstruators' data was subsequently analysed separately to elucidate the unique experiences of this group. RESULTS: A total of six themes were constructed from the data. Initial analysis determined three themes related to experiences of period pain and treatment uptake in both allistic and autistic menstruators. Social perception of menstruation was discussed, highlighting the normalisation of pain, the taboo nature, and gendered experience of menstruation, contributing to untreated menstrual pain. Issues within menstrual healthcare were also shared, including experiences of ineffective treatment, dismissive interactions, and insufficient menstrual education. Impaired functionality was repeatedly highlighted, with menstruators detailing significant limitations to their usual functioning due to menstrual pain and ineffective treatment. Three further themes were constructed from separate analysis of data from autistic menstruators. Autistic menstruators discussed the impact of menstruation on their sensory experiences and needs, with many identifying overstimulation during menstruation. Social exclusion was discussed as a factor contributing to the experience of menstrual pain and poor treatment uptake. The final theme identified pain communication differences between autistic and allistic menstruators resulting in reports of ineffective treatment and challenges in healthcare interactions. CONCLUSIONS: Communication differences, sensory aspects, and social factors contributed to the experience of period pain and treatment uptake for autistic menstruators. The perception of menstruation within society was highlighted by allistic and autistic menstruators as influential to their pain experience and engagement with treatment. Functionality was significantly impacted by pain for this sample. The study highlights societal and healthcare factors that could be improved to ensure accessibility of support and treatment for menstrual issues.

YouTube as a Source of Patient Information Regarding Placenta Accreta Spectrum.

OBJECTIVE: As the awareness of the accompanying morbidity of placenta accreta spectrum (PAS) has increased over recent decades. We sought to analyze the precision and reliability of the currently available content regarding PAS on YouTube. STUDY DESIGN: A YouTube search was performed on June 17, 2019 by using the search terms "placenta accreta," "PAS," and "invasive placentation." Search results were sorted by relevance, and up to 200 videos per search term were systematically evaluated by four independent reviewers. A quality assessment checklist relating to aspects of PAS was developed with a Likert's scale from 0 to 12 points to quantify video content. Videos were classified as poor educational quality (grade 0 to ≤4), moderate quality (grade >4-8), and high quality (grade >8-12). RESULTS: Of the 318 videos identified, 99 videos met inclusion criteria. The majority of videos (61.6%) were produced by a professional source, that is, appearing to be from a hospital, university, or educational service. Of the remaining videos, 16.2% were classified as personal, that is, posted from personal YouTube accounts and depicting a personal or family member experience, and 22.2% were classified as other. The majority of the "other" category consisted of news segments and short clips from talk shows. Overall, 60.6% of videos were of poor educational quality, 32.3% were of moderate quality, and 7.1% were deemed high quality. All seven of the high-quality videos were produced by a professional source and intended for an audience of medical professionals. There were neither high-quality videos intended for the general public nor the likely affected and relevant patient population. CONCLUSION: This study suggests that the currently available videos on YouTube regarding PAS are poor educational sources for patients seeking information, and demonstrates a need for high-quality content videos produced by medical professionals specifically focused on meeting the needs of patient population. KEY POINTS: · Awareness of the accompanying morbidity of placenta accreta spectrum has increased over recent decades.. · YouTube videos are poor educational sources for patients seeking information regarding PAS.. · YouTube videos and all social media warrant improvements regarding patient's information..

Predictors of Peak Expiratory Cough Flow in Individuals with Amyotrophic Lateral Sclerosis.

Dystussia is prevalent in individuals with amyotrophic lateral sclerosis (ALS), leading to a diminished physiologic capacity to effectively defend the airway. We aimed to identify predictors of peak expiratory cough flow rate in individuals with ALS. One hundred and thirty-four individuals with a confirmed diagnosis of ALS (El-Escorial criteria revised) completed the ALS Functional Rating Scale-Revised (ALSFRS-R) and underwent pulmonary function and cough spirometry testing. Pearson's correlation coefficients and hierarchical multiple regression modeling were conducted to determine predictors of voluntary cough peak expiratory flow rate (p < 0.05). The full model including age, bulbar disease, cough spirometry metrics, and respiratory parameters had a marginal R2 = 0.635, F (7, 126) = 30.241, p < 0.0005, adjusted R2 = 0.61. Maximum expiratory pressure, compression phase, and vital capacity did not contribute and were therefore removed (p < 0.05). The most parsimonious predictive model included age, bulbar disease, peak inspiratory flow rate and duration, peak expiratory rise time, and inspiratory pressure generation with a marginal R2 = 0.543. Although expiratory pressure generation has historically served as the therapeutic target to improve dystussia in ALS, the current dataset highlighted that the inability to quickly and forcefully inspire during the inspiratory phase of voluntary cough places patients at a mechanical disadvantage to generate subsequent high-velocity expiratory airflow to clear the airway. Thus, therapeutic training programs that include both inspiratory and expiratory strength targets may optimize airway clearance capacity in this challenging patient population.

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.

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.

Reflexive Airway Sensorimotor Responses in Individuals with Amyotrophic Lateral Sclerosis.

BACKGROUND: Progressive motor denervation in amyotrophic lateral sclerosis (ALS) leads to reduced expiratory cough flow and diminished airway clearance physiologic capacity. Although ALS is thought to primarily impact motor systems, preliminary data from our laboratory suggest degradation of afferent pathways that regulate reflexive cough responses to radiographically confirmed aspiration. We, therefore, aimed to delineate both sensory and motor responses to a tussigenic airway irritant in individuals with ALS compared to healthy controls. METHODS: Thirty-two individuals with ALS and 34 healthy age and gender-matched controls completed reflex cough testing. Capsaicin stimuli (0, 50, 100, 150, 200 µM) were presented in a randomized three-block design and motor (cough spirometry metrics) and sensory (patient-rated urge to cough, UtC) ratings collected. ALS patients underwent videofluoroscopy with penetration-aspiration ratings completed. Descriptives, Mann-Whitney U, and mixed models ANOVAs were performed. RESULTS: Sensory: Individuals with ALS demonstrated greater UtC sensitivity slopes (i.e., increased stimulus sensitivity) vs. healthy controls (p = 0.036). Within the ALS group, however, silent aspirators (PAS = 8) demonstrated blunted UtC sensitivity slopes compared to ALS patients who did not (PAS ≤ 7, p = 0.0001). Motor: Compared to healthy controls, ALS individuals demonstrated reduced peak expiratory flow rates (p = 0.004), longer peak expiratory rise time (p = 0.017), and lower cough volume acceleration (p = 0.000). CONCLUSIONS: ALS individuals demonstrated increased sensitivity to an upper airway irritant; however, they demonstrated slower and weaker expiratory cough motor output compared to healthy controls. In ALS silent aspirators, blunted sensorimotor responses were observed, suggesting that sensory degradation may occur at the final or most severe stage of bulbar disease progression.

Differences in voluntary and reflexive cough strength in individuals with amyotrophic lateral sclerosis and healthy adults.

INTRODUCTION: Dystussia impacts the ability to protect the airway. Voluntary cough provides a metric of airway defense but differs from the reflexive response to aspiration during swallowing. Therefore, we evaluated relationships between voluntary and reflexive cough among individuals with amyotrophic lateral sclerosis (ALS) and a healthy cohort. METHODS: Twenty-eight individuals with ALS and 26 healthy individuals completed voluntary and reflexive cough testing. Descriptive statistics, reliability, and paired t tests were conducted to evaluate differences in cough volume acceleration (CVA) and peak expiratory flow rate (PEFR) in voluntary vs reflexive cough. RESULTS: Compared with reflexive cough, voluntary CVA and PEFR were greater in individuals with ALS [t(27) = 4.83, P < .001 and t(27) = 8.69, P < .001] and the healthy cohort [t(21) = 5.91, P < .001 and t(21) = 12.26, P < .001], respectively. DISCUSSION: These findings hold important implications for the use and interpretation of voluntary peak cough flow during clinical swallowing evaluations.

Clinical factors associated with intubation in the high flow nasal cannula era.

BACKGROUND: Bronchiolitis is the most common cause for hospitalization in infants. While the use of high flow nasal cannula (HFNC) has increased, it has not uniformly reduced intubation rates. OBJECTIVE: We identified factors associated with respiratory failure in children with bronchiolitis on HFNC. METHODS: We conducted a retrospective study of previously healthy children <24 months of age with bronchiolitis, who were treated with HFNC in two pediatric emergency departments from 1/2014-1/2018. The primary outcome was the identification of demographic and clinical factors that are associated with intubation after an antecedent trial of HFNC. A multivariable logistic regression model was constructed to identify predictors of respiratory failure. RESULTS: Of 2657 children on HFNC, the median age was 7 months, while the median age of the intubated cohort was 3 months. Ten percent (271) progressed to mechanical ventilation within 48 h of PED presentation. Of the 301 patients that needed escalation to CPAP and/or BiPAP, 91 required intubation. Factors associated with intubation were young age and a high respiratory tool score; factors associated with no progression to intubation were a reduction in tachycardia after initiation of HFNC and presentation after day 5 of illness. A secondary analysis also revealed decreased rate of intubation with the use of bronchodilators. We identified demographic, clinical, and therapeutic factors that are associated with requiring intubation. CONCLUSION: Given the high burden of bronchiolitis in pediatric emergency departments, these factors can be considered upon presentation of children with bronchiolitis to selectively identify children at higher risk for respiratory failure.

Impact of expiratory strength training in amyotrophic lateral sclerosis: Results of a randomized, sham-controlled trial.

INTRODUCTION: The purpose of this study was to determine the impact of an in-home expiratory muscle strength training (EMST) program on pulmonary, swallow, and cough function in individuals with amyotrophic lateral sclerosis (ALS). METHODS: EMST was tested in a prospective, single-center, double-blind, randomized, controlled trial of 48 ALS individuals who completed 8 weeks of either active EMST (n = 24) or sham EMST (n = 24). The primary outcome to assess treatment efficacy was change in maximum expiratory pressure (MEP). Secondary outcomes included: cough spirometry; swallowing; forced vital capacity; and scoring on the ALS Functional Rating Scale-Revised. RESULTS: Treatment was well tolerated with 96% of patients completing the protocol. Significant differences in group change scores were noted for MEP and Dynamic Imaging Grade of Swallowing Toxicity scores (P < 0.02). No differences were noted for other secondary measures. DISCUSSION: This respiratory training program was well-tolerated and led to improvements in respiratory and bulbar function in ALS. Muscle Nerve 59:40-46, 2019.

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).

Reviews for multimorbidity risk in people with inflammatory conditions: a qualitative study.

BACKGROUND: People with inflammatory rheumatological conditions (IRCs) are at high risk of developing other conditions including cardiovascular disease and mood disorders. AIM: To explore perspectives of people with IRCs and healthcare practitioners (HCPs) on the content and delivery of a review consultation aimed at identification and management of multiple long-term conditions. DESIGN & SETTING: Semi-structured interviews and focus groups with people with IRCs and HCPs. METHOD: People with IRCs participated in individual semi-structured interviews by telephone or online platform. HCPs (including primary and secondary care clinicians) participated in online focus groups. Data were transcribed verbatim and analysed using inductive thematic analysis. RESULTS: 15 people with IRCs were interviewed; three focus groups with HCPs were conducted. Two main themes were identified: reflecting on the value of review consultations and what would a new review look like. Overall, people with IRCs and HCPs reflected that access to reviews is inequitable, leading to duplication of reviews and fragmentation in care. People with IRCs, at times, had difficulty conceptualising reviews, especially when discussing their future risk of conditions. People suggested that preparation before the healthcare review could align patient and HCP agendas as part of a flexible and person-centred discussion. CONCLUSION: Any review introduced for people with IRCs must move beyond a "tick-box" exercise. To gain maximum value from a review, preparation from both patient and HCP may be required alongside a person-centred approach whilst ensuring they are targeted at people most likely to benefit.

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.

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.

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.

Dextromethorphan/quinidine for the treatment of bulbar impairment in amyotrophic lateral sclerosis.

OBJECTIVE: No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study evaluated the short-term impact of dextromethorphan/quinidine (DMQ) treatment on speech and swallowing function in pALS. METHODS: This was a cohort trial conducted between August 2019 to August 2021 in pALS with a confirmed diagnosis of probable-definite ALS (El-Escorial Criteria-revisited) and bulbar impairment (ALS Functional Rating Scale score ≤ 10 and speaking rate ≤ 140 words per minute) who were DMQ naïve. Efficacy of DMQ was assessed via pre-post change in the ALS Functional Rating Scale-Revised bulbar subscale and validated speech and swallowing outcomes. Paired t-tests, Fisher's exact, and χ2 tests were conducted with alpha at 0.05. RESULTS: Twenty-eight pALS enrolled, and 24 participants completed the 28-day trial of DMQ. A significant increase in ALSFRS-R bulbar subscale score pre- (7.47 ± 1.98) to post- (8.39 ± 1.79) treatment was observed (mean difference: 0.92, 95% CI: 0.46-1.36, p < 0.001). Functional swallowing outcomes improved, with a reduction in unsafe (75% vs. 44%, p = 0.003) and inefficient swallowing (67% vs. 58%, p = 0.002); the relative speech event duration in a standard reading passage increased, indicating a greater duration of uninterrupted speech (mean difference: 0.33 s, 95% CI: 0.02-0.65, p = 0.035). No differences in diadochokinetic rate or speech intelligibility were observed (p > 0.05). INTERPRETATION: Results of this study provide preliminary evidence that DMQ pharmacologic intervention may have the potential to improve or maintain bulbar function in pALS.