Endobronchial Ultrasound Guided Transbronchial Needle Aspiration and PD-L1 Yields.

PURPOSE: Immunotherapy is a leading approach for treating advanced non-small cell lung cancer (NSCLC) by targeting the PD-1/PD-L1 checkpoint signaling pathway, particularly in tumors expressing high levels of PD-L1 (Jug et al. in J Am Soc Cytopathol 9:485-493, 2020; Perrotta et al. in Chest 158: 1230-1239, 2020). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive method to obtain tissue for molecular studies, including PD-L1 analysis, in unresectable tumors (Genova et al. in Front Immunol 12: 799455, 2021; Wang et al. in Ann Oncol 29: 1417-1422, 2018). This study aimed to assess the adequacy of PD-L1 assessment in EBUS-TBNA cytology specimens. METHODS: Data was collected retrospectively from patients who underwent EBUS-TBNA between 2017 and 2021 for suspected lung cancer biopsy. Samples positive for NSCLC were examined for PD-L1 expression. EBUS was performed by experienced practitioners, following institutional guidelines of a minimum of five aspirations from positively identified lesions. Sample adequacy for molecular testing was determined by the pathology department. RESULTS: The analysis involved 387 NSCLC cases (149 squamous cell, 191 adenocarcinoma, 47 unspecified). Of the 263 EBUS-TBNA specimens tested for PD-L1, 237 (90.1%) were deemed adequate. While 84% adhered to the protocol, adherence did not yield better results. Significantly higher PD-L1 adequacy was observed in squamous cell carcinomas (93.2%) compared to adenocarcinoma (87.6%). The number of aspirations and sedation type did not correlate with PD-L1 adequacy in either cancer type, but lesion size and location had a significant impact in adenocarcinomas. Adenocarcinoma exhibited higher PD-L1 expression (68%) compared to squamous cell carcinoma (48%). CONCLUSION: EBUS-TBNA offers high yields for assessing immunotherapy markers like PD-L1, with satisfactory adequacy regardless of NSCLC subtype, lesion size, or location.

Endobronchial Ultrasound Guided Transbronchial Needle Aspiration and Next Generation Sequencing Yields.

PURPOSE: The use of endobronchial ultrasound (EBUS) is standard practice for lung cancer diagnosis and staging. Next generation sequencing (NGS) for detection of genetic alterations is recommended in advanced, non-squamous, non-small-cell lung cancer (NSCLC). Existing protocols for NGS testing are minimal and reported yields vary. This study aimed to determine the yield of EBUS samples obtained for NGS using a sampling protocol at our institution and assess predictive factors to form collection protocols. METHODS: We reviewed EBUS bronchoscopies from 2016 to 2021 with non-squamous NSCLC diagnoses. For target lesions suspected to be malignant, the sampling protocol was: (a) two slides for on-site evaluation, (b) three to five fine needle aspirations rinsed into saline for immunohistochemical staining and in-house molecular markers, and (c) additional three to five rinses for NGS. Sufficiency for NGS processing was determined by the pathology department. RESULTS: Two hundred and seventy-eight non-squamous NSCLC samples were obtained by EBUS (205 adenocarcinoma; 73 not otherwise specified). EBUS was performed under general anesthesia in 75.5% of cases. The overall sample adequacy for NGS testing was 57.5%. Higher adequacy rates were observed when protocol was adhered to 66.0% versus 37.2% (p < 0.001). There was no statistically significant difference based on the size of the lesion or location of the sample. CONCLUSION: When a protocol of three to five dedicated needle rinses for NGS was followed, we nearly doubled our sample adequacy rate for NSG as compared to standard care. Studies are needed to determine the ideal collection and processing modality to preserve tissue samples for genetic sequencing.

Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.

Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Background: Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. Objectives: We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. Methods and analysis: In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. Ethics: This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. Clinical trial registration: This study is registered on ClinicalTrials.gov: NCT04375384.

The Aging Care 5Ms Competencies: A Modified Delphi Study to Revise Medical Student Competencies for the Care of Older Adults.

PURPOSE: To revise the 2009 Canadian Geriatrics Society (CGS) Core Competencies in the Care of Older Persons for Canadian Medical Students by applying current frameworks and using a modified Delphi process. METHOD: The working group chose the Geriatric 5Ms model and CanMEDS framework to develop and structure the competencies. National (i.e., Canadian) Delphi participants were recruited, and 3 Delphi survey rounds were conducted from 2019 to 2021. Each survey round collected quantitative data using a 7-point Likert scale (LS) and qualitative data using free-text comments. The purpose of the first round was to establish the importance of the components of the proposed competencies (categorized into 13 subsections) and identify additional themes. The second round assessed agreement with 31 proposed competencies organized into 7 themes: aging, caring for older adults, mind, mobility, medications, multicomplexity, and matters the most. The third survey-rated agreement levels after further revisions to the competencies were applied. The final 33 competencies were shared with survey participants for feedback and other stakeholders for external validation. RESULTS: Mean LSs for the importance of the 13 competency component subsections on the first survey varied from 5.11 to 6.54, with an agreement level of 73%-93%. New themes emerged from the qualitative comments. Mean LSs for the 31 competencies on the second survey ranged from 5.57 to 6.81, with an agreement level of 80%-97%. Mean LSs for the revised competencies on the third survey ranged from 5.83 to 6.65, with an agreement level of 83%-95%. CONCLUSIONS: The authors developed the 33 Aging Care 5Ms Competencies for Canadian medical students using a consensus process. The competencies fulfill an important need in medical education, and ultimately, society. The authors strongly believe that the competencies can be woven into existing undergraduate medical curricula through purposeful integration and collaboration, including with other specialties.

Exceptional response to cetuximab monotherapy after failure of immunotherapy with a checkpoint inhibitor in a patient with metastatic head and neck squamous cell cancer: case report and review of the literature.

Immunotherapy with PD-1 inhibitors monotherapy or combined with chemotherapy comprises the first-line palliative treatment for patients with recurrent or metastatic head and neck squamous cell cancers (R/M HNSCC). The established survival advantage among responders is overshadowed by the high percentage of patients failing the standard PD-1 inhibitor-based treatments. Salvage therapies are direly needed. However, no current standards are available. We present the case of a 65-year-old patient with heavily pretreated laryngeal squamous cell carcinoma who had an exceptional response to cetuximab monotherapy following the failure of immunotherapy with the PD-1 inhibitor nivolumab. We reviewed the literature for other cases of exceptional response to cetuximab, clinical studies investigating the combined or sequential administration of cetuximab and PD-1 inhibitors, and the mechanistic rationale for consideration of cetuximab as a potential salvage treatment after immunotherapy with PD-1 inhibitors. In addition to the specific epidermal growth factor receptor inhibitory effect, cetuximab, as an immunoglobulin G1 isotype, binds NK cells and elicits antibody-dependent cellular toxicity, triggering a domino of immunostimulatory, and immunoinhibitory effects that actually might decrease the cetuximab anticancer efficacy. However, in a tumor microenvironment exposed to previous treatment with a PD-1 inhibitor, the effects of the PD-1 inhibitor followed by cetuximab on innate and adaptative immune response appear to synergize. Specifically, persistent immune checkpoint inhibitors' consequences may negate downstream immunosuppressive effects of cetuximab caused through PD-1/PD-L1 upregulation, making it a more potent treatment option. Besides the potential synergistic effect on antitumor immune response with previous immune checkpoint inhibitors therapy, cetuximab is the only targeted agent approved for treating R/M HNSCC, making it a most advantageous candidate for further treatment validation studies as salvage treatment post-immunotherapy.

Influence of preoperative frailty on quality of life after cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Frailty has emerged as an important prognostic marker of increased mortality after cardiac surgery, but its association with quality of life (QoL) and patient-centered outcomes is not fully understood. We sought to evaluate the association between frailty and such outcomes in older patients undergoing cardiac surgery. METHODS: This systematic review included studies evaluating the effect of preoperative frailty on QoL outcomes after cardiac surgery amongst patients 65 years and older. The primary outcome was patient's perceived change in QoL following cardiac surgery. Secondary outcomes included residing in a long-term care facility for 1 year, readmission in the year following the intervention, and discharge destination. Screening, inclusion, data extraction, and quality assessment were performed independently by two reviewers. Meta-analyses based on the random-effects model were conducted. The evidential quality of findings was assessed with the GRADE profiler. RESULTS: After the identification of 3105 studies, 10 observational studies were included (1580 patients) in the analysis. Two studies reported on the change in QoL following cardiac surgery, which was higher for patients with frailty than for patients without. Preoperative frailty was associated with both hospital readmission (pooled odds ratio [OR] 1.48 [0.80-2.74], low GRADE level) as well as non-home discharge (pooled OR 3.02 [1.57-5.82], moderate GRADE level). CONCLUSION: While evidence in this field is limited by heterogeneity of frailty assessment and non-randomized data, we demonstrated that baseline frailty may possibly be associated with improved QoL, but with increased readmission as well as discharge to a non-home destination following cardiac surgery. These patient-centered outcomes are important factors when considering interventional options for older patients. STUDY REGISTRATION: OSF registries (https://osf.io/vm2p8).

Changing the channel: a qualitative analysis of an innovative video intervention to explore resident attitudes towards interprofessional collaboration on a Geriatric Medicine Unit.

Background: Medical learners develop a more positive attitude toward Interprofessional Collaboration (IPC) following Interprofessional Education (IPE) programs. However, IPE is not standardized, and the most effective teaching tool is unclear. The purpose of our study was to develop an IPE teaching tool for medical residents during an inpatient geriatric medicine rotation at an academic hospital, evaluate and explore the impact of the program on resident attitudes towards teamwork, and identify barriers and facilitators to interprofessional collaboration. Methods: An innovative video was developed which simulated a common IPC scenario. Near the start of the rotation, learners watched the video then participated in a facilitated discussion around principles of IPE, using the Canadian Interprofessional Health Collaborative (CIHC) framework, which highlights interprofessional communication, patient-centered care, role clarification, team functioning, collaborative leadership, and interprofessional conflict resolution. At the end of their four-week rotation, focus groups were conducted to explore resident attitudes towards IPE. The Theoretical Domain Framework (TDF) was used for qualitative analysis. Results: Data from 23 participants in five focus groups were analyzed using the TDF framework. Residents were able to identify barriers and facilitators to IPC in five TDF domains: environmental context and resources, social/professional role and identity, knowledge, social influences, and skills. Their observations correlated with the CIHC framework. Conclusion: The use of a scripted video and facilitated group discussion gave insights into residents' attitudes, perceived barriers, and facilitators towards IPC on a geriatric medicine unit. Future research could explore the use of this video intervention in other hospital services where team-based care is important.

Contexte: Les apprenants en médecine développent une attitude plus positive à l'égard de la collaboration interprofessionnelle (CIP) après avoir suivi un programme de formation interprofessionnelle (FIP). Toutefois, la FIP n'est pas standardisée et on ne sait pas quel outil d'enseignement est le plus efficace. Le but de notre étude était d'élaborer un outil de FIP pour les résidents en stage de gériatrie dans un hôpital universitaire, d'évaluer et d'explorer les effets du programme sur les attitudes des résidents à l'égard du travail d'équipe, et de recenser les facteurs qui entravent ou facilitent la collaboration interprofessionnelle. Méthodes: Une capsule vidéo innovante simulant un scénario courant de CIP a été créée. Au début de leur stage de résidence, les apprenants ont regardé la capsule et participé à une discussion animée sur les principes de la CIP, conformément au référentiel du Consortium pancanadien pour l'interprofessionnalisme en santé (CPIS), qui prône notamment la communication interprofessionnelle, les soins centrés sur le patient, la clarification des rôles, le fonctionnement de l'équipe, le leadership collaboratif et la résolution des conflits interprofessionnels. À la fin de leur stage de quatre semaines, des groupes de discussion ont été organisés pour explorer les attitudes des résidents à l'égard de la CIP. Un cadre de domaines théoriques (Theoretical Domains Framework) a été appliqué pour réaliser l'analyse qualitative. Conclusion: Au moyen d'une capsule scénarisée et d'une discussion de groupe dirigée, nous avons pu cerner les attitudes des résidents d'une unité de gériatrie par rapport à la CIP ainsi que leurs perceptions quant aux facteurs qui peuvent l'entraver ou la faciliter. Des travaux futurs pourraient explorer le recours à cette formule d'enseignement de la CIP dans d'autres services hospitaliers où les soins en équipe sont importants.

Tongue necrosis secondary to giant cell arteritis, successfully treated with tocilizumab: a case report.

BACKGROUND: Giant Cell Arteritis (GCA) is a large vessel vasculitis that most commonly presents with headache, scalp tenderness, jaw claudication, and vision changes. Various other, less common, manifestations have been reported in the literature such as scalp and tongue necrosis. Though most patients respond to corticosteroids, some cases of GCA are refractory to the high doses of corticosteroids. CASE PRESENTATION: We present a 73-year-old female with GCA refractory to corticosteroids presenting with tongue necrosis. This patient significantly improved with a dose of tocilizumab, an IL-6 inhibitor. CONCLUSION: To the best of our knowledge, this is the first case report of a patient with refractory GCA presenting with tongue necrosis that had rapid improvement with tocilizumab. Prompt diagnosis and treatment can prevent severe outcomes such as tongue amputation in GCA patients with tongue necrosis, and tocilizumab may be effective for corticosteroid-refractory cases.

Serendipitous synergism - an exceptional response to treatment with pembrolizumab in the course of a natural immunovirotherapy: a case report and review of the literature.

Immune checkpoint inhibitors (ICIs) are the current guideline recommended treatment for many malignancies considered to be terminal. Despite considerable advances, their utility remains limited, and the field requires synergistic partners to further improve outcomes. Oncolytic viruses (OV) are emerging as contenders for the role of the synergistic agent of choice due to their multi-mechanistic effect on activating the tumor 'cold' immune microenvironment. Herpes simplex virus 1, a naturally selective OV, is the most advanced virotherapeutic compound in clinical applications for use in combination with ICI. We here present the case of a 72 year-old patient with a heavily pre-treated, advanced maxillary sinus squamous cell cancer with distant metastases who developed complete response (CR) with only three administrations of a programmed death 1 inhibitor after treatment interference by a severe herpes zoster infection, based on the related alpha-herpesvirus varicella zoster virus (VZV). This exceptional response has been followed and confirmed with imaging studies over more than 5 years. Although the patient had several favorable predictors for response to immunotherapy, we reason that the exceptional response may in part be secondary to the serendipitous VZV infection. Documented cases of cancer patients that achieved CR after few administrations of treatment with ICI are rare, with most reporting follow up of just over 1 year or less. In this case, it is conceivable that the interference of the infection with VZV, soon after the start of immunotherapy with ICI, led to a lasting antitumor immunity and sustained CR. This hypothesis is supported by the concept of 'oncolytic immunotherapy' which is reviewed in this manuscript. In addition, persistence of a TP53 mutation found in a liquid biopsy, despite clinical and radiologic remission, is discussed.

Governments' accountability for Canada's pandemic response.

The COVID-19 pandemic-with its wide-reaching social, political, and economic implications-showcases the importance of public health governance. Governmental accountability is at the forefront of societal preoccupations, as state actors attempt to manage the pandemic by using sweeping emergency powers which grant them significant discretion. Though emergency measures have tremendous impacts on citizens' lives, elected officials and civil society have little input in how governments wield these powers. We reviewed available mechanisms in Canadian private, constitutional, and criminal law and found them to be unlikely sources of much-needed accountability. Therefore, we propose that provincial and territorial legislatures modify public health legislation to expand mechanisms to foster public confidence in decision-makers, and bolster accountability to parliaments and citizens.

Influence of preoperative frailty on quality of life after cardiac surgery: Protocol for a systematic review and meta-analysis.

BACKGROUND: Frailty has emerged as an important prognostic marker of adverse outcomes after cardiac surgery, but evidence regarding its ability to predict quality of life after cardiac surgery is currently lacking. Whether frail patients derive the same quality of life benefit after cardiac surgery as patients without frailty remains unclear. METHODS: This systematic review will include interventional studies (RCT and others) and observational studies evaluating the effect of preoperative frailty on quality-of-life outcomes after cardiac surgery amongst patients 65 years and older. Studies will be retrieved from major databases including the Cochrane Central Register of Controlled Trials, Embase, and Medline. The primary exposure will be frailty status, independent of the tool used. The primary outcome will be change in quality of life, independent of the tool used. Secondary outcomes will include readmission during the year following the index intervention, discharge to a long-term care facility and living in a long-term care facility at one year. Screening, inclusion, data extraction and quality assessment will be performed independently by two reviewers. Meta-analysis based on the random-effects model will be conducted to compare the outcomes between frail and non-frail patients. The evidential quality of the findings will be assessed with the GRADE profiler. CONCLUSION: The findings of this systematic review will be important to clinicians, patients and health policy-makers regarding the use of preoperative frailty as a screening and assessment tool before cardiac surgery. STUDY REGISTRATION: OSF registries (https://osf.io/vm2p8).

Impact of a geriatric consultation service on outcomes in older trauma patients: a before-after study.

PURPOSE: Early geriatric involvement is recommended for older trauma patients. We wished to determine the impact of geriatric consultation on mortality, hospital length of stay and discharge disposition in older patients who were admitted to our Level 1 trauma unit. METHODS: We completed a health records review of trauma unit patients, age ≥ 75 years old with Injury Severity Score (ISS) ≥ 12, before (11/2015-10/2017) and after (11/2017-10/2019) implementation of a geriatric trauma consultation initiative. Primary outcomes were mortality, hospital length of stay and discharge destination. Secondary objectives were adherence to the geriatric trauma consult process and identification of geriatric-specific issues. A multivariable analysis controlling for age, gender, multi-morbidity and ISS was undertaken. RESULTS: 157 patients pre-implementation and 172 post-implementation with mean age 83.8 years and 53.8% females were included. Geriatric consultation had no impact on in-hospital mortality [OR 0.70 (95% CI 0.31-1.58)] or length of stay [ß 0.68 (95%CI - 1.35-2.72)]. Patients who received a geriatric consultation were more likely to be discharged home (OR 2.01 (95% CI 1.24-3.24). The adherence to consultation process was 99.4%. Mobility, pain and cognitive impairment were the most common geriatric concerns, identified in 76.6, 61.1 and 50.0% of older trauma patients, respectively. CONCLUSION: Older trauma patients that receive geriatric trauma consultation are more likely to be discharged home. Collaboration between trauma and geriatric specialists is beneficial and may lead to meaningful improvements in outcomes for older trauma patients.

Improving Communications With Patients and Families in Geriatric Care. The How, When, and What.

There has been little published literature examining the unique communication challenges older adults pose for health care providers. Using an explanatory mixed-methods design, this study explored patients' and their family/caregivers' experiences communicating with health care providers on a Canadian tertiary care, inpatient Geriatric unit between March and September 2018. In part 1, the modified patient-health care provider communication scale was used and responses scored using a 5-point scale. In part 2, one-on-one telephone interviews were conducted and responses transcribed, coded, and thematically analyzed. Thirteen patients and 7 family/caregivers completed part 1. Both groups scored items pertaining to adequacy of information sharing and involvement in decision-making in the lowest 25th percentile. Two patients and 4 family/caregivers participated in telephone interviews in part 2. Interview transcript analysis resulted in key themes that fit into the "How, When, and What" framework outlining the aspects of communication most important to the participants. Patients and family/caregivers identified strategic use of written information and predischarge family meetings as potentially valuable tools to improve communication and shared decision-making.

TUBERCULOUS CHOROIDITIS IN PATIENT WITH VOGT-KOYANAGI-HARADA DISEASE.

PURPOSE: To describe a novel case of intraocular tuberculosis (TB) arising in a patient undergoing treatment for Vogt-Koyanagi-Harada disease, and to highlight the use of spectral domain optical coherence tomography for helping confirm the diagnosis and monitor treatment response. METHODS: Case report of a patient with Vogt-Koyanagi-Harada disease on prednisone, with acute clinical changes suspicious for bilateral tuberculous choroiditis. Spectral optical coherence tomography, fundus photography, and B-scan ultrasonography were all used to capture the acute lesions, and to monitor their responses after initiation of anti-TB therapy. RESULTS: New subretinal lesions arose bilaterally, as characterized by spectral domain optical coherence tomography, and appeared to regress after a first round of anti-TB therapy, thereby helping confirm the presumed diagnosis of intraocular TB. A new peripheral choroidal lesion arose shortly after temporary cessation of antimicrobial treatment, and again regressed once four-drug therapy was instituted, with no recurrent lesions thereafter. CONCLUSION: The use of multimodal imaging was instrumental in the management of a rare case of intraocular TB arising in the setting of underlying Vogt-Koyanagi-Harada disease.

Using the Mouse to Model Human Diseases: Cognitive Impairment in Systemic Lupus Erythematosus.

In this 2020 Dunlop-Dottridge Lecture, the authors discuss cognitive impairment (CI), one of the most prevalent neuropsychiatric syndromes in systemic lupus erythematosus (SLE). Patients often report CI as the most bothersome disease-related manifestation, with a great effect on their quality of life. Nevertheless, studies focusing on CI remain scarce and no effective targeted therapy has been identified. We herein present murine models of CI in SLE with insights into the pathogenesis of this condition as well as the role of the renin angiotensin system in microglial activation. We will discuss the role of neuroimaging as a useful objective assessment tool, describing our experience in previous and ongoing clinical trials of CI in patients with SLE.