A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma.

PURPOSE: We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551). PATIENTS AND METHODS: The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses. RESULTS: Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (>90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells. CONCLUSIONS: These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.

A New Electromechanical Wave Imaging Dispersion Metric for the Characterization of Ventricular Activation in Different Cardiac Resynchronization Therapy Pacing Schemes.

Conventional biventricular (BiV) pacing cardiac resynchronization therapy (CRT) is an established treatment for heart failure patients. Recently, multiple novel CRT delivering technologies such as His-Bundle pacing have been investigated as alternative pacing strategies for optimal treatment benefit. Electromechanical Wave Imaging (EWI), a high frame-rate echocardiography-based modality, is capable of visualizing the change from dyssynchronous activation to resynchronized BiV-paced ventricles in 3D. This proof-of-concept study introduces a new EWI-based dispersion metric to further characterize ventricular activation. Patients with His-Bundle device implantation (n = 4), left-bundle branch block (n = 10), right-ventricular (RV) pacing (n = 10), or BiV pacing (n = 15) were imaged, as well as four volunteers in normal sinus rhythm (NSR). EWI successfully mapped the ventricular activation resulting from His-Bundle pacing. Additionally, very similar activation patterns were obtained in the NSR subjects, confirming recovery of physiological activation with His pacing. The dispersion metric was the most sensitive EWI-based metric that identified His pacing as the most efficient treatment (lowest activation time spread), followed by BiV and RV pacing. More specifically, the dispersion metric significantly (p < 0.005) distinguished His pacing from the other two pacing schemes as well as LBBB. The initial findings presented herein indicate that EWI and its new dispersion metric may provide a useful resynchronization evaluation clinical tool in CRT patients under both novel His-Bundle pacing and more conventional BiV pacing strategies.

Persistent ethnicity-associated disparity in anti-tumor effectiveness of immune checkpoint inhibitors despite equal access.

We reviewed response to immune checkpoint inhibitors (ICI) of 207 patients with diagnoses of lung or head and neck cancer treated with chemotherapy/ICI combination therapy and ICI monotherapy between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine. Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority populations and provide equal access to care regardless of means. 174 patients had a diagnosis of lung cancer (non-small cell or small cell) and 33 had a diagnosis of head and neck squamous cell carcinoma (HNSCC). 38% self-identified as Black, 45% as non-Hispanic White, and 18% as Hispanic. The objective response rate (ORR) was similar for lung cancer (35.057%) and HNSCC patients (30.3%) (p=0.894). The ORR for Hispanic and Black patients was lower compared to non-Hispanic White patients (H 27.0%, B 32.5%, W 38.7%; H vs. W p=0.209; B vs. W p=0.398). When considering only patients treated with ICI monotherapy, the ORR for Hispanic patients dropped further to 20.7% while the ORR of Black and non-Hispanic White patients remained about the same (B 29.3% and W 35.9%, H vs. W p=0.133; B vs. W p=0.419). Immune related adverse events were the lowest in the Hispanic population occurring in only 30% of patients compared to 40% of patients in the Black cohort and 50% of the non-Hispanic White cohorts.

Therapeutic Targeting of Macrophage Plasticity Remodels the Tumor-Immune Microenvironment.

SIGNIFICANCE: Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy. See related commentary by Lee et al., p. 2515.

Inhibition of Cyclin Dependent Kinase 4/6 Overcomes Primary Resistance to Programmed Cell Death 1 Blockade in Malignant Mesothelioma.

BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with programmed cell death 1 (PD-1) blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remains unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM. METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 nonresponders). We used The Cancer Genome Atlas MPM cohort (n = 73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model. RESULTS: Immunogenomic analysis by applying our anti-PD-1 resistance signature to The Cancer Genome Atlas cohort revealed that deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by cyclin dependent kinase 4/6 (CDK4/6) inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a-/- AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth compared with anti-PD-1 or CDK4/6 inhibitor alone. CONCLUSIONS: We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.

What risk factors for sudden infant death syndrome are preterm and term medically complex infants exposed to at home?

OBJECTIVES: Risk factors for sudden infant death syndrome include premature birth, maternal smoking, prone or side sleeping position, sleeping with blankets, sharing a sleeping surface with an adult, and sleeping without an adult in the room. In this study, we compare parents' responses on sleep patterns in premature and term infants with medical complexity. METHODS: Parents of children enrolled in the Canadian Respiratory Syncytial Virus Evaluation Study of Palivizumab were phoned monthly regarding their child's health status until the end of each respiratory syncytial virus season. Baseline data were obtained on patient demographics, medical history, and neonatal course. Responses on adherence to safe sleep recommendations were recorded as part of the assessment. RESULTS: A total of 2,526 preterms and 670 term infants with medical complexity were enrolled. Statistically significant differences were found in maternal smoking rates between the two groups: 13.3% (preterm); 9.3% (term) infants (χ 2=8.1, df=1, P=0.004) and with respect to toys in the crib: 12.3% (term) versus 5.8% preterms (χ 2=24.5, df=1, P<0.0005). Preterm infants were also significantly more likely to be placed prone to sleep (8.8%), compared with term infants (3.3%), (χ 2=18.1, df=1, P<0.0005). CONCLUSION: All the infants in this study had frequent medical contacts. There is a greater prevalence of some risk factors for sudden infant death syndrome in preterm infants compared to term infants with medical complexity. Specific educational interventions for vulnerable infants may be necessary.

Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy.

BACKGROUND: Combination ipilimumab and nivolumab is approved for several malignancies. Toxicity most often occurs 6-10 weeks into treatment. Whether very early toxicity is harder to manage or influences efficacy is unknown. METHODS: Consecutive metastatic melanoma patients who developed hyperacute toxicity, defined as Grade 2+ irAE within 21 days of receiving ipilimumab + anti-PD-1 were retrospectively identified from nine centres. RESULTS: A total of 82 patients developed hyperacute toxicity (estimated incidence 9%), at a median 10 days (range 1-21). Toxicities included colitis (N = 23), rash (17), hepatitis (9), endocrine (9), pneumonitis (6) and neurotoxicity (4) and were G2 (38%), G3 (52%), G4 (6%) and G5 (2% myocarditis). Fifty-nine percent required treatment beyond oral steroids, including IV steroids (28%), infliximab and other immunosuppression (30%). A total of 29% patients developed an additional hyperacute toxicity and 26% another toxicity >21 days after treatment commencement but before further immunotherapy. The objective response rate (ORR) was 54%, and after a median 11.6 mo follow-up, median PFS was 7.4 mo. Increasing levels of immunosuppression was associated with a reduced PFS (12-month PFS 62% no immunosuppression versus 49% oral steroids versus 33% IV steroids versus 20% further immunosuppressants, p = 0.006). There was no significant difference in ORR or PFS by duration of immunosuppression. CONCLUSIONS: Hyperacute toxicities from combination immunotherapy have a wide spectrum and can be severe. Many patients require significant immunosuppression for prolonged durations and remain at risk of further severe toxicity. Melanoma outcomes in such patients appear similar to those of trial populations, although greater immunosuppression requirements may be associated with inferior outcomes.

Cardiac Resynchronization Therapy Response Assessment with Electromechanical Activation Mapping within 24 Hours of Device Implantation: A Pilot Study.

BACKGROUND: Cardiac resynchronization therapy (CRT) response assessment relies on the QRS complex narrowing criterion. Yet one third of patients do not improve despite narrowed QRS after implantation. Electromechanical wave imaging (EWI) is a quantitative echocardiography-based technique capable of noninvasively mapping cardiac electromechanical activation in three dimensions. The aim of this exploratory study was to investigate the EWI technique, sensitive to ventricular dyssynchrony, for informing CRT response on the day of implantation. METHODS: Forty-four patients with heart failure with left bundle branch block or right ventricular (RV) paced rhythm and decreased left ventricular ejection fraction (LVEF; mean, 25.3 ± 9.6%) underwent EWI without and with CRT within 24 hours of device implantation. Of those, 16 were also scanned while in left ventricular (LV) pacing. Improvement in LVEF at 3-, 6-, or 9-month follow-up defined (1) super-responders (ΔLVEF ≥ 20%), (2) responders (10% ≤ ΔLVEF < 20%), and (3) nonresponders (ΔLVEF ≤ 5%). Three-dimensionally rendered electromechanical maps were obtained under RV, LV, and biventricular CRT pacing conditions. Mean RV free wall and LV lateral wall activation times were computed. The percentage of resynchronized myocardium was measured by quantifying the percentage of the left ventricle activated within 120 msec of QRS onset. Correlations between percentage of resynchronized myocardium and type of CRT response were assessed. RESULTS: LV lateral wall activation time was significantly different (P ≤ .05) among all three pacing conditions in the 16 patients: LV lateral wall activation time with CRT in biventricular pacing (73.1 ± 17.6 msec) was lower compared with LV pacing (89.5 ± 21.5 msec) and RV pacing (120.3 ± 17.8 msec). Retrospective analysis showed that the percentage of resynchronized myocardium with CRT was a reliable response predictor within 24 hours of implantation for significantly (P ≤ .05) identifying super-responders (n = 7; 97.7 ± 1.9%) from nonresponders (n = 17; 89.9 ± 9.9%). CONCLUSION: Electromechanical activation mapping constitutes a valuable three-dimensional visualization tool within 24 hours of implantation and could potentially aid in the timely assessment of CRT response rates, including during implantation for adjustment of lead placement and pacing outcomes.

Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab.

The same mechanisms that mediate antitumor immunity from checkpoint inhibitors (CPIs) can also lead to unintended targeting of normal tissues, characterized as immune-related adverse events (irAEs). Those with pre-existing autoimmune disease are believed to be particularly vulnerable for exacerbating underlying autoimmunity or inducing severe irAEs. We report the first case of CPI-associated reactivation of primary membranous nephropathy (MN) in a patient with pleural mesothelioma responding to immunotherapy. Due to its specificity in targeting B-lymphocytes, rituximab was used to treat primary MN with the expectation that this would not interfere with the benefits gained from T cell-mediated antitumor immunity. Rituximab was effective in treating CPI-associated reactivation of MN, and the patient was successfully rechallenged with nivolumab and maintained stable kidney function and sustained clinical antitumor effect. While exacerbation of pre-existing autoimmune diseases from CPIs is common, therapy for autoimmune reactivation can be rationally directed by an understanding of the immunosuppressive mechanism with goals of cancer treatment.

Mucosal inflammation predicts response to systemic steroids in immune checkpoint inhibitor colitis.

BACKGROUND: Immune-related colitis is a common, often serious complication of immune checkpoint inhibition (ICI). Although endoscopy is not strictly recommended for any grade of diarrhea/colitis, emerging evidence suggests that endoscopic evaluation may have important therapeutic implications. In this retrospective study, we sought to comprehensively characterize the clinical and histologic features of ICI-induced colitis with a specific focus on evaluating the prognostic role of endoscopy. METHODS: Data were collected from the medical records of 130 patients with confirmed ICI-induced colitis. In a subset of patients (n=44) with endoscopic and pathologic data, endoscopic data were scored using the Mayo Endoscopic Score (MES) with scores ranging from 0 (no inflammation) to 3 (colonic ulceration). The impact of infliximab on antitumor outcomes was evaluated using progression-free survival (PFS) and overall survival (OS). RESULTS: We identified 130 patients with ICI-induced colitis across two institutions. All patients were treated with corticosteroids. Additional and/or alternative immunosuppression was employed in 59 cases, with 52 patients (42%) requiring at least one infusion of infliximab 5 mg/kg. Endoscopic assessment with biopsy was performed in 123 cases of suspected colitis (95%), with 44 cases available for MES tabulation. Presence of ulceration (MES 3) was associated with use of infliximab (p=0.008) and MES was significantly higher in patients who received infliximab compared with those who did not (p=0.003) with a median score of 2.5; conversely, those with an MES of zero rarely required secondary immunosuppression. Notably, symptoms of colitis based on Common Terminology Criteria for Adverse Events grade had no association with endoscopic findings based on MES classification. After adjustment for baseline patient and disease characteristics, there was no significant difference in steroid duration or cancer-related outcomes in patients treated with infliximab. CONCLUSIONS: In our study, we demonstrate the association of endoscopic features, specifically the MES, with immunosuppressive needs. Importantly, we also show that MES was not related to severity of patient symptoms. The data suggest that endoscopic features can guide clinical decision-making better than patient symptoms, both identifying high-risk patients who will require infliximab and those who are likely to respond to initial corticosteroids.

Noninvasive localization of cardiac arrhythmias using electromechanical wave imaging.

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. The 12-lead electrocardiogram (ECG) is the current noninvasive clinical tool used to diagnose and localize cardiac arrhythmias. However, it has limited accuracy and is subject to operator bias. Here, we present electromechanical wave imaging (EWI), a high-frame rate ultrasound technique that can noninvasively map with high accuracy the electromechanical activation of atrial and ventricular arrhythmias in adult patients. This study evaluates the accuracy of EWI for localization of various arrhythmias in all four chambers of the heart before catheter ablation. Fifty-five patients with an accessory pathway (AP) with Wolff-Parkinson-White (WPW) syndrome, premature ventricular complexes (PVCs), atrial tachycardia (AT), or atrial flutter (AFL) underwent transthoracic EWI and 12-lead ECG. Three-dimensional (3D) rendered EWI isochrones and 12-lead ECG predictions by six electrophysiologists were applied to a standardized segmented cardiac model and subsequently compared to the region of successful ablation on 3D electroanatomical maps generated by invasive catheter mapping. There was significant interobserver variability among 12-lead ECG reads by expert electrophysiologists. EWI correctly predicted 96% of arrhythmia locations as compared with 71% for 12-lead ECG analyses [unadjusted for arrhythmia type: odds ratio (OR), 11.8; 95% confidence interval (CI), 2.2 to 63.2; P = 0.004; adjusted for arrhythmia type: OR, 12.1; 95% CI, 2.3 to 63.2; P = 0.003]. This double-blinded clinical study demonstrates that EWI can localize atrial and ventricular arrhythmias including WPW, PVC, AT, and AFL. EWI when used with ECG may allow for improved treatment for patients with arrhythmias.

The Impact of Nonsteroidal Anti-Inflammatory Drugs, Beta Blockers, and Metformin on the Efficacy of Anti-PD-1 Therapy in Advanced Melanoma.

Anti-programmed cell death protein-1 (anti-PD-1) therapy has greatly improved outcomes of patients with melanoma; however, many fail to respond. Although preclinical studies suggest a potentially synergistic relationship with anti-PD-1 therapy and certain concurrent medications, their clinical role remains unclear. Here, we retrospectively evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs in 330 patients with melanoma treated with anti-PD-1 therapy from four academic centers. In the cohort, 37% of patients used NSAIDs including aspirin (acetylsalicylic acid; ASA; 47%), cyclooxygenase (COX)-2 inhibitors (2%), and non-ASA/nonselective COX inhibitor NSAIDs (59%). The objective response rates (ORRs) were similar in patients with NSAID (43.4%) and no NSAID (41.3%) use with no significant difference in overall suvival (OS). There was a trend toward improved progression-free survival (PFS) in patients who took NSAIDs (median PFS: 8.5 vs. 5.2 months; p = .054). Most patients (71.3%) took NSAIDs once daily or as needed. Multivariate analysis did not reveal an association with NSAID use with ORR, PFS, or OS. Concurrent use of metformin or beta blockers did not affect ORR, PFS, or OS. Our study found no conclusive association of concurrent NSAID or other medication use with improved outcomes in patients with melanoma treated with anti-PD-1 therapy. Larger and more systematic analysis is required to confirm these findings.

Predictors of benefits from frontline chemoimmunotherapy in stage IV non-small-cell lung cancer: a meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have dramatically expanded the therapeutic landscape of non-small-cell lung cancer (NSCLC). In a previous study, gender, smoking history, and PD-L1 status were found to influence the efficacy of single-agent ICI in NSCLC. This meta-analysis evaluated the clinical and molecular factors that could predict a benefit from adding ICIs to first-line chemotherapy in metastatic NSCLC. Patients and Methods: The pooled hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) among the selected subgroups were analyzed using the random effects model. The correlation between PD-L1 expression and outcome was analyzed by meta-regression. Results: Seven phase III randomized controlled trials comparing chemo-immunotherapy (CIT) with chemotherapy in untreated stage 4 NSCLC were included. CIT evenly improved PFS irrespective of age, gender, histology, smoking history, and performance status. Among patients with baseline hepatic metastasis treated with Atezolizumab-containing CIT, PFS improvement was only detected with the addition of Bevacizumab. Whereas patients with EGFR/ALK-driven cancer exhibited greater PFS with the addition of ICI to a Bevacizumab (BEV)-based regimen, the derived benefit was no longer statistically significant among those treated with non-BEV-based regimens. Although the superior PFS conferred by CIT was noticeable across all PD-L1 expression subgroups, this benefit correlated with PD-L1 level and was more pronounced in the "PD-L1 high" cohort. Except for patients harboring EGFR/ALK aberrations or squamous histology, CIT consistently improved OS across the other selected subgroups. Conclusions: The survival advantage associated with first-line CIT in metastatic NSCLC was observed in different patient populations, including those for which single-agent ICI has marginal therapeutic benefit. Our findings support the role of chemotherapy with or without VEGF blockade as enhancers of ICI activity in NSCLC.

Anti-PD-1-Induced Pneumonitis Is Associated with Persistent Imaging Abnormalities in Melanoma Patients.

Pneumonitis may complicate anti-programmed death-1 (PD-1) therapy, although symptoms usually resolve with steroids. The long-term effects on respiratory function, however, are not well defined. We screened melanoma patients treated with anti-PD-1, with and without ipilimumab (anti-CTLA-4), and identified 31 patients with pneumonitis. Median time to radiographic findings was 4.8 months. Twenty-three patients (74%) presented with respiratory symptoms, whereas 8 (26%) were asymptomatic, and 11 (35%) were hospitalized. With 22.1 months median follow-up, 27 patients (87%) had resolution of symptoms, whereas 4 had persistent cough, dyspnea, and/or wheezing. By contrast, the rate of radiographic resolution was lower: Only 11 (35%) had complete radiographic resolution, whereas 14 (45%) had improvement of pneumonitis with persistent scarring or opacities, and 6 (19%) had persistent or worsened ground-glass opacities and/or nodular densities. Persistence (vs. resolution) of radiographic findings was associated with older age and initial need for steroids but not with need for hospitalization, timing of onset, or treatment regimen (combination vs. monotherapy). Among patients with serial pulmonary function tests, lung function improved with time. Although symptoms of anti-PD-1-induced pneumonitis resolved quickly, scarring or inflammation frequently persisted on computerized tomography. Therefore, further study of subclinical pulmonary effects of anti-PD-1 is needed.

Correlates of response and outcomes with talimogene laherperpvec.

BACKGROUND AND OBJECTIVES: Patients with in-transit or limited cutaneous metastatic melanoma may benefit from intralesional injections with talimogene laherparepvec (TVEC), a modified oncolytic herpesvirus. However, its use in patients with adverse prognostic scores in a real-life clinical setting has not been studied. METHODS: We performed a two-center retrospective analysis of 40 patients with metastatic melanoma treated with TVEC from 2015-2017. Demographics, overall response, and survival after therapy were noted. RESULTS: Overall, there was a durable response rate of 40%; median progression-free survival (PFS) was 10.5 months and median overall survival (OS) was not reached. Bulky disease was associated with decreased OS (15.7 months vs not reached, P < .05) and mPFS (2.3 months vs not reached, P < .05), when compared with smaller tumors. Poor performance status (ECOG 2-3) was associated with worse OS (10.2 months vs not reached, P < .05) and PFS (2.1 months vs not reached, P < .05) compared to patients with ECOG 0-1. There was no difference in the outcomes with age greater than 75 or with prior therapies. Adverse events were relatively tolerable. CONCLUSIONS: These findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma in a real-life clinical setting, and suggest parameters to aid in appropriate therapy selection for optimal response.

A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis.

Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4+ T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO+GZMB+Ki67+) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV+ lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4+ and CD8+ T cells as culprits of checkpoint inhibitor-associated immune encephalitis.

Respiratory Syncytial Virus Prophylaxis in Neurologic and Muscular Disorders in the Canadian Respiratory Syncytial Virus Evaluation Study of Palivizumab.

BACKGROUND: This study aimed to examine the risk of respiratory-related hospitalization in children with neurologic and muscular disorders (NMDs) who received respiratory syncytial virus (RSV) prophylaxis in the Canadian RSV Evaluation Study of Palivizumab. METHODS: Canadian RSV Evaluation Study of Palivizumab is a prospective registry of children who received ≥1 palivizumab injection among 32 Canadian sites. Demographic data were collected at enrollment, and respiratory events were documented monthly. Cox proportional hazard analyses were conducted to compare respiratory illness-related hospitalization (RIH) and RSV-related hospitalization (RSVH) among children with NMD and those prophylaxed for standard indications (SI) and complex medical disorders. RESULTS: Group differences were found in enrollment age and weight, birth weight, household crowding, neonatal stay and supplemental oxygen requirement (all P < 0.05). RIH and RSVH incidences were 19.2%, 3.3% (NMD, n = 605); 6.0%, 1.5% (SI, n = 20,335), 9.4%, 1.6% (complex medical disorders, n = 4063), respectively. Children with NMD had a higher risk of RIH (hazard ratio [HR]: 1.90; 95% confidence interval (CI): 1.41-2.56; P < 0.0005) than those with SI. RSVH risk was greater in children with NMD compared with both the SI (HR: 2.26; 95% CI: 1.38-3.72; P = 0.001) and complex medical disorders groups (HR: 2.74; 95% CI: 1.55-4.84; P = 0.001). Children with more severe infantile onset NMD had a higher risk of RIH than those with general hypotonic disorders (HR: 1.69; 95% CI: 1.06-2.68; P = 0.027) but not RSVH. CONCLUSIONS: Children with NMD who received palivizumab had a higher risk of both RIH and RSVH. Our results imply that all children with NMD, regardless of disease severity, are at risk for respiratory-related illness and RSV infection.

Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.

Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor ≤2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with ≤10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.

Leadless pacemaker implantation: A feasible and reasonable option in transcatheter heart valve replacement patients.

BACKGROUND: Leadless pacemakers (LPMs) have been shown to have lower postoperative complications than traditional permanent pacemakers but there have been no studies on the outcomes of LPMs in patients with transcatheter heart valve replacements (THVRs). This study determined outcomes of LPMs compared to transvenous single-chamber pacemakers (SCPs) post-THVR. METHODS: This is a retrospective single-center study including 10 patients who received LPMs post-THVR between February 2017 and August 2018 and a comparison group of 23 patients who received SCP post-THVR between July 2008 and August 2018. LPM or SCP was implanted at the discretion of electrophysiologists for atrial fibrillation with slow ventricular response or sinus node dysfunction with need for single-chamber pacing only. RESULTS: LPMs were associated with decreased tricuspid regurgitation (P = 0.04) and decreased blood loss during implantation (7.5 ± 2.5 cc for LPMs vs 16.8 ± 3.2 cc for SCPs, P = 0.03). Five LPM patients had devices positioned in the right ventricular septum as seen on transthoracic echocardiogram. Frequency of ventricular pacing was similar between LPM and SCP groups. In the LPM group, one case was complicated by a pseudoaneurysm and one death was due to noncardiac causes. There was one pneumothorax and one pocket infection in the SCP group. CONCLUSIONS: In this small retrospective study, LPMs were feasible post-THVR and found to perform as well as SCPs, had less intraprocedural blood loss, and were associated with less tricuspid regurgitation. Further, larger studies are required to follow longer-term outcomes and complications.

Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1-based therapy.

BACKGROUND: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting. METHODS: Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy. RESULTS: A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months. CONCLUSIONS: The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.