Association of circadian timing of initial infusions of immune checkpoint inhibitors with survival in advanced melanoma.

Aims: Chronomodulation of immune checkpoint inhibitors (ICIs) is not well understood. The authors evaluated the circadian timing of initial ICI infusions. Patients & methods: A retrospective cohort study of patients with advanced melanoma (n = 121) was conducted. Results: Exclusive afternoon timing of the first four infusions was associated with worse overall survival (5.5 vs 24.9 months; p < 0.001) and progression-free survival (3.3 vs 7.6 months; p = 0.009) on Kaplan-Meier curves. In multivariable Cox analysis, the rate of overall survival was lower in patients who received all first four ICI infusions in the afternoon versus patients who received ≥1 of the first four infusions in the morning (hazard ratio: 2.4; p = 0.004). Conclusion: Deliberate morning scheduling for the first several ICI treatments may improve patient-centered outcomes.

Antithymocyte globulin for aplastic anemia secondary to pembrolizumab: a case report and review of literature.

Aplastic anemia is a rare but potentially serious complication of immune checkpoint inhibitor therapy. The authors present a case of pembrolizumab-induced aplastic anemia that was refractory to steroids but had some hematologic response to modified-dosing antithymocyte globulin (ATG). This is the first reported case of hematological response to ATG for immune checkpoint inhibitor-induced aplastic anemia and the first reported case of modified ATG dosing for this indication. Cases of immune checkpoint inhibitor-induced aplastic anemia and management options are also summarized. Given the high morbidity and mortality associated with ICI-induced aplastic anemia, more data is necessary to guide evidence-based management recommendations.

Immune checkpoint inhibitors (ICIs) are a form of anticancer therapy that enlists the body's own immune system to fight cancer cells. Although remarkably effective against some types of cancer, ICIs can also cause the augmented immune system to attack noncancer cells, resulting in unwanted off-target side effects. One rare but potentially serious complication of ICIs is aplastic anemia, where the body stops producing enough new blood cells. There is little known about ICI-induced aplastic anemia. The authors present a case of ICI-induced aplastic anemia that did not improve with standard treatment but had some response to antithymocyte globulin, which has not been previously reported. Previously published cases of ICI-induced aplastic anemia and management options are also summarized.

Survivals following discontinuation of PD-1 inhibitor treatment in advanced melanoma patients.

The aim of this study was to evaluate overall survival post-treatment discontinuation survival (OS PTD ) in advanced melanoma patients started on immunotherapy. This retrospective study included all unresectable advanced or metastatic melanoma patients who had permanent treatment discontinuation after receiving at least one cycle of palliative-intent programmed death-1 ± cytotoxic T-lymphocyte associated protein-4 inhibitor treatment from 2014 to 2019. Indications of permanent treatment discontinuation included treatment completion, toxicity or progression. OS PTD was defined as a time of permanent treatment discontinuation to the time of death. Our study ( N = 96) had 27, 12 and 57 patients who discontinued PD-1 inhibitor treatment due to treatment completion, toxicity and progression, respectively. Median treatment durations received for the treatment completion, toxicity and progression groups were 24, 6 and 3 months, respectively. As expected those patients who had disease progression on immunotherapy had very poor survival compared to those that completed treatment or stopped due to toxicity. A multivariable Cox model excluding the patients who progressed indicated no significant OS PTD differences between the toxicity and treatment completion group (HR, 0.894; 95% CI, 0.232-3.449; P = 0.871) who received single or dual immunotherapy. Our real-world study highlighted similar, durable survival at PD-1 inhibitor discontinuation due to either toxicity or treatment completion, despite longer treatment duration received in the completion group than toxicity group. Patients with progression on PD-1 inhibitor treatment have very poor survival. Our findings must be interpreted with caution due to its retrospective nature and small sample size.

Long-Term Toxicities of Immune Checkpoint Inhibitor (ICI) in Melanoma Patients.

ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3-4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment.

Systemic Treatment of Advanced Unresectable Hepatocellular Carcinoma after First-Line Therapy: Expert Recommendations from Hong Kong, Singapore, and Taiwan.

Background: Asia has a high burden of hepatocellular carcinoma (HCC) due to the high rates of chronic hepatitis B infection and accounts for 70% of HCC cases globally. In the past 20 years, the systemic treatment landscape of advanced HCC has evolved substantially - from tyrosine kinase inhibitors to immune-oncology agents plus anti-vascular endothelial growth factor agents. The appropriate sequence of therapies has become critical in optimizing patient outcomes given the increase in systemic therapeutic options. This article evaluates the evidence and provides expert recommendations for the use of systemic therapies after first-line treatment in patients with advanced HCC. Summary: Based on three virtual meetings held in early 2021, a team of 17 experts comprising oncologists, a hepatologist, and a hepatobiliary surgeon from Hong Kong, Singapore, and Taiwan reviewed available data about systemic treatments for HCC after first line and formulated 28 statements. These statements aimed to provide expert guidance on selecting first and subsequent lines of therapies as well as recommending therapies in special circumstances, such as poor liver function, posttransplantation, recent gastrointestinal bleeding, or autoimmune diseases. Data supporting the statements were drawn from clinical trials and real-world studies. The 28 statements were then evaluated anonymously using a 5-point Likert scale, and 24 reached consensus, predefined as achieving 75% agreement. Statements generated covered the selection of first-line systemic therapy, considerations and goals of second-line systemic therapies, treatment selection following first-line therapy, and treatment recommendations following first-line tyrosine kinase inhibitors, immune-oncology monotherapy, or immune-oncology combination therapy. The authors also shared expert opinion on the use of second-line systemic therapy in patients with liver dysfunction, liver transplantation, and recent gastrointestinal or autoimmune disease. Key Messages: These expert statements summarize the latest data and expert opinion on selecting systemic treatment following first-line therapy in patients with unresectable advanced or metastatic HCC.

Complete response and survival outcomes in patients with advanced cancer on immune checkpoint inhibitors.

Aim: To evaluate overall survival in advanced cancer patients who achieved complete response (CR) with immune checkpoint inhibitor (ICI) therapy. Methods: This retrospective study included patients with advanced unresectable or metastatic cancer who received at least one cycle of palliative-intent ICI. Best overall response was used to define response groups. Results: 21 (7%) of 322 patients achieved CR. Multivariate analysis demonstrated that CR was independently associated with better overall survival compared with disease progression (hazard ratio: 0.012; 95% CI: 0.002-0.090) and stable disease (hazard ratio: 0.063; 95% CI: 0.009-0.464) as well as a nonsignificant trend toward better overall survival compared with partial response (hazard ratio: 0.169; 95% CI: 0.023-1.252) regardless of cancer type, ICI regimen or ICI line. Conclusion: Patients who achieved CR had longer survival compared with patients who did not achieve CR.

No association between BMI and immunotoxicity or clinical outcomes for immune checkpoint inhibitors.

Background: The impact of BMI on immune checkpoint inhibitor toxicity and efficacy has not been clearly characterized. Methods: The authors conducted a retrospective single-center study of patients with advanced unresectable/metastatic cancer initiated on immune checkpoint inhibitors. Results: Of the 409 patients included in the study, 115 (28%) had a BMI ≥30. There was no difference in the development of immune-related adverse events, treatment response or overall survival with respect to BMI <30 versus ≥30 for the whole study population or the melanoma subgroup. Conclusion: Patients with BMI in the obese range (≥30) were not at increased risk of immunotoxicity. Furthermore, BMI was not correlated with treatment response or overall survival in patients receiving immune checkpoint inhibitors.

Several previous studies have suggested that obesity may be correlated with improved efficacy of immunotherapy and raised the concern that obesity may be associated with increased immunotoxicity; however, other studies have not replicated these findings. The authors evaluated the records from one center of 409 patients with advanced cancer on immune checkpoint inhibitors. There was no difference with respect to adverse events, treatment response or survival between obese and nonobese patients.

Improved overall survival in dual compared to single immune checkpoint inhibitors in BRAF V600-negative advanced melanoma.

Aim: To evaluate the efficacy of dual versus single immune checkpoint inhibitors (ICI) in BRAF wild-type advanced melanoma patients. Materials & methods: A retrospective study of all advanced BRAF wild-type melanoma patients on palliative-intent ICI between 2015 and 2020 (n = 67). Results: Dual ICI had better overall survival (OS) when compared with single ICI in BRAF wild-type patients (hazard ratio: 0.204; 95% CI: 0.064-0.649; p = 0.007), but lost its statistical significance (median OSl not reached vs 20.9 months; p = 0.213; adjusted hazard ratio: 0.475; 95% CI: 0.164-1.380; p = 0.171) when only including patients treated after 2018 when dual ICI was funded in our province. Dual ICI were significantly associated with more frequent (p = 0.005) and severe (p = 0.026) immune-related adverse events, and required more immune-related adverse events-indicated systemic corticosteroid use (p < 0.001) compared with single ICI. Conclusion: While limited by small sample size and retrospective nature, dual ICI may have non statistically significant trend toward better OS efficacy when compared with single ICI in BRAF V600 wild-type advanced melanoma patients.

Pacemaker Explantation in Patients With Lyme Carditis.

Early recognition of Lyme carditis is critical to preventing unnecessary pacemaker implantation for conduction abnormalities associated with this tick-born infection. Patients who do receive a pacemaker should be considered for device extraction after the completion of their antibiotic therapy if they recover normal atrioventricular node conduction. (Level of Difficulty: Intermediate.).

A novel yeast model detects Nrf2 and Keap1 interactions with Hsp90.

Nrf2 is the master transcriptional regulator of cellular responses against oxidative stress. It is chiefly regulated by Keap1, a substrate adaptor protein that mediates Nrf2 degradation. Nrf2 activity is also influenced by many other protein interactions that provide Keap1-independent regulation. To study Nrf2 regulation, we established and characterized yeast models expressing human Nrf2 (also known as NFE2L2), Keap1 and other proteins that interact with and regulate Nrf2. Yeast models have been well established as powerful tools to study protein function and genetic and physical protein-protein interactions. In this work, we recapitulate previously described Nrf2 interactions in yeast and discover that Nrf2 interacts with the molecular chaperone Hsp90. Our work establishes yeast as a useful tool to study Nrf2 interactions and provides new insight into the crosstalk between the antioxidant response and the heat shock response.

Long-term Outcomes in Treated Lyme Carditis.

Lyme disease is the most reported tick-borne illness in North America. Lyme carditis (LC) is an early-disseminated manifestation of Lyme disease, most commonly presenting as symptomatic high-degree atrioventricular block (AVB) which resolves with appropriate antibiotic therapy. However, long-term outcomes of treated LC have not previously been described. We present a series of 7 patients (median 28 years, 6 male) with serologically confirmed LC treated with a standard protocol developed at our center including antibiotics and pre-discharge stress test to assess AV node stability. At a mean follow-up of 20.8 months, all patients were asymptomatic, had resumed normal activities, and were free of conduction abnormalities. None required permanent pacing. Our study supports avoidance of permanent pacing for LC if conduction is stable at discharge.

Venous thromboembolism events in patients with advanced cancer on immune checkpoint inhibitors.

Aim: To evaluate the correlation between venous thromboembolism events (VTEs) and immune checkpoint inhibitor (ICI)-based regimens. Methods: This is a retrospective study of 403 patients with advanced cancer on ICI-based regimens. Results: We report 8% VTE incidence post-ICI initiation over a median of 11.1 months of follow-up. Compared with single-agent ICI, dual-ICI was significantly correlated with higher incidence of VTE (odds ratio [OR]: 4.196, 95% CI: 1.527-11.529, p = 0.005), but chemotherapy-immuno-oncology combination was not (OR: 1.374, 95% CI: 0.285-6.632, p = 0.693). Subsequent systemic therapy post-ICI was also independently associated with higher VTE incidence (OR: 2.599, 95% CI: 1.169-5.777, p = 0.019). Conclusion: Our findings suggest potential underreporting of VTE incidence in ICI clinical trials. As dual-ICI is becoming more prevalent in cancer management, clinicians should maintain vigilance regarding VTE in patients with advanced cancer on ICI-based regimens.

Safety and Clinical Outcomes of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Diseases.

Immunotherapy has revolutionized treatment outcomes in numerous cancers. However, clinical trials have largely excluded patients with autoimmune diseases (ADs) due to the risk of AD flares or predilection for developing organ-specific inflammation. The objective of this study was to evaluate the safety and efficacy of immunotherapy in patients with cancer and preexisting ADs. A retrospective, single-center study of patients with cancer initiated on immune checkpoint inhibitors between 2012 and 2019 was conducted. The primary outcome was the development of immune-related adverse events (irAEs) with respect to the presence of AD at baseline. Associations were assessed using Kaplan-Meier curves, bivariate and multivariable analyses. Of the 417 patients included in this study, 63 patients (15%) had preexisting ADs. A total of 218 patients (53%) developed at least 1 irAE. There was no association between the presence of baseline AD on the development, grade, or number of irAEs; time to irAE or irAE recovery; systemic corticosteroid or additional immunosuppressant treatment for irAEs; permanent treatment discontinuation; or overall response rate. Two smaller cohorts were studied, melanoma and non-small cell lung cancer, and there was no effect of baseline AD on overall survival on either cohort. However, a greater proportion of patients with baseline ADs had full recovery from their irAE (P=0.037). Furthermore, age below 65, baseline steroid use, and single-agent immunotherapy regimens were protective in terms of the development of irAEs. Our study suggests that immune checkpoint inhibitors have similar safety and efficacy profiles in patients with preexisting ADs.

The Use of Cabozantinib in Advanced Hepatocellular Carcinoma in Hong Kong-A Territory-Wide Cohort Study.

(1) Background: Cabozantinib is approved in sorafenib-exposed advanced hepatocellular carcinoma (aHCC). We evaluated the real-life pattern of use, efficacy, and tolerability of cabozantinib in aHCC. (2) Methods: This territory-wide study included consecutive aHCC patients who received cabozantinib between February 2018 and September 2020 in Hong Kong. The objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AE) were assessed. (3) Results: Overall, 42 patients were included. Approximately 83.3% had Child-Pugh A cirrhosis. About 64.3% received cabozantinib as a single agent, and the remaining 35.7% received cabozantinib as an add-on to immune checkpoint inhibitors (ICIs). For single-agent patients, the median follow-up was 6.7 months. The ORR was 3.7%, DCR was 44.4%, and the median OS was 8.28 months. About 74.1% of patients experienced any AEs with 7.4% having grade ≥3 AEs. Among patients who received prior ICIs (n = 16), the ORR was 6.3%, and the median OS was 8.28 months. An exploratory analysis of patients who received cabozantinib as an add-on to ICIs showed an ORR of 6.7% and a median OS of 15.1 months, with 73.3% having any AE and 13.3% having grade ≥3 AEs. (4) Conclusions: Cabozantinib had good anti-tumor activity, survival benefits, and acceptable tolerability in real-life aHCC patients.

Assessment of Radiation-Induced Malfunction in Cardiac Implantable Electronic Devices.

BACKGROUND: Radiation therapy (RT) is a standard cancer treatment modality, and an increasing number of patients with cardiac implantable electronic devices (CIEDs) are being referred for RT. The goals of this study were as follows: (i) to determine the incidence of CIED malfunction following RT; (ii) to characterize the various types of malfunctions that occur; and (iii) to identify risk factors associated with CIED malfunction following RT. METHODS: A retrospective study of patients with CIEDs who received RT between 2007 and 2018 at 4 Canadian centres (Sunnybrook Health Sciences Centre, Kingston General Hospital, Hamilton Health Sciences Centre, and University of Ottawa Heart Institute) was conducted. Patients underwent CIED interrogation after completion of RT, to assess for late damage to the CIEDs. Data on demographics, devices, and RT were compared for the primary outcome of device malfunction. RESULTS: Of 1041 patients with CIEDs who received RT, 811 patients with complete data were included. Device malfunctions occurred in 32 of 811 patients (4%). The most common device malfunctions were reduced ventricular/atrial sensing (in 13 of 32 [41%]), an increase in lead threshold (in 9 of 32 [22%]), lead noise (in 5 of 32 [16%]), and electrical reset (in 2 of 32 [6%]). Higher beam energy (≥ 10 MV) was associated with malfunction (P < 0.0001). Radiation dose was not significantly different between the malfunction and non-malfunction groups (58.3 cGy vs 65 cGy, respectively, P = 0.71). CONCLUSIONS: Although RT-induced CIED malfunctions are rare (occurring in 4% of patients with a CIED who undergo RT), collaborative efforts between radiation oncologists and cardiac rhythm device clinics to optimize CIED monitoring are needed, to detect and manage CIED malfunctions. Malfunctions are more common in patients receiving higher-beam energy ( ≥ 10 MV ) RT.

CONTEXTE: La radiothérapie (RT) est une modalité standard de traitement du cancer, et un nombre croissant de patients porteurs de dispositifs cardiaques électroniques implantables (DCEI) doivent recevoir un traitement de RT. Les objectifs de cette étude étaient les suivants : (i) déterminer l'incidence d'une défaillance du DCEI après une RT; (ii) caractériser les différents types de défaillances qui se produisent; (iii) déterminer les facteurs de risque associés à la défaillance du DCEI après une RT. MÉTHODOLOGIE: Une étude rétrospective des patients avec un DCEI ayant reçu une RT entre 2007 et 2018 dans quatre centres canadiens (Sunnybrook Health Sciences Centre, Kingston General Hospital, Hamilton Health Sciences Centre et Institut de cardiologie de l'Université d'Ottawa) a été menée. Le DCEI des patients a été interrogé après la fin de la RT, pour en évaluer les dommages tardifs. Les données sur les caractéristiques démographiques, les dispositifs et la RT ont été comparées pour le paramètre d'évaluation principal, soit la défaillance du dispositif. RÉSULTATS: Sur les 1 041 patients avec un DCEI ayant reçu une RT, 811 patients avec des données complètes ont été inclus. Des défaillances du dispositif sont survenues chez 32 des 811 patients (4 %). Les défaillances les plus fréquentes du dispositif étaient une détection ventriculaire/atriale réduite (chez 13 des 32 patients [41 %]), une augmentation du seuil de la sonde (chez 9 des 32 patients [22 %]), un bruit provenant de la sonde (chez 5 des 32 patients [16 %]) et une réinitialisation électrique (chez 2 des 32 patients [6 %]). Une énergie de faisceau plus élevée (≥ 10 MV) était associée à une défaillance (p < 0,0001). La dose de rayonnement ne présentait pas de différence significative entre le groupe où une défaillance a été constatée et l'autre groupe (58,3 cGy vs 65 cGy, respectivement, p = 0,71). CONCLUSIONS: Bien que les défaillances du DCEI causées par la RT soient rares (survenant chez 4 % des patients avec un DCEI qui subissent une RT), une collaboration est nécessaire entre les radio-oncologues et les cliniques de dispositifs de gestion du rythme cardiaque, afin d'optimiser la surveillance du DCEI et de détecter et de gérer ces défaillances. Les défaillances sont plus fréquentes chez les patients recevant une énergie de faisceau plus élevée au moment de la RT ( ≥ 10 MV ) .

The Value of the Surface ECG for the Diagnosis and Management of Lyme Carditis: A Case Report.

Lyme carditis (LC) is an early-disseminated manifestation of Lyme disease, most commonly presenting as a high-degree atrioventricular block (AVB). The degree of AVB can fluctuate rapidly within minutes, and progression to third-degree AVB is potentially fatal if not recognized and managed promptly. However, the AVB in LC is often transient and usually resolves with appropriate antibiotic therapy. LC should be on the differential diagnosis in young patients presenting with new high-degree AVB and factors that increase the index of suspicion for Lyme disease. The Suspicious Index in Lyme Carditis (SILC) score helps clinicians risk-stratify for LC. A systematic approach to the diagnosis and treatment of LC minimizes the unnecessary implantation of permanent pacemakers.

Evaluation and Management of Asymptomatic Bradyarrhythmias.

Asymptomatic bradyarrhythmias involving sinus node dysfunction and atrioventicular blocks are frequently noted in clinical practice. Its prevalence is expected to rise as devices that are developed for monitoring cardiac rhythm for longer duration become more widely available. Episodes of bradyarrhythmia that are asymptomatic are considered to have a benign course compared with those that cause symptoms and do not necessitate further treatment. However, in certain cases, they can be a harbinger of future symptoms or cardiac manifestations of systemic diseases. The evaluation and risk stratification of individuals presenting with asymptomatic bradyarrhythmias is important not only for preventing implantation of unnecessary permanent pacing devices but also for reducing significant morbidity by implementing proper treatment as required. In this article, we will review the current evidence on the pathophysiology, diagnosis, evaluation and management of patients with asymptomatic bradyarrhythmias.

Chagas' cardiomyopathy and Lyme carditis: Lessons learned from two infectious diseases affecting the heart.

Chagas' disease and Lyme disease are two endemic, vector-borne zoonotic infectious diseases that impact multiple organ systems, including the heart. Chagas' cardiomyopathy is a progressive process that can evolve into a dilated cardiomyopathy and heart failure several decades after the acute infection; in contrast, although early-disseminated Lyme carditis has been relatively well characterized, the sequelae of Lyme disease on the heart are less well-defined. A century of research on Chagas' cardiomyopathy has generated compelling data for pathophysiological models, evaluated the efficacy of therapy in large randomized controlled trials, and explored the social determinants of health impacting preventative measures. Recognizing the commonalities between Chagas' disease and Lyme disease, we speculate on whether some of the lessons learned from Chagas' cardiomyopathy may be applicable to Lyme carditis.

Value of electrocardiography in coronavirus disease 2019 (COVID-19).

In December 2019, reports of an unknown pneumonia not responsive to traditional treatments arose in Wuhan, China. The pathogen was subsequently identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to be responsible for the coronavirus disease-2019 (COVID-19) illness, and public health emergency of international concern was declared by the World Health Organization. There is increasing awareness of the cardiovascular manifestations of COVID-19 disease, and the adverse impact of cardiovascular involvement on its prognosis. In this setting, the electrocardiogram (ECG) is one of the leading tools to assess the extent of cardiac involvement in COVID-19 patients, due to its wide disponibility, low cost, and the possibility of remote evaluation. In this article, we review the role of the ECG in the identification of cardiac involvement in COVID-19, highlighting relevant clinical implications.