Predicting the Abscopal Effect: Associated Tumor Histologic Subtypes and Biomarkers.

Radiotherapy is a pillar of cancer treatment, which has historically been used primarily to treat localized disease with curative intent. With the increasing role of radiotherapy for metastatic disease and rapid integration of immunotherapy into the standard of care for various cancers, it has been observed that local radiation to one malignant site can lead to shrinkage of tumors at other sites, a phenomenon termed the "abscopal effect." Historically, there was little mechanistic elucidation as to how this phenomenon occurs. However, multiple groups have recently identified associated immuno-prognostic factors, such as high post-radiotherapy absolute lymphocyte count, neoantigens, myeloid-derived suppressor cells, and NK cells. The concomitant use of immunotherapy with radiotherapy has been documented to induce the abscopal effect. As immunotherapies continue to be incorporated into most cancer treatment approaches, understanding which patients are more likely to benefit from an abscopal effect may allow for optimization of both systemic and radiotherapeutic strategies. This review highlights the tumor histologic subtypes and biomarkers of the greatest utility for the recognition and identification of patients likely to benefit from the abscopal effect.

Safety of catheter ablation for atrial fibrillation in patients with cancer: a nationwide cohort study.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in patients with cancer, especially breast, gastrointestinal, respiratory, urinary tract, and hematological malignancies. Catheter ablation (CA) is a well-established, safe treatment option in healthy patients; however, literature regarding safety of CA for AF in patients with cancer is limited and confined to single centers. OBJECTIVE: We aimed to assess the outcomes and peri-procedural safety of CA for AF in patients with certain types of cancer. METHODS: The NIS database was queried between 2016 and 2019 to identify primary hospitalizations with AF and CA. Hospitalizations with secondary diagnosis of atrial flutter and other arrhythmias were excluded. Propensity score matching was used to balance the covariates between cancer and non-cancer groups. Logistic regression was used to analyze the association. RESULTS: During this period, 47,765 CA procedures were identified, out of which 750 (1.6%) hospitalizations had a diagnosis of cancer. After propensity matching, hospitalizations with cancer diagnosis had higher in-hospital mortality (OR 3.0, 95% CI 1.5-6.2, p = 0.001), lower home discharge rates (OR 0.7, 95% CI 0.6-0.9, p < 0.001) as well as other complications such as major bleeding (OR 1.8, 95% CI 1.3-2.7, p = 0.001) and pulmonary embolism (OR 6.1, 95% CI 2.1-17.8, p < 0.001) but not associated with any major cardiac complications (OR 1.2, 95% CI 0.7-1.8, p = 0.53). CONCLUSION: Patients with cancer who underwent CA for AF had significantly higher odds of in-hospital mortality, major bleeding, and pulmonary embolism. Further larger prospective observational studies are needed to validate these findings.

Inpatient cardiovascular outcomes in patients with cancer affected by viral influenza infection.

BACKGROUND: Influenza disproportionately affects individuals with underlying comorbidities. Long-term follow-up studies have shown that patients with cancer with influenza have higher mortality. However, very little is known about the in-hospital mortality and cardiovascular outcomes of influenza infection in cancer hospitalisations. METHODS: We compared the in-hospital mortality and cardiovascular outcomes in patients with cancer with and without influenza by screening the National Inpatient Sample from 2015 to 2017. A total of 9 443 421 hospitalisations with any cancer were identified, out of which 14 634 had influenza while 9 252 007 did not. A two-level hierarchical multivariate logistic regression analysis adjusted for age, sex, race, hospital type and relevant comorbidities was performed. RESULTS: The group with cancer and influenza had higher in-hospital mortality (OR 1.08; 95% CI 1.003 to 1.16; p=0.04), acute coronary syndromes (OR 1.74; 95% CI 1.57 to 1.93; p<0.0001), atrial fibrillation (OR 1.24; 95% CI 1.18 to 1.29; p<0.0001) and acute heart failure (OR 1.41; 95% CI 1.32 to 1.51; p<0.0001). CONCLUSION: Patients with cancer affected by influenza have higher in-hospital mortality and a higher prevalence of acute coronary syndrome, atrial fibrillation and acute heart failure.

Incidence, Current Guidelines and Management of Gastrointestinal Bleeding after Transcatheter Aortic Valve Replacement: A Systematic Review.

BACKGROUND: There is a significant increase in morbidity and mortality in patients complicated by major bleeding following transcatheter aortic valve replacement (TAVR). It has become more challenging to manage such complications when the patient needs to be on anticoagulation or antiplatelet agent post-procedure to prevent thrombotic/embolic complications. METHODS: We systematically reviewed all available randomized controlled trials and observational studies to identify incidence rates of gastrointestinal bleeding post-procedure. After performing a systematic search, a total of 8731 patients from 15 studies (5 RCTs and 10 non-RCTs) were included in this review. RESULTS: The average rate of gastrointestinal bleeding during follow-up was 3.0% in randomized controlled trials and 1.9% among observational studies. CONCLUSION: Gastrointestinal bleeding has been noted to be higher in the RCTs as compared to observational studies. This review expands knowledge of current guidelines and possible management of patients undergoing TAVR.

Assessing the Educational Value of Pancreatic Cancer Videos on YouTube®.

Online resources such as YouTube® can serve as the go-to resource for patients and their caregivers after a life-changing diagnosis of pancreatic cancer. There is a need to analyze the content and educational value of these videos for patients with pancreatic cancer. The top 100 most viewed videos on pancreatic cancer on YouTube® were assessed and data were collected on various variables such as views, likes, dislikes, and comments. Videos categorized as patient educational videos were further analyzed for their content, source, and educational value. Videos uploaded by patients were the most discussed (p = 0.014) and liked (p = 0.0028) videos on YouTube®. The content of the videos (personal experience, advertisement, patient education, medical professional education, alternative treatments, and increased pancreatic cancer awareness) varied depending on the uploader (patients, healthcare providers, professional societies, media) of the videos (p = 0.0007). Patient education videos were poor in being comprehensive on their education of pancreatic cancer based on our rubric (mean score of 7.67 ± 2.63 of 20 possible points). The current study shows that the educational values of YouTube® videos related to pancreatic cancer remain limited. There is significant room for healthcare providers to use the platform to develop and share comprehensive videos that can be used as more effective sources of patient education.

Impact of Chronic Kidney Disease on In-Hospital Outcomes of Hospitalizations With Acute Limb Ischemia Undergoing Endovascular Therapy.

PURPOSE: Studies on outcomes related to endovascular treatment (EVT) in advanced stages of chronic kidney disease (CKD) and end-stage renal disease (ESRD) among hospitalizations with acute limb ischemia (ALI) are limited. METHODS: The Nationwide Inpatient Sample was quarried from October 2015 to December 2017 to identify the hospitalizations with ALI and undergoing EVT. The study population was subdivided into 3 groups based on their CKD stages: group 1 (No CKD, stage I, stage II), group 2 (CKD stage III, stage IV), and group 3 (CKD stage V and ESRD). The primary outcome was all-cause in-hospital mortality. RESULTS: A total of 51 995 hospitalizations with ALI undergoing EVT were identified. The in-hospital mortality was significantly higher in group 2 (OR = 1.17; 95% CI 1.04 - 1.32, p=0.009) and group 3 (OR = 3.18; 95% CI 2.74-3.69, p<0.0001) compared with group 1. Odds of minor amputation, vascular complication, atherectomy, and blood transfusion were higher among groups 2 and 3 compared with group 1. Group 2 had higher odds of access site hemorrhage compared with groups 1 and 3, whereas group 3 had higher odds of major amputation, postprocedural infection, and postoperative hemorrhage compared with groups 1 and 2. Besides, groups 2 and 3 had lower odds of discharge to home compared with group 1. Finally, the length of hospital stay and cost of care was significantly higher with the advancing CKD stages. CONCLUSION: Advanced CKD stages and ESRD are associated with higher mortality, worse in-hospital outcomes and higher resource utilization among ALI hospitalizations undergoing EVT. CLINICAL IMPACT: Current guidelines are not clear for the optimum first line treatment of acute limb ischemia, especially in patients with advanced kidney disease as compared to normal/mild kidney disease patients. We found that advanced kidney disease is a significant risk factor for worse in-hospital morbidity and mortality. Furthermore, patients with acute limb ischemia and advanced kidney disease is associated with significantly higher resource utilization as compared to patients with normal/mild kidney disease. This study suggests shared decision making between treating physician and patients when considering endovascular therapy for the treatment of acute limb ischemia in patients with advanced kidney disease.

Low left atrial appendage emptying velocity is a predictor of atrial fibrillation recurrence after catheter ablation.

BACKGROUND: Recurrence of atrial fibrillation (AF) after catheter ablation (CA) remains common and studies have shown about 5%-9% annual recurrence rate after CA. We sought to assess the echocardiogram derived left atrial appendage (LAA) emptying velocity as a predictor of AF recurrence after CA. OBJECTIVE: To determine if LAA emptying is a marker of recurrence of AF post-CA METHODS: A total of 303 consecutive patients who underwent CA for AF between 2014 and 2020 were included. Baseline clinical characteristics and echocardiographic data of the patients were obtained by chart review. LAA emptying velocities were obtained from transesophageal echocardiogram (TEE). LA voltage was obtained during the mapping for CA. Chi-square test and nominal logistic regression were used for statistical analysis. An receiver operator characteristic curve was used to determine LAA velocity cut-off. RESULTS: Mean patient age was 61.7 ± 10.5; 32% were female. Mean LAA emptying velocity was 47.5 ± 20.2. A total of 103 (40%) patients had recurrence after CA. In the multivariable model, after adjusting for potential confounders, LAA emptying velocity of ≥52.3 was associated with decreased AF recurrence postablation (odds ratio [OR]: 0.55; 95% confidence interval  [CI]: 0.31-0.97; p = .03*). There were 190 (73%) patients in normal sinus rhythm during TEE and CA, and sensitivity analysis of these patients showed that LAA velocity ≥52.3 remained associated with decreased AF recurrence (OR: 0.35; 95% CI: 0.15-0.82; p = .01*). CONCLUSION: LAA emptying velocity measured during preprocedural TEE can serve as a predictor of AF recurrence in patients undergoing CA.

Can glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors help in mitigating the risk of atrial fibrillation in patients with diabetes?

The role of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) in mitigating the risk of atrial fibrillation (AF) remains unknown. We interrogated the Food and Drug Administration's Adverse Event Reporting System (FAERS) database to study the association between AF-related adverse events and the use of GLP-1 RA and DPP-4i. A signal of disproportionate reporting of AF was detected with the DPP-4i group compared with all the other drugs in the FAERS database [ROR, 2.56; 95% confidence interval (CI), 2.10-3.12], whereas there was no disproportionality signal detected with the GLP-1 RA group (ROR, 0.90; 95% CI, 0.78-1.03) although liraglutide showed a significant disproportionality signal (ROR, 2.51; 95% CI, 2.00-3.15). Our analysis supports the existing body of literature demonstrating the cardiac safety of GLP-1 RA but raises concerns about the apparent increase in the risk of AF associated with DPP-4i. Further clinical and translational studies are needed to validate these findings.

Anti-cancer Drugs Associated Atrial Fibrillation-An Analysis of Real-World Pharmacovigilance Data.

Background: Several anti-cancer drugs have been linked to new onset atrial fibrillation (AF) but the true association of these drugs with AF is unknown. The FDA Adverse Event Reporting System (FAERS), a publicly available pharmacovigilance mechanism provided by the FDA, collects adverse event reports from the United States and other countries, thus providing real-world data. Objectives: To identify anti-cancer drugs associated with AF using the FAERS database. Methods: The FAERS database was searched for all drugs reporting AF as an adverse event (AE). The top 30 anti-cancer drugs reporting AF cases were shortlisted and analyzed. Proportional reporting ratio (PRR) was used to measure disproportionality in reporting of adverse events for these drugs. Results: When analyzed for AF as a percentage of all reported AE for a particular drug, Ibrutinib had the highest percentage (5.3%) followed distantly by venetoclax (1.6%), bortezomib (1.6%), carfilzomib (1.5%), and nilotinib (1.4%). The percentage of cardiac AE attributable to AF was also highest for ibrutinib (41.5%), followed by venetoclax (28.4%), pomalidomide (23.9%), bortezomib (18.2%), and lenalidomide (18.2%). Drugs with the highest PRR for AF included ibrutinib (5.96, 95% CI= 5.70-6.23), bortezomib (1.65, 95% CI = 1.52-1.79), venetoclax (1.65, 95% CI = 1.46-1.85), carfilzomib (1.53, 95% CI = 1.33-1.77), and nilotinib (1.46, 95% CI = 1.31-1.63). Conclusions: While newer anti-cancer drugs have improved the prognosis in cancer patients, it is important to identify any arrhythmias they may cause early on to prevent increased morbidity and mortality. Prospective studies are needed to better understand the true incidence of new onset AF associated with anti-cancer drugs.

National trends in hospitalizations among patients with colorectal cancer in the United States.

Colorectal cancer is the second leading cause of cancer-related death in the United States, with a rising incidence, especially in young adults. Care for patients with colorectal cancer is associated with significant healthcare costs and expenditures. We retrospectively interrogated the National Inpatient Sample for admissions in patients with colorectal cancer from 2007 to 2017. A total of 1,962,705 admissions were identified: 50.2% were men, 64.4% were white, and the median age was 68. Most admissions (47.8%) that were coded for anatomical location of malignancy were for ascending colon cancer. The average in-hospital mortality was 4.9%, with a lower mortality in admissions with ascending colon cancer (2.9, P < 0.001). The median length of stay was 5 days, with a longer stay in admissions with transverse colon cancer (9 days, P < 0.0001). The median cost of hospitalization was $12,295 and was significantly higher for patients with descending colon malignancy ($16,369, P < 0.0001). The number of annual hospitalizations stayed steady overall but increased by 98.6% for rectosigmoid cancer. Our findings highlight the high costs of hospitalization and the overall economic burden associated with inpatient admissions among patients with colorectal cancer.

p16 Represses DNA Damage Repair via a Novel Ubiquitin-Dependent Signaling Cascade.

Squamous cell carcinoma driven by human papillomavirus (HPV) is more sensitive to DNA-damaging therapies than its HPV-negative counterpart. Here, we show that p16, the clinically used surrogate for HPV positivity, renders cells more sensitive to radiotherapy via a ubiquitin-dependent signaling pathway, linking high levels of this protein to increased activity of the transcription factor SP1, increased HUWE1 transcription, and degradation of ubiquitin-specific protease 7 (USP7) and TRIP12. Activation of this pathway in HPV-positive disease led to decreased homologous recombination and improved response to radiotherapy, a phenomenon that can be recapitulated in HPV-negative disease using USP7 inhibitors in clinical development. This p16-driven axis induced sensitivity to PARP inhibition and potentially leads to "BRCAness" in head and neck squamous cell carcinoma (HNSCC) cells. Thus, these findings support a functional role for p16 in HPV-positive tumors in driving response to DNA damage, which can be exploited to improve outcomes in both patients with HPV-positive and HPV-negative HNSCC. SIGNIFICANCE: In HPV-positive tumors, a previously undiscovered pathway directly links p16 to DNA damage repair and sensitivity to radiotherapy via a clinically relevant and pharmacologically targetable ubiquitin-mediated degradation pathway.

Inpatient cardiovascular outcomes in patients with cancer affected by viral influenza infection.

BACKGROUND: Influenza disproportionately affects individuals with underlying comorbidities. Long-term follow-up studies have shown that patients with cancer with influenza have higher mortality. However, very little is known about the in-hospital mortality and cardiovascular outcomes of influenza infection in cancer hospitalisations. METHODS: We compared the in-hospital mortality and cardiovascular outcomes in patients with cancer with and without influenza by screening the National Inpatient Sample from 2015 to 2017. A total of 9 443 421 hospitalisations with any cancer were identified, out of which 14 634 had influenza while 9 252 007 did not. A two-level hierarchical multivariate logistic regression analysis adjusted for age, sex, race, hospital type and relevant comorbidities was performed. RESULTS: The group with cancer and influenza had higher in-hospital mortality (OR 1.08; 95% CI 1.003 to 1.16; p=0.04), acute coronary syndromes (OR 1.74; 95% CI 1.57 to 1.93; p<0.0001), atrial fibrillation (OR 1.24; 95% CI 1.18 to 1.29; p<0.0001) and acute heart failure (OR 1.41; 95% CI 1.32 to 1.51; p<0.0001). CONCLUSION: Patients with cancer affected by influenza have higher in-hospital mortality and a higher prevalence of acute coronary syndrome, atrial fibrillation and acute heart failure.

Adverse events related to AtriCure EPi-Sense Coagulation Device-Analysis of the FDA MAUDE database.

INTRODUCTION: The AtriCure EPi-Sense Device is used for the hybrid convergent procedure, an emerging treatment for persistent atrial fibrillation (AF) and long-standing persistent AF. However, data on the AE related to the EPi-Sense device are scarce. METHODS: Keyword "EPI-SENSE" was searched on the MAUDE database. There were 80 device reports from 2016 to 2020. After excluding reports when the device was not returned for evaluation, 79 device reports were included for final analysis. RESULTS: The adverse events (AE) were broadly classified into 11 categories. The most common complications were pericardial effusion (25.3%), stroke (17.7%), and atrioesophageal fistula (AEF) (8.9%). Death was reported in 15 (19%) cases, 3 of which were due to pulmonary embolism, 6 due to AEF, 3 due to unknown cause, 1 due to sepsis, 2 due to events related to acute renal failure. DISCUSSION: Pericardial effusion is a common AE reported in patients with convergence procedures and is well documented in the CONVERGE trial. The convergent procedure is unique in that the epicardial ablations are performed on the posterior wall with the radiofrequency probe directed towards the heart and away from the esophagus which in theory should reduce esophageal injuries. Despite that, a high number of AEF were noticed. Finally, there were also some reports of saline perfusion malfunction which can lead to injuries due to overheating. CONCLUSION: This analysis of the AE related to the EPi-Sense device highlights several major AE that are previously unreported.

Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function.

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.

Cardiovascular complications associated with novel agents in the chronic lymphocytic leukemia armamentarium: A pharmacovigilance analysis.

INTRODUCTION: Over the last few years, improved outcomes in patients with chronic lymphocytic leukemia (CLL) have been credited to the introduction of novel agents for its treatment. However, the overall cardiovascular safety profile of these agents has not been studied adequately. METHODS: We searched the Food and Drug Administration Adverse Event Reporting System (FAERS) database for adverse events reported for several of these novel agents: ibrutinib, acalabrutinib, venetoclax, and idelalisib. RESULTS: A total of 6074 cardiac adverse events were identified; ibrutinib (4832/36581; 13.2%) was found to have the highest risk of cardiac adverse events. The frequency of atrial fibrillation was highest (41.5%) in the ibrutinib group, while the idelalisib and acalabrutinib groups had the highest reported frequencies of heart failure (25.1%) and myocardial infarction (13.6%), respectively. Hypertension was noted to be relatively higher in the acalabrutinib (25.6%) and venetoclax (11.8%) groups. Overall reported mortality associated with cardiac events was highest in the venetoclax (29.4%) and idelalisib (27.1%) groups. CONCLUSION: Novel agents in the CLL armamentarium have been associated with several cardiovascular adverse events. Further studies are needed to identify high-risk groups that would benefit from robust cardiovascular surveillance after initiation of treatment with these novel agents.