Dysfunction In Cancer Patients Research Articles

#2078 Study of spectrum of renal dysfunction in cancer patients on ICPI as mono or combination with conventional chemo in north India

Abstract Background and Aims Although use of ICPI's have revolutionized the treatment of cancer patient with significantly improving the longevity of these patients but it also is associated with various adverse reactions known as iRAE's related to its use, which in due course is being revealed gradually. Kidney related iRAE's are important and also limitation to therapy, which could be a detrimental factor for these patients availing the beneficial effects of these revolutionary medications. Previous literature on these therapeutics had the limitations of being retrospective, small case series and case reports and evaluating only one or two parameters of kidney dysfunction, also the criteria used for evaluations had the limitation of standardization. With this we aimed to study the spectrum of renal dysfunction in cancer patients, receiving ICPI with or without conventional chemotherapy using standard criteria. Method Study involved patients with malignancy who had received at least 1 dose of ICPI as mono or combination with conventional chemotherapy. The primary end-point was 6 month assess the clinical spectrum & outcome of renal dysfunction, and the secondary end-points were the patient-level risk factors for renal dysfunction, the impact of renal dysfunction on clinical outcomes. Results Conducted through October 2021-2022, enrolled N = 156 (66 male & 90 females) & followed up for 6 months. 109 (69.9%) subjects developed KDIGO–AKI—Stage I (51.4%) & Stage II (35.8%) & non required RRT. The median duration for onset of AKI was 131 days. Proteinuria was observed in n = 143 (91.67%). n = 116 (74.3%) developed new-onset proteinuria. n = 40 (25.6%) were proteinuric at the start of the study & 27/40 (67.5%) were observed to have >50% increase in proteinuria, qualifying for proteinuria with therapy. 92/143 proteinuric subjects (64.3%) developed >1 g/day proteinuria. On subcategorizing proteinuria it was observed that 82/92 (57.3%) had 1–3 g/day proteinuria and ≥3.0 g/day proteinuria was observed in 10/92 (7.0%). Definitive ICPI–AKI could be attributed to only 2 subjects, as they underwent kidney biopsy for their kidney dysfunction and significant proteinuria. Secondary amyloid deposits in the glomeruli and mesangium was found in 1 subject & the other subject showed acute tubulointerstitial deposits with granular cast. Proteinuria and kidney dysfunction resolved with stoppage of the ICPI and steroids administration, which was consistent with the limited literature available for the management of ICPI related amyloidosis & iRAE. n = 88 had partial recovery of kidney dysfunction following an AKI event & complete recovery was seen in n = 3 (2.7%). >50% recovery in eGFR was observed in n = 41 (37.6%). Electrolyte abnormality commonly observed were hyponatremia, hypokalemia & hypomagnesemia & was seen in distributed almost equally, followed by hypocalcemia. Hypernatremia, hyperkalemia, hypermagnesemia & hypercalcemia were less commonly reported. Lastly mortality was also observed in n = 16 (10.2%), but could not be directly attributed to ICPI use, kidney dysfunction, malignancy type, comorbid conditions & other concomitants medication use. Conclusion To conclude this present prospective cohort study is a comprehensive assessment of the spectrum of renal dysfunction in cancer patients, among recipients of ICPI with or without conventional chemotherapy using standard criteria to the best of our knowledge, which has been the limitation of previous literature. We have shown a vast spectrum of kidney dysfunction possibly attributed to the ICPI's in malignancy patients. Viewed in respect to better QoL with ICPI therapy in malignancy patients, kidney related iRAE's could limit the patients from their beneficial effects. A possible persistent immune injury might have led to partial recovery of kidney dysfunction in majority. An unusual finding of secondary amyloid deposits with pembrolizumab, which possible might have occurred due to persistence of high levels of inflammatory markers due to these drugs. Thus underscoring the need for a close follow-up and recommend kidney biopsy to better & definitively identify the glomerular pathology & treatment accordingly.

ROLE OF CARDIOVASCULAR IMAGING IN CARDIO-ONCOLOGY: A LITERATURE REVIEW

Antitumor drugs are toxic to the cardiovascular system and directly affect cardiac function and anatomy. During the treatment of oncology, patients may experience complications in the form of asymptomatic myocardial dysfunction, severe heart failure, exacerbation of symptoms of coronary heart disease, thromboembolic complications, arterial and pulmonary hypertension, pericardial complications, valve defects and arrhythmias. A number of diagnostic tools are currently available to cardio-oncologists to detect cardiotoxicity, and the choice of imaging method depends on the availability of the specific diagnostic modality and its resolution. The main method for assessing the condition of the heart in cancer patients is echocardiography - a widely available method that enables to assess the structure of the heart and hemodynamics without exposing the patient to an additional dose of ionizing radiation. If imaging is insufficient, the recommended method for assessing cardiac structure and function is magnetic resonance imaging. Computed tomography of the chest, heart and coronary arteries is also used to diagnose complications of cancer treatment. In addition, nuclear medicine techniques, including gated radionuclide ventriculography, are also used to diagnose cardiotoxicity. Electroanatomical mapping systems combined with remote navigation are promising. Early detection of subclinical left ventricular myocardial dysfunction in cancer patients receiving potentially cardiotoxic drugs is advisable and aimed at secondary prophylaxis and prevention of mortality from cardiovascular diseases.

Incidence of chemotherapy-related cardiac dysfunction in cancer patients.

Cancer patients are increasingly affected by chemotherapy-related cardiac dysfunction. The reported incidence of this condition vary significantly across different studies. A better comprehensive understanding of chemotherapy-related cardiac dysfunction incidence in cancer patients is imperative. Therefore, we performed a meta-analysis to establish the overall incidence of chemotherapy-related cardiac dysfunction in cancer patients. We searched articles in PubMed and EMBASE from database inception to May 1, 2023. Studies that reported the incidence of chemotherapy-related cardiac dysfunction in cancer patients were included. A total of 53 studies involving 35 651 individuals were finally included in the meta-analysis. The overall pooled incidence of chemotherapy-related cardiac dysfunction in cancer patients was 63.21 per 1000 person-years (95% CI: 57.28-69.14). The chemotherapy-related cardiac dysfunction incidence increased steeply within half a year of cancer chemotherapy. Also, the trend of chemotherapy-related cardiac dysfunction incidence appeared to have plateaued after a longer duration of follow-up. In addition, chemotherapy-related cardiac dysfunction incidence rates are significantly higher among patients with age ≥50 years versus patients with age <50 years (99.96 vs. 34.48 per 1000 person-years). The incidence rate of cardiac dysfunction was higher among breast cancer patients (72.97 per 1000 person-years), leukemia patients (65.21 per 1000 person-years), and lymphoma patients (55.43 per 1000 person-years). Our meta-analysis unveiled a definitive overall incidence rate of chemotherapy-related cardiac dysfunction in cancer patients. In addition, it was found that the risk of developing this condition escalates within the initial 6 months postchemotherapy, subsequently tapering off to become statistically insignificant after a duration of 6 years.

Abstract 684: DT-9045, a novel PAR2 inhibitor with best-in-class properties that reduces resistance to both EGFR-targeting therapies and immunotherapy in oncology models

Abstract Protease-activated receptor 2 (PAR2) is a promising therapeutic target in oncology and immuno-oncology. It is upregulated and associated with poor prognosis in several cancer types. A pan-cancer meta-analysis showed that PAR2 is one of the genes most significantly associated with resistance to immune checkpoint blockade (ICB) and T cells dysfunction in cancer patients. Mechanistically, being expressed by various cells of the tumor microenvironment, PAR2 promotes both survival and proliferation of cancer cells and dampens the anti-cancer immune response. Domain Therapeutics has developed a novel PAR2 inhibitor, DT-9045, with best-in-class properties. Indeed, compared to its most advanced competitors, DT-9045 is a small molecule, orally bioavailable, insurmountable, biased, and active in tumor-like conditions (i.e. acidic pH and high level of activating proteases). This compound is also highly potent and selective on PAR2. Pharmacokinetic properties are suitable with a once-a-day oral administration. In vitro, DT-9045 completely prevented PAR2-mediated resistance to EGFR-targeting drugs. In vivo, its combination with anti-PD1 therapy showed a significant increase in efficacy over monotherapies in preclinical syngeneic mouse cancer models. This result was similar to the one observed in PAR2 knockout mice, indicating that oral administration of DT-9045 induces a complete inhibition of the receptor. We have further demonstrated that treatment with a PAR2 inhibitor enhances dendritic cell-mediated T cell activation and intratumoral infiltration of CD4+ and CD8+ T cells as well as a decrease in M2 macrophage infiltration. In conclusion, Domain Therapeutic has identified a novel PAR2 inhibitor, DT-9045, with clear competitive advantages. This preclinical candidate has shown strong potency in alleviating the resistance to both EGFR-targeting therapies and immunotherapy in preclinical cancer models. IND-enabling studies are currently ongoing to bring this new hope for cancer patients to the clinic. Citation Format: Thibaut Brugat, Maleck Kadiri, Samya Aouad, Anne-Laure Blayo, Baptiste Rugeri, Antoine Mousson, Aurélie Janvier, Edith Steinberg, Luc Baron, Mandy Recolet, Xavier Wirth, Maria Jesus Garcia-Leon, Quentin Ruet, Meriem Semache, Laurent Sabbagh, Orphée Blanchard, Christel Franchet, Stanislas Mayer, John Stagg, Nathalie Lenne, Stephan Schann. DT-9045, a novel PAR2 inhibitor with best-in-class properties that reduces resistance to both EGFR-targeting therapies and immunotherapy in oncology models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 684.

Cardioprotection of cancer patients receiving cardiotoxic chemotherapy — current status

Certain drugs used for the treatment of cancer can have a toxic effect on various organs and tissues, including the heart. Not only high-dose monotherapy can lead to damage to the heart muscle, but also a combination of two or three chemotherapy drugs can do so. Cancer patients receiving combination of potentially cardiotoxic anticancer therapy have an increased risk of cardiovascular complications. Heart rhythm disturbances, arterial and venous thrombosis, coronary heart disease, valvular lesions, arterial hypertension and, in particular, chronic heart failure may be induced by chemotherapy. An important aspect is to identify groups of individuals with an initially high or very high risk of cardiotoxicity. Such patients should be under the supervision of a cardiologist or a multidisciplinary team for the entire duration of antitumor therapy and undergo additional examinations. Without the necessary laboratory and instrumental monitoring, it is impossible to predict in advance the development of heart failure, which often complicates life-saving chemotherapy, and in some cases even causes its cancellation. It is turned out that cardioprotection aimed at preventing myocardial dysfunction in cancer patients can prevent the development of heart failure and not to interrupt patients’ life-saving treatment even at a late stage of the disease. In the case of verified chronic heart failure, which occurred before the chemotherapy or during antitumor treatment, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers are used, drugs with a proven cardioprotective potential. Data is gradually accumulating on the significant effect of other groups of drugs used on the regression of chronic heart failure in cancer patients. The purpose of this review is to briefly outline the mechanisms of cardiotoxicity in various chemotherapy regimens, as well as current and future options for cardioprotection in cancer patients receiving cardiotoxic chemotherapy.

Acute heart failure following pazopanib treatment: a literature review featuring two case reports.

Tyrosine kinase inhibitors (TKIs) have transformed cancer treatment but are associated with cardiovascular toxicity, including heart failure. This review examines the cardiotoxicity of pazopanib, a VEGFR-TKI, through two case reports and explores potential mechanisms. The importance of vigilant clinical monitoring to prevent cardiac dysfunction in cancer patients receiving pazopanib is emphasized. We present two cases of acute heart failure following pazopanib treatment. Case 1 involves a comorbidity-free, 62-year-old woman with metastatic renal cell carcinoma who experienced irreversible heart failure. In case 2, a 40-year-old woman with a history of anthracycline-containing chemotherapy developed reversible left ventricular systolic dysfunction following pazopanib discontinuation. Both patients received appropriate management for their heart failure symptoms. Case 1's condition rapidly deteriorated, leading to her unfortunate demise 3 months after starting pazopanib. In contrast, case 2's cardiac function improved after discontinuing pazopanib. The advent of TKIs has revolutionized cancer treatment, but their association with cardiovascular toxicity necessitates meticulous monitoring of patients. The cases presented here highlight the importance of recognizing and managing cardiotoxicity, particularly in patients without prior cardiovascular risk factors. Understanding the underlying mechanisms and risk factors for TKI-induced heart failure is crucial to optimize patient care and treatment outcomes. Oncologists should be vigilant in identifying clinical symptoms and closely monitoring cardiac function throughout TKI therapy.

An Assessment of Cardiac Dysfunction in Cancer Patient Receiving Chemotherapy: A Hospital-Based Non-Invasive Study

Objectives: To assess cardiac dysfunction in cancer patients receiving anthracycline based chemotherapy and to detect cardiac dysfunction in the initial stage. Materials and Methods: An open labelled prospective single site study of assessment of cardiac dysfunction in patient receiving chemotherapy. Results: Post chemotherapy, more number of patients had evidence of cardiac dysfunction on the basis of history and physical examination but statistically significant association was found only in fatigability, pallor, oedema and rales. Among the users or Doxorubicin and Epirubucin based chemotherapy, cardiac dysfunction was observed in 19.56% (n = 9) and 4.3% (n = 2) respectively. Among those on Doxorubicin, in the cumulative dose range of 510-600 mg, two patients (20%) had clinical cardiac dysfunction and one patient (10%) had subclinical cardiac dysfunction. Conclusion: Cardiac dysfunction is one of the dreaded complications of chemotherapy agent anthracycline. It adds to the co morbidity of cancer. Small increase in the risk of common and serious adverse health events, such as cardiac disease, has important public health implications. Effective steps have taken at proper time; can prevent the onset or exacerbation of these complications.

SAT453 Endocrine Related Adverse Events Of Immune Checkpoint Inhibitors In Cancer Patients Visiting Tertiary Care Center In Saudi Arabia

Abstract Disclosure: A.M. Alqahtani: None. A.S. Alghassab: None. L.A. Alghamdi: None. M. Almalki: None. Introduction: Immune checkpoint inhibitors (ICIs) have been approved for the treatment of a different types of cancers. Those agents may result in exaggerated immune response leading to numerous toxicities referred to as immune-related adverse events particularly endocrinopathies affecting most commonly the thyroid and pituitary glands. Methods: We carried out a retrospective analysis of endocrine dysfunction in cancer patients receiving immune checkpoint inhibitors therapy namely pembrolizumab, nivolumab and ipilimumab between July 2018 and July 2022. A total of 123 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as the clinical perspective of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Results: A total of 123 patients were included in our study. Among them, Female participants were 67 (54.5%) and males were 56 (45.5%) with mean age of 53.7 years. Majority of the included patients (91.1%) received single agent and only 8.9% received combination therapy. The most used ICI in our cohort was pembrolizumab 73.9% followed by nivolumab 17.8% and the combination of either one of them (beside ipilimumab) was used in 8.9% of the time. The most frequent indication for ICIs was breast cancer (27.6%) followed by lung cancer (19.5%) and metastatic renal cell carcinoma (8.9%). The average number of cycles was 12 cycles, and the average duration of treatment was 12 months. The total incidence of all endocrinopathies was 22.7%. Out of 123 patients, 24 patients developed thyroid dysfunction in term of thyroiditis (1), subclinical hypothyroidism (7) or overt hypothyroidism (16). Hypophysitis occurred in one patient only. There was no occurrence of new onset diabetes mellitus in all groups. Pembrolizumab is thought to be the culprit in 18 patients of thyroid dysfunction and the patient who developed hypophysitis. Nivolumab was responsible about 4 cases of thyroid dysfunction. The rest of the cases were attributed to the combination therapy. The mean TSH level at the time of hypothyroidism diagnosis (overt hypothyroidism and subclinical hypothyroidism) was 95.8 mIU/L. And the mean free thyroxine level in overt hypothyroidism group was 6.3 pmol/L. Conclusion: Our cohort demonstrated an increased risk of thyroid dysfunction among cancer patients who receive immune checkpoint inhibitors. Pituitary dysfunction is infrequent adverse effect of these agents. Endocrine assessment is recommended prior to initiation of therapy and periodically afterward. Special attention should be given to pituitary dysfunction as it might be overlooked due to non-specific symptoms. Presentation: Saturday, June 17, 2023

Prognostic value of coronary atherosclerosis and CAC score for the risk of chemotherapy-related cardiac dysfunction (CTRCD): The protocol of ANTEC study.

Cardiological complications of oncological treatment, including the most serious one, heart failure, constitute a significant and still unsolved clinical problem. A history of dyslipidemia and complications of atherosclerosis, including coronary artery disease, are established risk factors for cardiotoxicity in cancer patients. In recent years, a protective effect of statin treatment on the development of heart failure in cancer patients has been observed. This protocol describes a study aiming to assess the prognostic value of coronary atherosclerosis burden and the CAC score on the onset of cardiac dysfunction associated with cancer therapy. ANTEC (Atherosclerosis iN chemoTherapy-rElated Cardiotoxicity) is a single-site, prospective, observational study to evaluate the influence of the coronary atherosclerosis and CAC score assessed by computed tomography on the development of left ventricular systolic dysfunction in cancer patients with at least moderate cardiotoxicity risk. A group of 80 patients diagnosed with cancer prior to high-dose anthracycline chemotherapy (doxorubicin ≥ 240 mg / m2 body weight or epirubicin ≥ 600 mg / m2 body weight), without a history of heart failure and coronary artery disease, will be included in the study. Patient follow-up is planned for 12 months. In all patients, coronary computed tomographic angiography (CCTA) will be performed once at the beginning of the study. The primary endpoint is the onset of cancer therapy-related cardiovascular toxicity, defined as mild, moderate, severe and very severe according to ESC 2022 Cardio-oncology guidelines. During follow up, echocardiography with GLS assessment will be performed every three months. Additionally, new biomarkers of atherosclerosis (IL-6, MPO, TNF-alpha) will be measured every 6 months. The study registration identifier on clinicaltrials.gov is NCT05118178. This study is listed on cinicaltrials.gov with identifier NCT05118178.

Spectrum of Renal Involvement in Cancer Patients: A Cross-sectional Descriptive Study

Introduction: Cancer is associated with multiple renal manifestations like Acute Kidney Injury (AKI), Chronic Kidney Disease (CKD), proteinuria, and electrolyte imbalance. The reason behind renal dysfunction in cancer patients is multifactorial and can be attributed to underlying cancer and treatment modalities, in addition to co-morbidities surgical procedures and infections. Aim: To assess the spectrum of renal involvement in cancer patients presenting at a tertiary care hospital. Materials and Methods: The cross-sectional descriptive study, was conducted in the Department of Medicine of University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India. One hundred consecutive patients referred for nephrology consultation with diagnosed cancer, irrespective of cancer aetiology between the age group of 15-70 years with deranged kidney function test were recruited. Detailed medical and treatment history, including the type of cancer-solid or haematological, cancer status-cured or continuing, treatment given-chemotherapy, radiotherapy or surgery or a combination and associated co-morbidities like diabetes mellitus and hypertension were recorded. Routine investigations and special investigations, including assessment of estimated Glomerular Filtration Rate (eGFR) and estimation of Albumin-Creatinine Ration (ACR) was done. Patients were then segregated, based on their kidney function test into groups with AKI or CKD and underlying cause was valuated. Summary statistics was presented as mean, median or frequency and data analysed using Statistical Package of Social Sciences (SPSS) version 24.0. Results: The mean age of the study population was 53.73±12.20 years with 63% male and 37% female participants; 87% patients had solid cancers, while 13% had haematological cancers. The median duration, since the diagnosis was seven months and the patients were undergoing chemotherapy, radiotherapy or a combination of both; seven patients had surgery for underlying malignancy and an additional six had received chemotherapy or radiation therapy along with surgery. At the time of recruitment, 78% patients had AKI and 22% patients were diagnosed with CKD. Chemotherapy-induced nephropathy was the most common cause of AKI (n=46). In the CKD group diabetes (n=7) was the most common aetiology. Conclusion: The kidneys in cancer patients can be involved in a number of ways, as a consequence of the cancer itself, its treatment, superimposed infections or associated comorbidities. Chemotherapy-induced nephropathy is the most common cause of AKI, whereas, diabetes is the most common cause of CKD in cancer patients.

Cisplatin attenuates taste cell homeostasis and induces inflammatory activation in the circumvallate papilla.

Rationale: Gustation is important to several biological functions in mammals. However, chemotherapy drugs often harm taste perception in cancer patients, while the underlying mechanism is still unclear for most drugs and there is no effective way to restore taste function. This study investigated the effects of cisplatin on the taste cell homeostasis and gustatory function. Methods: We used both mice and taste organoid models to study the effect of cisplatin on taste buds. Gustometer assay, gustatory nerve recording, RNA-Sequencing, quantitative PCR, and immunohistochemistry was performed to analyze the cisplatin-induced alteration in taste behavior and function, transcriptome, apoptosis, cell proliferation and taste cell generation. Results: Cisplatin inhibited proliferation and promoted apoptosis in the circumvallate papilla, leading to significant impairment in taste function and receptor cell generation. The transcriptional profile of genes associated with cell cycle, metabolic process and inflammatory response was significantly altered after cisplatin treatment. Cisplatin inhibited growth, promoted apoptosis, and deferred taste receptor cell differentiation in taste organoids. LY411575, a γ-secretase inhibitor, reduced the number of apoptotic cells and increased the number of proliferative cells and taste receptor cells, potentially suggesting as a taste tissue protective agent against chemotherapy. LY411575 treatment could offset the increased number of Pax1+ or Pycr1+ cells induced by cisplatin in the circumvallate papilla and taste organoids. Conclusion: This study highlights the inhibitory effects of cisplatin on taste cell homeostasis and function, identifies critical genes and biological processes regulated by chemotherapy, and proposes potential therapeutic targets and strategy for taste dysfunction in cancer patients.

Opioid-Induced Sexual Dysfunction in Cancer Patients.

Simple SummarySexual disorders affect up to 80% of cancer patients, depending on the type of cancer, yet they are commonly overlooked and untreated. Opioid-induced sexual dysfunction (OISD) is reported in half of opioid users. The pathophysiology of OISD—still a subject for research—may include disorders of both the endocrine and nervous systems, expressed in, among other things, erectile dysfunction and declined sexual desire, sexual arousal, orgasm, and general satisfaction with one’s sex life. The etiology of sexual dysfunction in cancer patients is usually multifactorial, so the management should be multifaceted and individualized by targeting pathophysiological factors. The treatment options for OISD are few and include testosterone replacement therapy, bupropion, opioid antagonists, phosphodiesterase type 5 inhibitors, plant-derived substances, and non-pharmacological treatments, although the evidence is insufficient. One of the treatment options may also be a choice of an opioid that is less likely to cause sexual dysfunction, yet further research is necessary.Sexual dysfunction is common in patients with advanced cancer, although it is frequently belittled, and thus consistently underdiagnosed and untreated. Opioid analgesics remain fundamental and are widely used in cancer pain treatment. However, they affect sexual functions primarily due to their action on the hypothalamus–pituitary–gonadal axis. Other mechanisms such as the impact on the central and peripheral nervous systems are also possible. The opioid-induced sexual dysfunction includes erectile dysfunction, lack of desire and arousal, orgasmic disorder, and lowered overall sexual satisfaction. Around half of the individuals taking opioids chronically may be affected by sexual dysfunction. The relative risk of sexual dysfunction in patients on chronic opioid therapy and opioid addicts increased two-fold in a large meta-analysis. Opioids differ in their potential to induce sexual dysfunctions. Partial agonists and short-acting opioids may likely cause sexual dysfunction to a lesser extent. Few pharmaceutical therapies proved effective: testosterone replacement therapy, PDE5 inhibitors, bupropion, trazodone, opioid antagonists, and plant-derived medicines such as Rosa damascena and ginseng. Non-pharmacological options, such as psychosexual or physical therapies, should also be considered. However, the evidence is scarce and projected primarily from non-cancer populations, including opioid addicts. Further research is necessary to explore the problem of sexuality in cancer patients and the role of opioids in inducing sexual dysfunction.

Neuromuscular junction dysfunctions due to immune checkpoint inhibitors therapy: An analysis of FAERS data in the past 15 years.

IntroductionThe adverse effects of neuromuscular junction dysfunctions caused by immune checkpoint inhibitor (ICI) drugs have not been thoroughly assessed in the clinics.ObjectiveTo assess the neuromuscular junction dysfunctions in cancer patients with adverse events caused by ICI therapy by searching the Food and Drug Administration Adverse Event Reporting System (FAERS) database.MethodsThe FAERS data from January 2004 to December 2020 were collected to analyze the association between neuromuscular connection dysfunction and ICI use. Disproportionate analysis and Bayesian analysis were used to quantify the association between the neuromuscular junction dysfunctions and ICIs. The onset time and outcome of neuromuscular junction dysfunctions in different ICI regimens were also compared.ResultsOut of 88,617 adverse event reports, 557 neuromuscular junction dysfunction reports (0.63%) were analyzed. Marketed ICI drugs, including ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab, avelumab, as well as their combinations, showed positive associations with four detection methods. Most of the adverse event reports were associated with the use of nivolumab (53.32%) and pembrolizumab (31.96%). However, nivolumab-related neuromuscular junction dysfunctions were similar with pembrolizumab (33.33% vs 33.14%, p > 0.05). The onset time of neuromuscular junction dysfunctions showed no significant difference among different ICIs (p > 0.05).ConclusionsAnalysis of FAERS data identified that over 30% (32.85%) of reports of neuromuscular junction dysfunctions resulted in death. Ongoing monitoring, risk evaluations, and further comparative studies of ICIs should be considered.

Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells.

Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.g., PD1 and LAG3). Here, we demonstrated that approximately a third of cancer patients analyzed in this study have peripheral CD8+ T cells that expressed robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR) due to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cleavage. This is associated with poor disease prognosis and decreased CD8+ T-cell function, which could be partially reversed by anti-LAG3. Systemic immune dysfunction was restricted to CD8+ T cells, including, in some cases, a high percentage of peripheral naïve CD8+ T cells, and was driven by the cytokine IL6 via STAT3. These data suggest that additional studies are warranted to determine if the combination of increased LAG3IC in peripheral CD8+ T cells and elevated systemic IL6 can serve as predictive biomarkers and identify which cancer patients may benefit from LAG3 blockade.

Neutrophil extracellular traps promote cancer-associated inflammation and myocardial stress

ABSTRACT Cancer is associated with systemic pathologies that contribute to mortality, such as thrombosis and distant organ failure. The aim of this study was to investigate the potential role of neutrophil extracellular traps (NETs) in myocardial inflammation and tissue damage in treatment-naïve individuals with cancer. Mice with mammary carcinoma (MMTV-PyMT) had increased plasma levels of NETs measured as H3Cit-DNA complexes, paralleled with elevated coagulation, compared to healthy littermates. MMTV-PyMT mice displayed upregulation of pro-inflammatory markers in the heart, myocardial hypertrophy and elevated cardiac disease biomarkers in the blood, but not echocardiographic heart failure. Moreover, increased endothelial proliferation was observed in hearts from tumor-bearing mice. Removal of NETs by DNase I treatment suppressed the myocardial inflammation, expression of cardiac disease biomarkers and endothelial proliferation. Compared to a healthy control group, treatment-naïve cancer patients with different malignant disorders had increased NET formation, which correlated to plasma levels of the inflammatory marker CRP and the cardiac disease biomarkers NT-proBNP and sTNFR1, in agreement with the mouse data. Altogether, our data indicate that NETs contribute to inflammation and myocardial stress during malignancy. These findings suggest NETs as potential therapeutic targets to prevent cardiac inflammation and dysfunction in cancer patients.

Long-Term Cognitive Dysfunction in Cancer Survivors.

Cancer-related cognitive impairment (CRCI) is a frequent side effect experienced by an increasing number of cancer survivors with a significant impact on their quality of life. Different definitions and means of evaluation have been used in available literature; hence the exact incidence of CRCI remains unknown. CRCI can be described as cognitive symptoms reported by cancer patients in self-reported questionnaires or as cognitive changes evaluated by formal neuropsychological tests. Nevertheless, association between cognitive symptoms and objectively assessed cognitive changes is relatively weak or absent. Studies have focused especially on breast cancer patients, but CRCI has been reported in multiple types of cancer, including colorectal, lung, ovarian, prostate, testicular cancer and hematological malignancies. While CRCI has been associated with various treatment modalities, including radiotherapy, chemotherapy, hormone therapy and novel systemic therapies, it has been also detected prior to cancer treatment. Therefore, the effects of cancer itself with or without the psychological distress may be involved in the pathogenesis of CRCI as a result of altered coping mechanisms after cancer diagnosis. The development of CRCI is probably multifactorial and the exact mechanisms are currently not completely understood. Possible risk factors include administered treatment, genetic predisposition, age and psychological factors such as anxiety, depression or fatigue. Multiple mechanisms are suggested to be responsible for CRCI, including direct neurotoxic injury of systemic treatment and radiation while other indirect contributing mechanisms are hypothesized. Chronic neuroinflammation mediated by active innate immune system, DNA-damage or endothelial dysfunction is hypothesized to be a central mechanism of CRCI pathogenesis. There is increasing evidence of potential plasma (e.g., damage associated molecular patterns, inflammatory components, circulating microRNAs, exosomes, short-chain fatty acids, and others), cerebrospinal fluid and radiological biomarkers of cognitive dysfunction in cancer patients. Discovery of biomarkers of cognitive impairment is crucial for early identification of cancer patients at increased risk for the development of CRCI or development of treatment strategies to lower the burden of CRCI on long-term quality of life. This review summarizes current literature on CRCI with a focus on long-term effects of different cancer treatments, possible risk factors, mechanisms and promising biomarkers.

Prevalence and predictors of right ventricular dysfunction in cancer patients treated with cardiotoxic chemotherapy – a prospective cardiovascular magnetic resonance study

Abstract Background Right ventricular (RV) function has an established incremental prognostic value in cardiomyopathy. Studies on cancer therapeutics-related cardiac dysfunction (CTRCD) primarily focused on the left ventricle (LV), with conflicting results from small studies dedicated to RV dysfunction. Purpose We sought to investigate the influence of chemotherapy on RV function relative to LV function using serial cardiac magnetic resonance (CMR). Methods Patients were enrolled as part of Cardiotoxicity Prevention Research Initiative (CAPRI) Registry aimed at evaluating CMR-based markers for surveillance of CTRCD. Patients underwent non-contrast CMR imaging prior to initiation of anthracyclines and/or trastuzumab and serially every 3 months during the first year, then annually thereafter. We included patients who had a baseline and ≥1 follow-up scan and excluded those with baseline LV ejection fraction (EF)&amp;lt;50%, providing 320 patients completing 1,453 CMR studies. Cine images were analysed to calculate chamber volumes indexed to body surface area and EF. We defined LV CTRCD using CMR modality specific criteria of a drop in LV EF ≥5% from baseline to &amp;lt;57%; RV CTRCD as a drop ≥5% to &amp;lt;49% in females and &amp;lt;47% in males. We used linear mixed models to study the changes in ventricular volumes and EF with time. Results The majority of patients were females (80%), had breast cancer (68%) or lymphoma (32%), with a mean age of 52.7±13 years. Figure 1 shows temporal changes in mean ventricular volumes and function over the first year. Mean changes in RV function followed those of the LV, with the nadir of EF and maximum of volumes occurring at 6 months. Respective values for mean decrease in LV and RV EF at this time point versus baseline were 4.1 and 2.9% (p&amp;lt;0.001). Concomitant mean increase in indexed RV end-diastolic (ED) and end-systolic (ES) volumes were 1.6 and 2.7 ml/m2 (p=0.2 and &amp;lt;0.001). There was significant interaction of chemotherapy regimen with time for RV volumes (p=0.001 and 0.003), but not RV EF (p=0.7), with worst changes occurring with combined anthracyclines and trastuzumab. In all, 70 (22%) and 28 (9%) patients met criteria for LV and RV CTRCD, respectively. Among those who developed RV CTRCD, 10 had persistently normal LV function. Figure 2 shows the results of logistic regression to predict RV CTRCD. Significant univariable predictors included combined chemotherapy regimen and baseline LV and RV volumes and LV EF. Adjusting for age, sex, and chemotherapy regimen, baseline RV ED volume remained associated with RV CTRCD (odds ratio 1.6; p=0.005). Conclusion In this large study, RV volumes and function were similarly influenced by chemotherapy versus comparable LV-based measures. Using similar threshold criteria, the incidence of RV CTRCD was lower than for LV CTRCD; however, one third of those who develop RV CTRCD showed normal LV function. Future studies are warranted to study the prognostic influence of RV injury in cancer patients. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Alberta InnovatesGenome Alberta Figure 1. Temporal changes in LV &amp; RV functionFigure 2. Predictors of RV CTRCD

Tumor-Induced Cardiac Dysfunction: A Potential Role of ROS.

Cancer and heart diseases are the two leading causes of mortality and morbidity worldwide. Many cancer patients undergo heart-related complications resulting in high incidences of mortality. It is generally hypothesized that cardiac dysfunction in cancer patients occurs due to cardiotoxicity induced by therapeutic agents, used to treat cancers and/or cancer-induced cachexia. However, it is not known if localized tumors or unregulated cell growth systemically affect heart function before treatment, and/or prior to the onset of cachexia, hence, making the heart vulnerable to structural or functional abnormalities in later stages of the disease. We incorporated complementary mouse and Drosophila models to establish if tumor induction indeed causes cardiac defects even before intervention with chemotherapy or onset of cachexia. We focused on one of the key pathways involved in irregular cell growth, the Hippo–Yorkie (Yki), pathway. We used overexpression of the transcriptional co-activator of the Yki signaling pathway to induce cellular overgrowth, and show that Yki overexpression in the eye tissue of Drosophila results in compromised cardiac function. We rescue these cardiac phenotypes using antioxidant treatment, with which we conclude that the Yki induced tumorigenesis causes a systemic increase in ROS affecting cardiac function. Our results show that systemic cardiac dysfunction occurs due to abnormal cellular overgrowth or cancer elsewhere in the body; identification of specific cardiac defects associated with oncogenic pathways can facilitate the possible early diagnosis of cardiac dysfunction.

Endothelial dysfunction in cancer patients before and after chemotherapy: focus on biomarkers

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The reported study was funded by Russian Foundation for Basic Research (RFBR) project number 19-315-90034 Background. Nowadays gastric cancer is one of the leading causes of world cancer mortality. Modern chemotherapy (CT) significantly improves survival and quality of life among these patients. Unfortunately, anticancer drugs induce some biomolecular disorders, which influence endothelial dysfunction and microcirculation lesions, subsequently leading to vasculo- and cardiotoxicity. The aim To study the dynamics of endothelial dysfunction’s (ED) biomarkers (endothelin-1 (ET-1), von Willebrand factor (VWF)) in patients with gastric cancer before and after CT. Material and methods The study included 25 patients with histologically confirmed gastric cancer (adenocarcinoma) stage II - IV, who have been treated by CT including platinum compound (oxaliplatin, cisplatin) and fluoropyrimidine group (5-fluorouracil, capecitabine) and are proven to be cardiovasculotoxic. All patients underwent blood tests, computer nailfold capillaroscopy and finger photoplethysmography (non-invasive assessment of vascular wall stiffness and endothelial function), electrocardiography (ECG), 24-hour ECG, echocardiography before CT and within a month after the last course. Results The median patients’ age was 64 ± 13 years; 68% were male; 52% had a prior cardiac illness: arterial hypertension (n = 12, 48%), coronary artery disease (n = 7, 28%), chronic heart failure (n = 3, 12%). The data obtained showed that ET-1 median levels were below normal values and did not change during CT: 0,95pg/ml (0,6;1,4) vs. 0,94pg/ml (0,7;1,4), р&amp;lt;0,9 (N = 1–3pg/ml), before and after CT respectively. The level of VWF remained within normal ranges and did not significantly differ in cancer patients before and after treatment 0,75IU/ml (0,7;0,9) vs. 0,8IU/ml (0,74;0,9), р&amp;lt;0,6 (N = 0,5–1,5IU/ml). Even before CT, endothelial dysfunction was detected, which significantly worsened after the treatment (occlusion index (IO) before and after CT 1.7 (1.38; 1.9) vs. 1.3 (1.2; 1.5), p &amp;lt; 0.0002, respectively). During data analysis, significant correlations were found: between ET-1 level and IO (r = 0.554, p = 0,006), ET-1 and percentage of capillary recovery (r= -0.7, p = 0,029) [both parameters characterize functional abnormalities of the microvasculature], ET-1 and the quantity of supraventricular extrasystoles (r=-0.48, p = 0,032). Conclusion In this study, the dynamics of ED biomarkers in patients with gastric cancer were studied. Even though reliable changes were not proven for the assessed molecular parameters ET-1 and VWF during CT (supposing depletion of endothelin system, small patient cohort), the above parameters may be used for identifying early signs of close and long-term cardio/vasculotoxicity due to significant positive correlations with microvasculature lesions. Further bigger trials for identification of other accurate and effective laboratory methods of detecting early features of vasculotoxicity are required.

Lower endothelium-dependent microvascular function in adult breast cancer patients receiving radiation therapy

PurposeCancer patients with a history of radiotherapy are at an increased risk of ischemic heart disease. Preclinical animal studies demonstrate markedly impaired acetylcholine (ACh)-mediated endothelium-dependent vasorelaxation within days to weeks post-irradiation, however, whether microvascular function is affected in the intact human circulation during cancer radiation therapy has yet to be determined.Materials and methodsUsing laser-Doppler flowmetry, microvascular endothelium-dependent and independent responses were evaluated through iontophoresis of acetylcholine (ACh) (part 1, n = 7) and sodium nitroprusside (SNP) (part 2, n = 8), respectively, in women currently receiving unilateral chest adjuvant radiation therapy for breast cancer. Measurements were performed at the site of radiation treatment and at a contralateral control, non-radiated site. Cutaneous vascular conductance (CVC) was calculated by normalizing for mean arterial pressure.Results and ConculsionsIn part 1, patients received an average radiation dose of 2104 ± 236 cGy. A significantly lower peak ACh-mediated endothelium-dependent vasodilation was observed within the radiated microvasculature when compared to non-radiated (radiated: 532 ± 167%, non-radiated 1029 ± 263%; P = 0.02). In part 2, the average radiation dose received was 2251 ± 196 cGy. Iontophoresis of SNP elicited a similar peak endothelium-independent vasodilator response in radiated and non-radiated tissue (radiated: 179 ± 58%, non-radiated: 310 ± 158; P = 0.2). The time to 50% of the peak response for ACh and SNP was similar between radiated and non-radiated microvasculature (P < 0.05). These data provide evidence of early endothelium-dependent microvascular dysfunction in cancer patients currently receiving chest radiation and provide the scientific premise for future work evaluating coronary endothelial function and vasomotor reactivity using more detailed and invasive procedures.