The therapeutic landscape of non-small cell lung cancer (NSCLC) has been profoundly transformed by the widespread adoption of molecular profiling and the development of targeted therapies, like tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs), and bispecific antibodies (BsAbs). These agents have significantly improved survival and quality of life in molecularly selected subgroups, potentially converting NSCLC into a chronic disease requiring prolonged treatment exposure. However, extended survival has led to increasing recognition of cancer treatment-related cardiovascular (CV) disease as a clinically relevant and sometimes dose-limiting complication. Unlike conventional chemotherapy, CV toxicities associated with targeted therapies frequently arise from on-target or off-target interference with signaling pathways that are essential for myocardial survival, endothelial function, vascular regulation, and the cardiac conduction system. From common pathophysiological mechanisms, a broad spectrum of clinical manifestations arises, ranging from asymptomatic electrocardiographic changes to arterial hypertension, dyslipidemia, venous thromboembolism, arrhythmias, and heart failure. This review provides a comprehensive overview of CV toxicities associated with targeted therapies in NSCLC, integrating mechanistic insights with clinical evidence. We summarize class-specific CV risk profiles across EGFR, ALK/ROS1, RET, MET, NTRK, BRAF, and KRAS-G12C inhibitors, as well as ADCs and BsAbs, highlighting both shared and distinct patterns of cardiotoxicity. As targeted therapies continue to expand across disease stages and treatment lines, CV toxicity is expected to play an increasingly important role in therapeutic decision-making. Integrating CV considerations into oncologic care is therefore essential to preserve treatment continuity, optimize long-term outcomes, and maximize the benefits of modern targeted therapies in NSCLC.

Venous thromboembolism in cancer patients constitutes a complex and clinically significant disease due to its pathophysiology, morbidity and mortality. Pulmonary embolism is a potentially life-threatening disease, and therefore it represents the second leading cause of death among cancer patients, surpassed only by cancer itself. In recent years, direct-acting oral anticoagulants have emerged as the preferred option for the treatment of cancer-related venous thromboembolism, although low-molecular weight heparins are still specifically recommended for patients with high bleeding risk. The management of anticoagulant therapy beyond the first 6 months following pulmonary embolism remains a challenging scenario, requiring careful evaluation of the balance between benefits and risks. Anti-thrombotic prophylaxis is not routinely recommended in the outpatient setting, although emerging data suggest validated risk tools could help identify high-risk populations who might benefit. This review summarizes available clinical trial data, meta-analyses, real-world studies, both national and international guidelines providing a practical approach to the management of pulmonary embolism in patients with cancer.

Radiotherapy (RT) is used in head and neck squamous cell carcinoma (HNSCC) with excellent effectiveness, but it is burdened by important side effects, which may negatively impact patients’ quality of life (QoL). In particular when associated with chemotherapy (CT), that has a radiosensitising effect (and its own toxicities), it is responsible for several adverse events, causing social discomfort and lower QoL, in patients who are already experiencing several tumor-related discomforts. Prehabilitation is a healthcare intervention consisting of several specialist visits prior to the start of treatment, with the aim of improving the patient’s health status, resolving symptoms that interfere with treatment and impact QoL, and finally to better avoid or overcome complications. Of all cancer patients, HNSCC patients are among those who could benefit most from prehabilitation, both because of the high number of symptoms and toxicities and their difficult management. Despite this and the emerging data, prehabilitation is not often considered for the majority of patients undergoing (C)RT. In this review, we tried to understand what are the main areas in which interventions can be made prior to the (C)RT start, the possible side effects of the treatment, the effectiveness in their prevention and management, and the impact that prehabilitation may have in adherence to therapy and on the principal survival outcomes, providing important guidance for the planning of future studies. Although there is no strong data evaluating multidisciplinary prehabilitation strategies, evidence shows that optimizing the patient’s health status and preventing possible complications improve the QoL, reduce the incidence and severity of adverse events, and improve treatment adherence. While cardiology prehabilitation is of paramount importance for all patients undergoing concomitant CRT in the prevention of possible side effects, the remaining interventions are useful independently of the type of treatment proposed. Geriatricians have a key role in both elderly patients and younger patients characterized by many comorbidities to comprehensively assess health status and indicate which treatment may be the best in terms of risk/benefit ratio. Collaboration between nutritionists and phoniatrics, on the other hand, ensures adequate nutritional intake for the patient, where possible orally. This is because optimizing both body weight and muscle mass and qualities has been shown to impact key survival outcomes. Finally, HNSCC patients have the second highest suicide rate, and the disease has side effects such as pain, dysfiguration, and sialorrhea that can reduce the patient’s social life and create shame and embarrassment: A psychological intake, in addition to the usefulness to the patient, can also provide current support to caregivers and family members. Therefore clinicians must define a personalized pathway for patients, considering the characteristics of the disease and the type of treatment proposed, to optimize health status and prevent possible side effects while also improving QoL and treatment adherence.

Summary Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion‐dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo‐controlled, randomised study to evaluate the iron chelator deferasirox in patients with low‐ or intermediate‐1–risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.

Purpose of the Review Arterial hypertension (AH) is the most common cardiovascular (CV) risk factor in the community and in oncologic patients. It also represents the most important CV condition predisposing to anticancer treatment-related cardiotoxicity. This risk is heightened in the presence of cardiac AH-mediated organ damage (HMOD). Influence of AH and HMOD on the development of cardiotoxicity will be reviewed, with a focus on specific scenarios and implications for management of oncologic patients. Recent Findings Not adequately controlled AH before or during anticancer treatments and/or development of AH during or after completion of such therapies have detrimental effects on the clinical course of oncologic patients, particularly if HMOD is present. Summary As overlooking CV health can jeopardize the success of anticancer treatments, the goal for clinicians caring for the oncologic patient should include the treatment of AH and HMOD.

BACKGROUND:Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs. PATIENTS AND METHODS:We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor. RESULTS:This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070). CONCLUSIONS:To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.

Tini, Giacomo; Sarocchi, Matteo; Ameri, Pietro; Tocci, Giuliano; Battistoni, Allegra; Arboscello, Eleonora; Spallarossa, Paolo; Porto, Italo Author Information

Background: the European Society of Cardiology Heart Failure Association (HFA) together with the International Cardio-Oncology Society (ICOS) proposed charts for baseline CV risk assessment of cancer patients scheduled to receive anthracyclines and anti-human epidermal growth factor receptor-2 (HER2) agents. Methods: We investigated HFA/ICOS risk stratification, prescriptions of cardioactive drugs, and occurrence of CV events in a multicentric breast cancer (BC) cohort from 3 Italian Outpatient Cardio-Oncology Clinics. Results: 373 BC patients who underwent a baseline Cardio-Oncologic evaluation were included, of whom 202 scheduled to receive anthracyclines and 171 anti-HER2. Mean age was 60 +/- 12 years and 49% of BC patients had >= 2 CV risk factors. In the anthracyclines group, 51% were at low-risk, 43% at medium-risk and 6% at high-risk; while in the anti-HER2 group, 27% patients were at low-risk, 58% at medium-risk and 15% at high-risk. In both groups, a medium-to-high risk was associated with use of cardioactive therapies (p < 0.0001). There were no LVD events in anthracycline recipients, and 16 LVD among anti-HER2 patients. A medium-to-high risk was not associated with LVD occurrence (p = 0.17). Conclusions: Patients with medium-to-high HFA/ICOS risk were more likely to receive cardioactive therapies, possibly explaining the lack of association of risk categories with LVD occurrence.

Background: Women with breast cancer (BC) represent a special population particularly exposed to cardiovascular disease (CVD) risk. However, cardiologic assessment in BC is mostly limited to detection of left ventricular dysfunction cardiotoxicity (LVD-CTX) due to anticancer treatments. Our aim was to comprehensively investigate CV profile and events in a contemporary BC cohort. Methods and Results: Records of BC patients referred for a Cardio-Oncologic evaluation before starting anticancer treatments, between 2016 and 2019, were retrospectively reviewed (n = 508). Information regarding prevalence and control of CV risk factors, and novel CVD diagnoses were extracted. Occurrence of LVD-CTX, CV events other than LVD-CTX and mortality was assessed. Mean age of study population was 64 ± 13 years; 287 patients were scheduled to receive anthracycline and 165 anti-HER2 therapy. Overall, 53% of BC women had ≥2 CV risk factors, and 67% had at least one of arterial hypertension, dyslipidaemia or diabetes mellitus not adequately controlled. Eighteen (4%) patients were diagnosed a previously unknown CVD. Over a mean follow-up of 2.5 ± 1 years, 3% of BC patients developed LVD-CTX, 2% suffered from other CV events and 11% died. CV risk factors were not associated with LVD-CTX, except for family history of CAD. On the contrary, patients with other CV events exhibited a worse CV profile. Those who died more commonly experienced CV events other than LVD-CTX (p = 0.02). Conclusions: BC women show a suboptimal CV risk profile and are at risk of CV events not limited to LVD-CTX. A baseline Cardio-Oncologic evaluation was instrumental to implement CV prevention and to optimize CV therapies.

Peri-procedural myocardial injury (PPMI) is a common complication after transcatheter valve replacement (TAVR), often remaining clinically silent. The role of valve type on PPMI and the association between PPMI and mortality are still unclear. We sought to evaluate predictors and outcome of PPMI after TAVR, and the impact of self-expandable valve (SEV) vs. balloon-expandable valve (BEV) deployment on PPMI. Consecutive patients who underwent successful TAVR in a single-center from January 2014 to December 2019 were included. PPMI was defined according to a modified Valve Academic Research Consortium (VARC)-2 definition as a post-procedure elevation of troponin (with a peak value ≥ 15-times the upper-reference limit) < 72 h after TAVR. We included 596 patients, of whom 258 (43.3%) were men. Mean age was 83.4 ± 5.5 years. We deployed 368 (61.7%) BEV and 228 (38.3%) SEV. PPMI was observed in 471 (79.0%) patients. At multivariable analysis, SEV (OR 2.70, 95% CI 1.64–4.55, p < 0.001), creatinine clearance (OR 0.98, 95% CI 0.97–1.00, p = 0.011), and baseline ejection fraction (OR 1.05, 95% CI 1.02–1.07, p < 0.001) were independent predictors of PPMI; these findings were also confirmed using a propensity-weighted analysis. Thirty-day and 1-year all-cause mortality rates were 2.5% and 8.1%, respectively. No associations between PPMI and 30-day (p = 0.488) or 1-year (p = 0.139) all-cause mortality were found. Independent predictors of 30-day mortality were increasing EUROSCORE II (HR 1.16 per score point, 95% CI 1.08–1.19, p < 0.001) and life-threatening/major bleeding complications (HR 5.87, 95% CI 1.28–26.58, p = 0.019), whereas EUROSCORE II (HR 1.08, 95% CI 1.04–1.13, p = 0.031) and acute kidney injury (HR 2.59, 95% CI 1.20–5.35, p = 0.020) were related to 1-year mortality. PPMI is frequent after TAVR, but it does not affect 30-day or 1-year all-cause mortality. SEV implantation is associated with an increased frequency of PPMI.

Heart failure symptoms, in particular dyspnea, may be difficult to frame in a patient with cancer. We report the case of an oncological patient whose dyspnea could have been attributable to various causes and whose management was challenging in the context of the coronavirus disease-2019 pandemic. (Level of Difficulty: Beginner.)

Background: We reviewed frequency, microbiological pattern, predictors, and outcomes of early infections following transcatheter aortic valve replacement (TAVR). Methods: Five hundred thirty-nine patients who underwent successful TAVR at a single, high-volume center between January 2014 and December 2019 were enrolled. We defined early infections as occurring within 30-day from TAVR. Results: Mean age was 83.5 +/- 5.4 years; 230 (42.7%) patients were men. Median follow-up was 12.0 (5.7-18.3) months; 30-day and 1-year death rates were 8/539 (1.5%) and 30/539 (5.6%), respectively. Early infections occurred in 61/539 (11.3%) patients, of whom 2 had infections in two sites. Of the 63 infections, 10 were bloodstream infections (BSI), 5 urinary tract, 27 pulmonary (2 with sepsis), 6 access site infections, 1 enterocolitis, and 14 were clinically diagnosed (no specific site). We observed 31/63 (49.2%) microbiologically-documented infections: Gram+ bacteria were isolated in 12/31 (38.7%), Gram-in 17/31 (54.3%), both Gram+ and Gram in 2/31 (6.5%); in thirty-two infections no specific pathogen could be isolated (clinically-documented infections). Early infections were more prevalent in patients who died within 30-day (8.2% vs. 0.6%, p < 0.001) or 1-year (14.8% vs. 4.4%, p < 0.001) from TAVR. At multivariable analysis, early infections were independently associated with 30-day (HR: 8.82, 95% CI: 1.11-19.83, p = 0.035) and 1-year mortality (HR: 2.10, 95%CI: 1.28-6.21, p = 0.041). The predictive value for 1-year mortality was maintained even restricting the analysis to documented infections only, or to more severe infections (BSI and pneumonia only) (all p < 0.05). Conclusions: Early infections occur in 1/10th of TAVR and are associated with increased short-and long-term mortality. Whereas a causal relationship between early infections and the risk of death cannot be unequivocally proven, careful surveillance of infected patients may improve TAVR results. (c) 2021 Elsevier B.V. All rights reserved.

AIMS:Acute kidney injury (AKI) may complicate transcatheter aortic valve replacement (TAVR) leading to higher mortality. The relationship between AKI, obesity, and mortality, however, is controversial. We sought to investigate the impact of body habitus on the prognostic value of AKI in TAVR. METHODS:Among the 645 patients who underwent successful TAVR in a single high-volume centre, we retrospectively evaluated the association between AKI-TAVR and 30-day, 6-month, and 1-year mortality, and whether this relationship was affected by BMI. AKI was defined according to the Valve Academic Research Consortium-2 criteria. Patients were categorized into three groups by BMI: low-to-normal weight (<25 kg/m2), overweight (25-30 kg/m2), obese (>30.0 kg/m2). RESULTS:Three-hundred and twenty-four (50.2%) patients were low-to-normal weight, 223 (34.6%) overweight, and 98 (15.2%) obese. AKI occurred in 141 (21.9%), similarly across BMI groups. Thirty-day, 6-month, and 1-year mortality rates were 2.2, 3.7, and 7.9%, without differences across BMI groups. Among patients who developed AKI-TAVR, 30-day (8.7 vs. 2.0 vs. 0.0%), 6-month (13.0 vs. 6.1 vs. 4.3%), and 1-year (20.3 vs. 12.2 vs. 4.3%) mortality showed a decreasing trend across increasing BMI categories (all P < 0.05); the same trend was not observed for patients without AKI-TAVR. In multivariate models, AKI was associated with 30-day [odds ratio (OR): 2.46, 95% confidence interval (CI): 1.70-8.67], 6-month (OR: 2.75, 95% CI: 1.32-7.59), and 1-year mortality (OR: 1.84, 95% CI: 1.22-3.71, all P < 0.05). The interaction between AKI and BMI, when added to the models, was consistently significant (all P < 0.05). CONCLUSION:Higher BMI is associated with better survival in TAVR patients who develop AKI.

Immune-checkpoint inhibitors (ICIs) represent a successful paradigm in the treatment of cancer. ICIs elicit an immune response directed against cancer cells, by targeting theso-calledimmune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Such response, however, is not entirely tumor-specific and may result in immune-related adverse events (irAEs), involving a number of organs and systems. Cardiovascular (CV) irAEs are rare, although potentially severe. In particular, several cases of ICI-related myocarditis with life-threatening course have been reported: the possibility of fulminant cases, thus, requires a high level of awareness among both oncologists and cardiologists. Aggressive work-up and management of symptomatic patients taking ICIs is fundamental for early recognition and initiation of specific immunosuppressive therapies. Notably, myocarditis occurs within few weeks from ICIs initiation, offering opportunity for a targeted screening. Troponin testing is the cornerstone of this screening, yet uncertainties remain regarding timing and candidates. Moreover, troponins positivity should be carefully interpreted. We herein review the main aspects of ICI-related myocarditis and suggest a practical approach. In particular, we focus on the opportunities that a baseline CV evaluation offers for subsequent management by collecting clinical and instrumental data, essential for the interpretation of troponin results, for differential diagnosis and for the formulation of a diagnostic and therapeutic workup.

observed in patients who recovered a normal LVEF, compared to those with persistent cardiac dysfunction, even if asymptomatic, thus underscoring the inadequacy of a symptom-guided approach.Lack of cardio-oncology consultation may represent a missed opportunity for early diagnosis and intervention.

Myocarditis is an uncommon, but fearsome complication of immune checkpoint inhibitors (ICPis) because it may result in life-threatening heart failure, cardiogenic shock, and arrhythmias. Among more than 20,000 patients treated with nivolumab and/or ipilimumab until April 2016 and included in a safety database of Bristol-Myers Squibb regardless of adverse events (AEs), 0.09% experienced myocarditis and less than 0.03% experienced fatal myocarditis. Of all 964 patients at the Massachusetts General Hospital who received ICPis between November 2013 and July 2017, 1.14% developed myocarditis and 0.52% had major cardiovascular AEs. According to a recent study, 122 cases of ICPi-related myocarditis were recorded since 2013 in VigiBase, the WHO database of individual patient safety reports. Classification was severe in 84%, and death was more frequent with combination than with single immune therapy (66% v 40%).