Risk profiles and incidence of cardiovascular events across different cancer types.

BACKGROUND: Cancer survivors are at increased risk for cardiovascular (CV) disease, although additional data are needed to better understand the incidence of CV events across different malignancies. This study sought to characterize the incidence of major adverse CV events [myocardial infarction, stroke, unstable angina (MACE), or heart failure (HF)] across multiple cancer types after cancer diagnosis. PATIENTS AND METHODS: Patients were identified from a USA-based administrative claims database who had index cancer diagnoses of breast, lung, prostate, melanoma, myeloma, kidney, colorectal, leukemia, or lymphoma between 2011 and 2019, with continuous enrollment for ≥12 months before diagnosis. Baseline CV risk factors and incidence rates of CV events post-index were identified for each cancer. Multivariable Cox hazards models assessed the cumulative incidence of MACE, accounting for baseline risk factors. RESULTS: Among 839 934 patients across nine cancer types, CV risk factors were prevalent. The cumulative incidence of MACE was highest in lung cancer and myeloma, and lowest in breast cancer, prostate cancer, and melanoma. MACE cumulative incidence for lung cancer was 26% by 4 years (2.7-fold higher relative to breast cancer). The incidence of stroke was especially pronounced in lung cancer, while HF was highest in myeloma and lung cancer. CONCLUSIONS: CV events were especially increased following certain cancer diagnoses, even after accounting for baseline risk factors. Understanding the variable patient characteristics and associated CV events across different cancers can help target appropriate CV risk factor modification and develop strategies to minimize adverse CV events and improve patient outcomes.

ESMO Expert Consensus Statements on Cancer Survivorship: promoting high-quality survivorship care and research in Europe.

BACKGROUND: The increased number of cancer survivors and the recognition of physical and psychosocial challenges, present from cancer diagnosis through active treatment and beyond, led to the discipline of cancer survivorship. DESIGN AND METHODS: Herein, we reflected on the different components of survivorship care, existing models and priorities, in order to facilitate the promotion of high-quality European survivorship care and research. RESULTS: We identified five main components of survivorship care: (i) physical effects of cancer and chronic medical conditions; (ii) psychological effects of cancer; (iii) social, work and financial effects of cancer; (iv) surveillance for recurrences and second cancers; and (v) cancer prevention and overall health and well-being promotion. Survivorship care can be delivered by structured care models including but not limited to shared models integrating primary care and oncology services. The choice of the care model to be implemented has to be adapted to local realities. High-quality care should be expedited by the generation of: (i) focused and shared European recommendations, (ii) creation of tools to facilitate implementation of coordinated care and (iii) survivorship educational programs for health care teams and patients. The research agenda should be defined with the participation of health care providers, researchers, policy makers, patients and caregivers. The following patient-centered survivorship research areas were highlighted: (i) generation of a big data platform to collect long-term real-world data in survivors and healthy controls to (a) understand the resources, needs and preferences of patients with cancer, and (b) understand biological determinants of survivorship issues, and (ii) develop innovative effective interventions focused on the main components of survivorship care. CONCLUSIONS: The European Society for Medical Oncology (ESMO) can actively contribute in the efforts of the oncology community toward (a) promoting the development of high-quality survivorship care programs, (b) providing educational material and (c) aiding groundbreaking research by reflecting on priorities and by supporting research networking.

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab.

BACKGROUND: Pertuzumab, a human epidermal growth factor receptor (HER) 2 dimerization inhibitor, has demonstrated promising efficacy in combination with trastuzumab in patients with metastatic breast cancer. As HER signaling pathways are not only involved in oncogenesis, but also in myocardial homeostasis, an analysis of cardiac safety data was undertaken in a large group of patients treated with pertuzumab. PATIENTS AND METHODS: A complete database of patients treated with full-dose pertuzumab was used to describe the incidence of asymptomatic left ventricular systolic dysfunction (LVSD) and symptomatic heart failure (HF). RESULTS: Information for 598 unique patients was available for the current analysis. Of the patients treated with pertuzumab alone (n = 331) or pertuzumab in combination with a non-anthracycline-containing cytotoxic (n = 175) or trastuzumab (n = 93), 23 (6.9%), 6 (3.4%), and 6 (6.5%), respectively, developed asymptomatic LVSD and 1 (0.3%), 2 (1.1%), and 1 (1.1%), respectively, displayed symptomatic HF. None of the 15 patients receiving both pertuzumab and erlotinib demonstrated LVSD. CONCLUSIONS: Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac side-effects when pertuzumab was given in combination with other anticancer agents.

Neuregulin in heart failure : reverse translation from cancer cardiotoxicity to new heart failure therapy.

Trastuzumab is a monoclonal antibody to the ErbB2 (Her2nue) receptor over-expressed in Her2(+) breast cancer. Trastuzumab-related cardiotoxicity has revealed the importance of ErbB2 signaling in the heart. Neuregulin (NRG-1) is an important stress-mediated paracrine growth factor that signals through the family of ErbB receptors to promote cardioprotection (myocyte cell survival, proliferation, differentiation, hypertrophy, and angiogenesis). Animal models with disrupted NRG/ErbB signaling fail to develop normally or result in impaired cardiac function post-natally. Pre-clinical animal studies and early-phase human studies suggest that recombinant NRG-1 holds promise as a new therapy for the treatment of various forms of heart failure. Much work is needed to further understand the exact mechanisms of cardiac repair and to find a safe mode of application for recombinant NRG-1 in heart failure.

Computerized tomographic finding of saddle pulmonary embolism is associated with high mortality in cancer patients.

BACKGROUND: Large pulmonary embolism (PE) is associated with high mortality in cancer patients. Several risk stratification methods have been used in PE setting. While computer-assisted tomography (CT) is now the preferred diagnostic modality for PE, its prognostic value is not well established. METHODS: A retrospective study of patients discharged from our centre between 2000 and 2006 with a PE diagnosis identified 52 patients with thrombus in the main pulmonary artery or the right or left branch. Clinical, echocardiographic and CT data were reviewed; vital status was determined 1 month and 1 year after index event. Patients were divided into saddle (defined as main pulmonary artery thrombus) and non-saddle PE. Multivariate logistic regression was applied to predict vital status, with patient age and CT parameters as predictors. RESULTS: Eighteen out of 52 patients were found to have a saddle PE. No significant difference was found between the group characteristics, although saddle PE patients were more likely to receive thrombolytic therapy (27.8% vs 2.9%, P = 0.02) and have an echocardiogram within 30 days of PE (61.1% vs 29.4%, P = 0.03). Overall mortality at 1 month was 9.6% with no difference between groups. At 1 year, mortality rates in saddle PE were significantly higher (83.3% vs 41.2%, P = 0.004). Presence of saddle PE was associated with an odds ratio of death within 1 year of 7.41 (95% confidence interval: 1.75-31.46, P = 0.007). CONCLUSION: The relatively simple distinction of saddle versus non-saddle PE by CT findings may provide a straightforward method for risk stratification, and remains useful up to 1 year after the index event.

X-ray microbeams: Tumor therapy and central nervous system research.

Irradiation with parallel arrays of thin, planar slices of X-ray beams (microplanar beams, or microbeams) spares normal tissue, including the central nervous system (CNS), and preferentially damages tumors. The effects are mediated, at least in part, by the tissue's microvasculature that seems to effectively repair itself in normal tissue but fails to do so in tumors. Consequently, the therapeutic index of single-fraction unidirectional microbeam irradiations has been shown to be larger than that of single-fraction unidirectional unsegmented beams in treating the intracranial rat 9L gliosarcoma tumor model (9LGS) and the subcutaneous murine mammary carcinoma EMT-6. This paper presents results demonstrating that individual microbeams, or arrays of parallel ones, can also be used for targeted, selective cell ablation in the CNS, and also to induce demyelination. The results highlight the value of the method as a powerful tool for studying the CNS through selective cell ablation, besides its potential as a treatment modality in clinical oncology.

Assessment of the method and timing of repair of a brachial plexus traction injury in an animal model for obstetric brachial plexus palsy.

A Sunderland type IV traction injury to the C6 root of adult sheep or newborn lamb brachial plexus was used as a model for obstetric traction injury to the C5 root in humans. In one experimental cohort the injury was created and repaired using interfascicular nerve autografts or coaxially aligned freeze-thawed skeletal muscle autografts in a group of adult sheep and in a group of newborn lambs. In a second cohort a similar injury was created and repaired either immediately or after a delay of 30 days, using either interfascicular nerve autografts or coaxially aligned freeze-thawed skeletal muscle autografts in four groups of six newborn lambs. In all cases both functional and morphometric indices of nerve regeneration were poorer in the injured and repaired nerves than in normal nerves. In lambs the method of repair made no difference and no significant differences were found for any of the indices of nerve function or morphology. In sheep the use of muscle grafts was associated with a poorer outcome than the use of nerve autografts. Where a delay of 30 days had elapsed between injury and repair, the results using nerve autografts were not significantly different. Where freeze-thawed muscle autografts had been used, the maturation of the regenerated nerve fibres after delay was significantly poorer than after immediate repair. The electrophysiological variables CV(max) and jitter, which may be applied clinically, were found to be good discriminators of recovery in all of the animals and in respect of all procedures.

Obstetric brachial plexus palsy: a comparison of the degree of recovery after repair of a C6 ventral root avulsion in newborn and adult sheep.

The C6 motor rootlets were avulsed from the spinal cord in six newborn lambs to simulate a birth lesion of the upper root of the brachial plexus. Six 1-year-old sheep were used for comparison, and treated in a similar manner. The injury was repaired immediately in each group using an autologous coaxial freeze-thawed skeletal muscle graft. The animals were allowed to recover for 1 year after the surgery. The C6 root was then examined electrophysiologically and morphologically. The results were compared with those obtained from a group of untreated intact 1-year-old sheep. The fibre and axon diameters and myelin sheath thickness were significantly different in the group repaired as lambs when compared with the group repaired at the age of 1 year. There was also a significantly increased maximum conduction velocity and a greater range of conduction velocities within the nerve in the lambs. Central motor latency was significantly slower in the sheep than in the lambs. These findings would suggest a greater potential for recovery in the lambs after brachial plexus root avulsion injuries.

The use of conventional and invaginated autologous vein grafts for nerve repair by means of entubulation.

Nerve repair by entubulation has re-emerged recently as a possible means of enhancing the microenvironment at the site of repair by inclusion within the tube of various trophic factors. To this end, a modification of the vein-graft technique has been used by turning it inside out before repair, to expose the adventitial surface to the regenerating axons. A comparative study of standard vein grafting versus the inside-out technique was carried out in two equal-sized groups of inbred Lewis rats. Jugular vein isografts were derived from litter mates. The sciatic nerve was transected and repaired by entubulation using the standard vein graft in one group and the inside-out graft in the other group. Morpho-metric and electrophysiological assessment were carried out 3 months after repair. When the animals were assessed it was found that both the standard-vein-graft group and the inside-out group exhibited a reduction in all of the morphometric and electrophysiological variables when compared to normal nerves. The mean axon diameter, fibre diameter and myelin sheath thickness were, however, found to be greater in the group that underwent the inside-out repair. The superior morphometric results seen in the inside-out group were not matched by improved electrophysiological performance. It is concluded that the use of the inside-out technique confers no functional benefit over standard vein grafting.

Native valve infective endocarditis: what is the optimal timing for surgery?

IE remains a dreaded disease masquerading under a myriad of presentations in an evolving epidemiological environment. In our continuing endeavor against this deadly disease, echocardiography has evolved into an indispensable diagnostic tool to define structural complications and guide therapy. Timing of surgical intervention for IE remains a subject of intense debate and depends on the cardiac and systemic complications of the infection, the virulence of the organism, and the responsiveness to medical therapy. A judicious agreement among cardiologist, cardiovascular surgeon, and infectious disease specialist should define whether surgical intervention is warranted and, if so, the optimal timing. Further optimization of guidelines will help in the diagnosis and treatment of endocarditis but will never be a substitute for sound judgment and experience.

High-output heart failure resulting from a remote traumatic aorto-caval fistula: diagnosis by echocardiography.

Congestive heart failure (CHF) due to high output states is known to occur in a variety of systemic illnesses and in patients with arterial-venous fistulas. This paper reports the case of a 45-year-old man admitted to the emergency room with a diagnosis of new onset atrial fibrillation and CHF, whose past medical history was not significant except for a gunshot wound to his abdomen 22 years previously. The etiology of his CHF together with the cardiomegaly and hyperdynamic left ventricular systolic function was unknown. A subcostal view routinely done during transthoracic echocardiography revealed a severely dilated inferior vena cava and the presence of an aorto-caval fistula by color doppler. The patient underwent successful corrective repair with dramatic improvement in symptoms and resolution of the atrial fibrillation, and cardiac size returned to normal. This rare case emphasizes that patients with refractory CHF must be closely examined with particular attention to palpation and auscultation over all scars, irrespective of the duration since any traumatic or surgical event.

Obstetric brachial plexus palsy: a large animal model for traction injury and its repair. Part 1: age of the recipient.

A Sunderland type IV traction injury to the C6 root of the sheep or lamb brachial plexus was used as a model for obstetric traction injury to the C5 root in humans. The injury was created and immediately repaired using interfascicular nerve autografts in a group of adult sheep and a group of newborn lambs. The animals were examined using electrophysiological and morphometric techniques 1 year after operation. It was found that the recovery of neuromuscular function was superior in the lambs. The implication is that nerves in newborn animals have a better potential for regeneration than that seen in older individuals. This is discussed with reference to the management of obstetric brachial plexus palsy.

Prediction of human transplantation arteriopathy and coronary events with lung/heart count ratios during intravenous dipyridamole thallium-201 imaging.

BACKGROUND: Cardiac allograft arteriopathy often limits long-term survival in transplantation recipients but has been difficult to detect by standard diagnostic methods. Because of the diffuse nature of transplantation coronary disease, we postulated that a lung/heart ratio during dipyridamole thallium imaging might better predict arteriopathy-related complications than diagnostic methods that detect discrete luminal stenoses. METHODS AND RESULTS: Sixty-six unselected heart transplantation recipients were evaluated with annual coronary arteriograms, endomyocardial biopsy, and intravenous dipyridamole thallium testing (initial study group). The mean lung/heart ratio on an anterior planar image was 0.40 for all patients; therefore <0.40 was arbitrarily defined as normal. After October 1992, 98 patients were tested (validation study group) and a lung/heart ratio cutoff of 0.40 was evaluated prospectively. Coronary end points were defined as (1) at least 1 coronary artery stenosis >/=50% of the luminal diameter, (2) sudden cardiac death, and (3) acute myocardial infarction. Stepwise logistic regression analysis was performed to identify independent predictors of future coronary end points. For the initial study group, the lung/heart ratio on the first annual thallium study was the only independent predictor of subsequent cardiac end points (0.47 +/- 0.13 [SD] with end points vs 0.38 +/- 0.11 without end points, P <.05). For the validation study group, independent predictors of subsequent coronary events included the lung/heart ratio and the radionuclide left ventricular ejection fraction. No patient with a lung/heart ratio <0.40 and a left ventricular ejection fraction >/=0.50 developed a cardiac event during 21 +/- 11 months of follow-up. CONCLUSIONS: A lung/heart ratio >/=0.40 on dipyridamole thallium testing is a sensitive predictor of coronary events after heart transplantation. Patients with heart transplantion who have a lung/heart ratio <0.40 and normal systolic left ventricular function are at low risk for subsequent coronary events and may not require annual surveillance by coronary arteriography.

Biodegradable controlled release glass in the repair of peripheral nerve injuries.

The experiments in this paper were concerned with the recovery of function and ease of application of an entubulation technique using a biodegradable, controlled release glass tube (CRG) for the repair of a transected peripheral nerve. The peroneal nerves of 15 New Zealand White rabbits were repaired with either a CRG tube filled with freeze-thawed muscle, or a conventional freeze thawed muscle graft (FTMG). These were compared with controls in which a CRG was used to enclose the cut ends of a nerve separated by a 1 cm gap. Electrophysiological and morphometric assessment was carried out 6 months after repair. No statistical difference was found in any test between the FTMG and the CRG tube filled with freeze thawed muscle. The CRG tube and 1 cm gap produced inferior levels of recovery of function when compared with the other two repair groups.

An electrophysiological and morphological comparison of the microwave muscle graft and the freeze-thawed muscle graft.

The purpose of this study was to assess the feasibility of using a microwave oven to produce denatured muscle grafts for the repair of 1 cm deficits in the rabbit peroneal nerve. Recovery of function was assessed after 6 months by electrophysiological and histological examination of the peroneal nerve and target muscles. The results were compared to normal rabbits and to a group whose nerves were repaired with freeze-thawed muscle grafts (FTMG). The results of this study showed that heating muscle in a microwave oven does produce a graft which may be used as an alternative to the FTMG. However, the technical difficulties in preparing a microwave muscle graft make the use of this technique in the clinical setting unlikely.

In vitro nerve repair--in vivo. The reconstruction of peripheral nerves by entubulation with biodegradeable glass tubes--a preliminary report.

Biodegradeable "controlled release" inorganic polymer glass tubes can be manufactured to fit the dimensions of any nerve and their rate of solubility can be adjusted to encompass the time taken for nerve regeneration. They have been used in a number of biological applications. The facial nerve was repaired in a group of five sheep by entubulation with biodegradeable glass tubes. The sheep were assessed 10 months after repair and compared with a similar sized group of normal sheep. It was found that while there was a reduction in the peak velocity of conduction in the repaired nerves and in the range of conduction velocities, the minimum conduction velocity was within normal limits. There was a diminution in all of the measured variables of nerve morphometry but in no case did this reach statistical significance. These findings are consistent with the view that regeneration of the nerves had taken place to a degree at least as effective as that seen in nerves of a similar size repaired by conventional means.