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.

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.

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.

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.

Frequency of late potentials on signal-averaged electrocardiograms during thallium stress testing in coronary artery disease.

Late potentials detected by signal-averaged electrocardiography (SAECG) are an important noninvasive indicator identifying patients with previous myocardial infarction at risk for developing ventricular tachycardia. The role of myocardial ischemia in the development of late potentials is undefined. This study attempts to determine if late potentials on SAECG can be produced during scintigraphically proven ischemia. A signal-averaged electrocardiogram was obtained before and immediately after single-photon emission computed tomography thallium exercise testing in 51 patients. Reversible ischemia was documented in 25 cases with no significant changes in the parameters of SAECG; patients with previous myocardial infarction (n = 10) also had no significant changes from baseline. Multivariate analysis with respect to reversible ischemia and previous myocardial infarction was unrevealing. Patients with late potentials at baseline (n = 10) who developed reversible ischemia (n = 5) had a shorter QRS duration than those with late potentials at baseline and no reversible ischemia. The data indicate that exercise-induced scintigraphically proven ischemia does not alter SAECG even in the presence of previous myocardial infarction. Patients with late potentials at baseline may actually have a shortened QRS duration during reversible ischemia as opposed to the expected lengthening of the QRS.

Reliability of technetium-99m Q12 and thallium-201 myocardial activity measurements after triphenyl tetrazolium chloride myocardial staining by perfusion.

RATIONALE AND OBJECTIVES: Investigations in animal models of severe myocardial ischemia or infarction use triphenyl tetrazolium chloride (TTC) staining to document infarction size histologically and to correlate these data with uptake measurements of radiolabeled tracers. Previously published data suggest that TTC staining itself has an important impact on myocardial tracer activity measurements. The authors hypothesized that TTC staining by perfusion has no significant effect on relative regional myocardial activity measurements of technetium-99m Q12 and thallium-201 in an open-chest canine model. METHODS: Eight dogs underwent left anterior descending artery occlusion for 2 hours with 30 minutes of reperfusion, followed immediately by injection of technetium-99m Q12 (n = 4) or thallium-201. Total myocardial activity was recorded in a dose calibrator, and regional myocardial samples were obtained by Cope needle biopsies from the ischemic and normal zones, both before and after TTC staining. RESULTS: The mean percent activity retention for the whole heart after perfusion staining with TTC was significantly reduced when compared to the preperfusion value for both technetium-99m Q12 and thallium-201. Regional measurements revealed no significant difference between the mean percent retention of technetium-99m Q12 in the ischemic and normal zones. After TTC perfusion, regional mean percent retention of thallium-201 was similar in the ischemic and normal zones. CONCLUSIONS: In a canine model of myocardial ischemia and infarction with reperfusion, TTC staining can be performed by coronary artery perfusion without significantly affecting comparative regional measurements of either technetium-99m Q12 or thallium-201. Whole heart tracer retention is significantly reduced by TTC perfusion staining, but thallium-201 is more affected than technetium-99m Q12.

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.

Nonpharmacologic treatment of heart failure in the elderly.

Nonpharmacologic therapy is an integral part of the management of elderly patients with heart failure. Reinforcement of dietary sodium restriction and other nutritional concerns are critical features of therapy. Quality standards for the management of patients with heart failure are being developed, and the implementation of these standards is a goal of clinicians. A multidisciplinary approach to elderly patients with heart failure is beneficial.

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.

Ticlopidine-induced neutropenia mimicking sepsis early after intracoronary stent placement.

We report a case of ticlopidine-induced profound neutropenia early in the course of therapy, which was manifest as a febrile systemic illness mimicking sepsis. This clinical presentation was potentially indicative of a contaminated intracoronary stent. The patient's signs and symptoms of illness promptly resolved with removal of ticlopidine, and no infection was documented. Review of indications for ticlopidine use, potential adverse effects, and monitoring recommendations are discussed.

The use of absolute refractory period in the estimation of early postmortem interval.

The estimation of the time since death (postmortem interval) is one of the most difficult problems in forensic pathology. Most methods currently employed use temperature-based algorithms intended to model the cooling of the body after death and thus estimate the postmortem interval. These methods are subject to considerable inaccuracy but their reliability can be improved if a range of other observed criteria such as lividity and rigor are also taken into consideration. The aim of the present study was to investigate the feasibility of using the absolute refractory period as an adjunct to the estimation of postmortem interval. The relationship between the 'postmortem interval' and the 'duration of absolute refractory period' was investigated using the rat sciatic nerve. A strong correlation between the duration of the absolute refractory period and the postmortem interval was observed. When both absolute refractory period and temperature were used in conjunction, the strength of this correlation was increased.

Stimulated jitter measurement in the assessment of recovery after different methods of peripheral nerve repair.

The recording of stimulated jitter offers a quantitative method for following the recovery of neuromuscular function after peripheral nerve repair. In groups of rats, electrophysiological recording of jitter was carried out on control animals and on animals 90 days after sciatic nerve division and subsequent repair with either direct end-to-end suture (NS), nerve graft (NG) or freeze thawed muscle graft (FTMG). It was found that values for jitter were highest in the FTMG group. The NS and NG groups demonstrated statistically similar jitter values when compared with each other and with the normal. It was concluded that the speed of nerve regeneration is slower in the FTMG group, at least initially, and that 90 days after sciatic nerve repair the FMTG group had an increase in the number of immature neuromuscular junctions when compared with the NS or NG groups. Jitter measurement would appear to offer a means of detecting small differences in nerve regeneration. The value of this in future developments in nerve repair is discussed.

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 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.

Stimulated jitter measurements in the assessment of recovery after peripheral nerve repair.

The recording of stimulated jitter may offer a highly sensitive, quantitative method for following the recovery of neuromuscular function after peripheral nerve repair. In groups of rats, electrophysiological recording of jitter was carried out on control animals and animals which had had the sciatic nerves divided and repaired 14, 30, 60 and 90 days previously. It was found that values for jitter were highest in the early stages of regeneration and declined with time so that they were within normal limits by 90 days after repair. It is concluded that jitter measurement may be helpful as a test for the postoperative recovery of function in repaired nerves.

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.