Current challenges and perspectives in lung cancer care during COVID-19 waves

Purpose of review

In the era of the SARS-Cov2 pandemic, the multidisciplinary care of patients with lung cancer is the main challenge for clinicians. The depiction of complex networking between SARS-CoV2 and cancer cells is crucial to understanding the downstream signalling pathways leading to more severe clinical behaviour of COVID-19 among lung cancer patients.

Recent findings

The immunosuppressive status caused by both blunted immune response and active anticancer treatments (e.g. radiotherapy, chemotherapy) affects also the response to vaccines. Furthermore, the COVID-19 pandemic has significantly influenced early detection, therapeutic management, and clinical research for patients with lung cancer.

Summary

SARS-CoV-2 infection does undoubtedly represent a challenge for care of patients with lung cancer. Since symptoms of infection may overlap with underlying condition, diagnosis must be reached and treatment should start as soon as possible. Although any cancer treatment should be procrastinated as long as infection is not cured, every choice must be pondered on individual basis, according to clinical conditions. Underdiagnosis should be avoided, and both surgical and medical treatment must be tailored to each patient. Therapeutic scenario standardization represents a major challenge for clinicians and researchers.

INTRODUCTION

Lung cancer is a significant public health problem with >2 million cases worldwide [1]. Survival remains poor and early diagnosis is critical [2–4]. Early data from cohort studies in COVID-19 patients have highlighted the impact on main clinical outcomes among patients with active cancers. Therefore, several international cohorts and registry studies have been promoted to better define the risk of severe COVID-19 in oncologic groups of patients as well as investigate this complex networking.

The immunosuppressive status caused by blunted immune response and active anticancer treatments affects also the response to vaccines and leads to a more severe clinical presentation of SARS-CoV-2 infection among patients affected by lung cancer. Furthermore, the COVID-19 pandemic has significantly influenced early detection, therapeutic management, and clinical research for patients with lung cancer. In this review, we initially discuss epidemiological data regarding mortality rate in patients with COVID-19 and cancer, discuss the main possible mechanisms which may explain the severity of COVID-19 among lung cancer patients, summarise the main implications of lung cancer care during the COVID-19 pandemic and strategies to improve lung cancer management. 

Box 1.

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EPIDEMIOLOGICAL DATA FROM INTERNATIONAL REGISTRIES

Studies with relevant information regarding mortality rate in COVID-19 patients are summarized in Table 1.

Table 1.

Cancer and COVID-19: international registries

Author	Registry	Aim	Population	Country	Outcomes measures	Findings
Grivas P et al.[6]	COVID-19 and Cancer Consortium (CCC19)	To identify prognostic clinical factors in patients with cancer and COVID-19	4169 pts with active or prior cancer38% active cancer, 81% solid cancer, 40% on anticancer therapy within 3 months from COVID-19 diagnosis 58% hospitalized	USA, Canada, Spain	COVID-19 severity (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated) and death within 30 days	Age >40 years, male sex, smoking, >2 comorbidities, ECOG PS ≥1, progressive cancer, hematologic or >1 cancer and severe baseline COVID-19 at presentation were associated with worse 30-day outcomes
Docherty et al.[8]	International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study	Clinical characteristics and mortality risk factors for patients with COVID-19	20 133 hospitalized patients with COVID-191797 (8.6%) with malignant neoplasms	UK	Admission to critical care and in-hospital mortality	Age, male sex, chronic comorbidities, obesity and cancer were independent risk factors for death
Pinato et al.[10]	Outcomes from COVID-19 in European Patients with Cancer	Clinical factors associated with severe COVID-19 and mortalityThe role of anticancer therapy on survival	890 patients with cancer and COVID-19, 83.4% solid cancer, 62.5% active malignancy, 53.2% on anticancer therapy	UK, Spain, Italy, Germany	COVID-19 complications: sepsis, septic shock, ARDS, multiorgan failure, mortality	Male gender, age ≥65, ≥2 comorbidities significantly associated with severe COVID-19Systemic anticancer therapy was not associated with COVID-19 severity and mortality.
Grassino et al.[11]	The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT)	Effect of COVID-19 on patients with thoracic malignancies.	200 patients with thoracic cancer; 76% NSLC; 74% of patients were on therapy; 76% were hospitalized	Global (20 countries)	ICU admission; death	Age ≥65, active smoking, higher stage of cancer, were associated with increased risk of death
Lee et al.[13]	UK Coronavirus Cancer Monitoring Project (UKCCMP)	Clinical and demographic characteristics and COVID-19 outcomes in patients with cancer	800 patients with cancer and symptomatic COVID-19; 52% mild COVID-19	UK	All-cause mortality	Age, male gender and comorbidities were identified as risk factors for mortality.Recent chemotherapy was not associated with a worse mortality rate after multivariate analysis.
de Joode et al.[14]	Dutch oncology COVID-19 consortium (DOCC)	To identify risk factors associated with COVID-19 worse outcome.	351 patients with cancer and COVID-19; 13.4% NSLC; 43.6% on chemotherapy	Netherlands	COVID-19 mortality	Age ≥ 65, male gender, prior or other malignancy, and active diagnosis of haematological malignancy or lung cancer were independent risk factors for a fatal outcome of COVID-19
Joerger et al.[15▪]	Swiss Group for Clinical Cancer Research, SAKK 80/20 CaSA	Outcome of COVID-19 on cancer patients and prognostic factors	455 patients with cancer; 26.3% haematological cancer, 12.5% with lung cancer; 49.2% on systematic anticancer therapy	Switzerland	Mortality, rate of hospitalization, ICU admission	Age ≥65 vs. and palliative treatments associated with poor outcomes.
Lièvre et al.[16]	French observational cohort GCO-002 CACOVID-19	Identify risk factors in cancer patients with COVID-19 associated with severity and mortality	1289 with cancer 24% with thoracic cancer; 82% symptomatic COVID-19; 59% systematic anticancer therapy	French	Mortality, admission to ICU and/or mechanical ventilation	Male gender, PS >2, admission to ICU were associated with death.Thoracic primary tumour and corticosteroids prior to COVID-19 2 diagnosis related to an increased COVID-19 severity

COVID-19, coronavirus disease 2019; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ICU, intensive care unit; NSLC, nonsmall lung cancer.

COVID-19 and cancer consortium (CCC19) study reported a case fatality rate of 13% in COVID-19 in patients with active or previous cancer. Cancer type and anticancer therapy were not associated with survival [5]. Another analysis in a larger population revealed that increased age, smoking habit, male gender, multiple comorbidities, haematological malignancies and recent chemotherapy were associated with more frequent intensive care unit (ICU) admission, mechanical ventilation and death in COVID-19 patients with cancer [6]. In particular, platinum-etoposide, R-CHOP-like, and DNA methyltransferase inhibitor regimens were associated with the highest overall all-cause mortality during 30 days follow-up. Immunosuppressive effect, COVID-19 lung involvement in patients with lung cancer receiving platinum doublets, and variability of anticancer regimens may play a role in these results. In addition, another observational cohort study, revealed that patients with lymphoma, leukaemia, and myeloma had a more severe COVID-19 trajectory compared with patients with solid organ tumours, and recent use of chemotherapy among these patients was associated with increased risk of death during COVID-19. Of interest, patients with lung cancer were not characterized by an increased case–fatality rate compared with the remaining patients with COVID-19 and cancer [7]. This result was explained by under-representation of lung cancer patients and a possible effective shielding of patients with lung cancer at an early stage.

Data from the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study reported that cancer was associated with increased mortality in hospitalized patients with COVID-19: hazard ratio (HR): 1.13 (1.02–1.24). Shortness of breath and fever were present in about 70% of patients and only 4.5% of patients reported no symptoms on admission [8]. Overall mortality rate among hospitalized patients with cancer and COVID-19 was 35%, and among patients admitted to ICU up to 45%. Patients admitted for other conditions which tested positive during hospitalization, were also included in this study [9].

An observational multicentre study including 890 patients with cancer and COVID-19, reported a mortality rate of 33.3%. Active cancer was present in 62.5% of patients and advanced stage cancer in 43.8% of participants. At COVID-19 diagnosis, 53.2% of participants were on active anticancer therapy. Cytotoxic therapy, immunotherapy and targeted therapy were not associated with COVID-19 severity and anticancer therapy was associated with lower odds of complicated COVID-19 disease: odds ratio (OR): 0.68 (0.48–1.00). It should be mentioned that patients on anticancer treatment were younger, most frequently female and presented less comorbidities [10]. The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) study is a multicentre observational study composed of a longitudinal and cross-sectional cohort, where patients with thoracic malignancies and COVID-19 were included. At the time of COVID-19 diagnosis 74% of patients were on anticancer therapy, 76% were hospitalized and overall mortality rate was 33%. Only 9% of patients were admitted at the ICU. The authors explained the low rate of ICU admissions by the heterogeneity of the included hospitals (general hospitals, comprehensive cancer centres), and institutional choices related to equipment, personal and presence of terminal illness. Smoking habit resulted as the only factor negatively associated with poor prognosis in this population [11,12]. UK Coronavirus Cancer Monitoring Project (UKCCMP) clinical registry, included patients with active cancer and COVID-19 infection. 52% of patients had a mild COVID-19 disease course and 35% received chemotherapy within one month prior to COVID-19 infection. Multivariate analysis adjusted for confounders revealed that chemotherapy had no effect on mortality from COVID-19 disease. Furthermore immunotherapy, hormonal therapy, targeted therapy, and radiotherapy had no significant effect on mortality related to COVID-19 course [13] (ONS).

Dutch Oncology COVID-19 Consortium (DOCC) study revealed that in COVID-19 patients with cancer or on cancer treatment during the last 5 years, mortality rate was 32.5%. Age, male gender, haematological malignancy and lung cancer were independent risk factors for a fatal outcome of COVID-19. Recent anticancer treatments (<30 days prior to positivity for COVID-19) was not associated with fatal COVID-19 fata outcome [14].

A cross-sectional study conducted by the Swiss Group for Clinical Cancer Research (SAKK 80/20), focused on information regarding COVID-19 in patients with active or previous cancer. The majority of participants were affected by haematological malignancy 26.3% and the frequency of lung cancer was 12.5%. The mortality rate in all patients with cancer was 21.5% and 51.6% in patients admitted at ICU. Age over 65 years, and noncurative cancers were independent associated with mortality, but haematological vs. other cancer types, did not result significantly associated with mortality. Immunotherapy, chemotherapy and steroids did not influence survival [15^▪].

A French national multicentre observational cohort where data from patients with solid cancer and COIVD-19 were analysed, observed that the mortality rate in overall was 29%. Among patients affected by thoracic cancer, mortality rate reached 36%, which was the highest mortality rate of all tumour locations. Corticosteroid therapy prior to COVID-19 was associated with worse prognosis including ICU admission, mechanical ventilation and death. Cytotoxic chemotherapy administered within 3 months before the COVID-19 diagnosis, was not associated with negative outcome OR 1.32 (0.92–1.89). However, in this study COVID-19 diagnosis was based not only on RT-PCR positivity but also clinical presentation and or computer tomography (CT) imaging and serological positivity for SARS-CoV-2 infection. Indeed, sub-analysis of patients with RT-PCR positivity revealed that chemotherapy was significantly associated with worse outcome: OR 1.53 (1.00–2.34) [16].

Table 1 summarizes the above-mentioned studies.

MECHANISMS OF SARS-COV-2 INFECTION: IMPLICATIONS FOR SEVERE COVID-19 IN PATIENTS WITH LUNG CANCER

Since the beginning of the SARS-CoV-2 pandemic, the management of COVID-19 patients with lung cancer has been challenging because of the absence of comprehensive recognition of complex underlying mechanisms [17]. In this section we discuss about the possible pathophysiological mechanism which may influence the severity of COVID-19 disease among lung cancer patients. Patients with lung cancer are characterized by alternations of alveolar epithelium, pulmonary vessels and modification of immune cells properties. Cancer cells promote inflammation, lead to chronic proliferation, alter energy metabolism and evade the immune system [18]. In addition, in the lung cancer tissue was found an upregulation of angiotensin-converting enzyme 2 (ACE2), the main receptor of SARS-CoV-2 [19,20] but the signal pathways that stimulate this upregulation is not well established [21,22]. Although it has been shown that SARS-CoV-2 can enter the cells via other mechanisms, its preferential way is through the interaction between ACE2 and the SARS-CoV-2 spike protein (S) [20–23]. SARS-CoV-2 infection can be divided in three feedback loops: the viral; hyperinflammatory, and the hypercoagulation loop. The viral loop is related to hyperactivation of the immune response which induces the hyperinflammatory loop that is the cause of the uncontrolled inflammatory response, recruitment of the immune cells to the infection sites and generation of cytokine storm. The last loop is due to the interaction between the over-activation of the inflammatory response and coagulation pathways with the hyperactivation of the complement system, which in COVID-19 patients is the cause of microvascular thrombosis, microangiopathy, thrombocytopenia, prolongation of the prothrombin time. The result of this cascade of events leads to an immune-mediated lung dysfunction with consequent acute respiratory distress syndrome [24–26]. In this scenario, different mechanisms could play together and predispose patients with lung cancer to develop severe conditions if infected [27]. First, the compromised immune system associated with the higher expression of ACE2 in lung cancer tissue could promote viral infection and predispose to severe pathology. Second, a further increase of specific chemokine as C-X-C motif or C−C motif and interleukin (IL)-1 due to SARS-CoV-2 infection in lung cancer patients already characterized by a high level of inflammation could lead to the cytokine storm that is associated with the worst outcome and a loss of function of the lung [28]. Third, in patients with lung cancer, SARS-CoV-2 infection could quickly progress to a severe phase because in these patients the immune system is weakened by the chemotherapy, radiotherapy, or immune checkpoint inhibitors treatment. The risk of the infection is higher than in the general population because each of these treatments potentially induces an increased possibility of infection or an increased risk of inflammatory syndrome and acute COVID-19 pneumonia [29]. In addition, patients with cancer have several risk factors for developing thromboses such as surgery, immobilization, the presence of the central catheter for administration of the chemotherapeutics drugs, and the hypercoagulable state due to the presence of tumour cells. The predisposition to thrombi formation is probably due to several interdependent mechanisms and the main role is played by tissue factor, inflammatory cytokines, and platelets. Altogether, these mechanisms increase the risk of thrombosis that can be further exacerbated by COVID-19 infection leading to a poor prognosis [30–32].

SAFETY AND EFFICACY OF SARS-COV-2 VACCINE IN PREVENTING SEVERE COVID-19 AMONG LUNG CANCER PATIENTS

In response to the global public health crisis caused by the COVID-19 pandemic, efforts were accelerated to develop safe and effective vaccines against SARS-CoV-2 [33,34].

In a prospective study involving 306 thoracic cancer patients receiving vaccine Gounant et al. reported no anaphylactic reaction or severe reactions. Two thirds of the population developed mild symptoms after the first and/or second dose lasting <36 h [35,36]. After a 6.7-month median follow-up, 2.6% of patients contracted proven symptomatic SARS-CoV-2 infection, with rapid favourable evolution. Higher rate of adverse effects, but none severe, has been described in lung cancer patients receiving immunotherapy [37]. Importantly, safety is similar to the general population whit local and grade 1 systemic reactions and no new immune-related adverse effects or exacerbation of existing immune-related adverse effects were observed.

With regard to efficacy, cancer patients seem to develop a weaker serological response to vaccinations than the healthy population, regardless of the type and stage of the tumour and the therapy received [38]. In these subjects, cancer as well as related treatments may impair the immune response after vaccination with dramatic consequences in case of infection. Zenga et al. analysed the antibody response after COVID-19 vaccine of 160 cancer patients and that of 46 healthy volunteers by using a sensitive high-throughput lentivirus-based SARS-CoV-2 neutralization assay [39]. Authors reported that 31% of lung cancer patients did not develop a sufficient antibody response. Specifically, patients undergoing immunotherapy showed a lower and less lasting antibody response over time than other cancer patients. There is also evidence that patients with lung cancer may developed a decreased antibody response when treated with radiotherapy and immunosuppressive therapy compared to patients treated only with radiotherapy [40^▪]. Although these are all encouraging data on the safety and efficacy of the COVID-19 vaccine in lung cancer patients, hesitation to receive the vaccine is still high [41]. However, more studies will be needed to definitively assess the long-term efficacy of COVID-19 vaccines. Studies with a larger sample size and longer observation period would be needed to evaluate the use of any additional doses in immunocompromised patients for adequate protection.

LUNG CANCER MULTIDISCIPLINARY MANAGEMENT IN PATIENTS DURING COVID-19 PANDEMIC

Impact of COVID-19 on lung cancer early detection

Lung cancer mortality remains high despite the progresses in defining the complex underlying mechanisms [42,43] and novel insights into the therapeutic landscape [44–46]. Surgery is the only radical treatment for lung cancer. However, advanced stages at the time of the diagnosis and the presence of concurrent comorbid conditions limit the access to surgery [47–49]. National Lung Screening Trial annual lung cancer screening using low-dose computed tomography (LDCT) documented significant reduction in lung cancer-specific mortality by at least 20% [50].

However, the impact of COVID-19 on lung cancer screening and management is significant, mainly related to the delaying of care. Stay at home orders, associated to COVID-19 pandemic have caused a temporary global stoppage of the usual healthcare activity, particularly in the form of the cancellation or delay of nonemergent medical services such as cancer screening programs, including lung cancer screening. Indeed, a recent study reported that the screening of cancer declined drastically because of COVID-19 [51]. Other findings demonstrated a 38% reduction in new lung cancer diagnoses in 2020 in contrast to the pre-COVID-19 era [52,53^▪▪]. Khorana et al. demonstrated an increase in death in patients with cancer for each week of delay to the initiation of cancer treatments [54]. Furthermore, elderly, ex-smokers, and patients with comorbidities had a high risk of developing severe complications after COVID-19 infections [55]. Furthermore, COVID-19 hospital transmission in hospitalized patients with lung cancer is important however a study revealed that hospital transmission was very rare and concluded that there was no avoidance or delay in hospital care can be justified by concern about viral transmission [56].

COVID-19 transmission has also important consequences in diagnostic and therapy techniques.

Indeed, Serra et al. detected as diagnostic methods used, a slight decrease in the diagnoses reached through endoscopy and/or surgery, albeit none statistically significant. As aerosol-generating procedures, bronchoscopy is associated with the risk of SARS-CoV-2 accidental transmission, possible putting healthcare workers at risk [57,58]. However, data presented by Gao et al.[59] and Torrego et al.[60] about bronchoscopy on intubated patients with COVID-19 suggest procedural safety and a low risk of SARS-CoV-2 transmission when appropriate recommendations are followed, as procedures performed in negative pressure, all involved healthcare workers used appropriate personal protective equipment and the number of workers involved was minimized. Therefore, diagnostic and therapeutic bronchoscopy need to be carefully evaluated on individual basis taking in consideration potential benefits in early diagnosis and molecular lung cancer profiling [61], potential application of therapeutic endobronchial interventions [62,63] and SARS-CoV2 infection risk of lung cancer patients.

The COVID-19 pandemic had dramatic consequences on molecular testing for thoracic malignancies, and Liquid biopsy may be a valid alternative for the diagnostic purposes of patients with cancer, considering the SARS-CoV-2 infection risk]. Indeed, plasma-circulating tumour DNA (ctDNA) was approved as a predictive biomarker for selective treatments in NSCLC patients [64]. Rolfo et al. propose to implement a home phlebotomy service and/or mobile units for blood draws and transport followed by a central NGS analysis of ctDNA [65]. CtDNA concentration was higher in advanced-stage cancer patients compared to early stage [66]. Furthermore, liquid biopsy, in recent years have shown a promising approach to detecting tumour-associated mutations in the early stage of NSCLC, as reported by Perez-Ramirez et al. and Chen et al.[67,68]. Hence, this unprecedented health emergency represented a pivotal step to integrate liquid biopsy into routine clinical practice to minimize the danger of SARS-CoV-2 infection for oncological patients.

Surgical challenges in limited NSCLC stages

In patients with early-stage NSCLC, surgical resection remains the mainstay of management and the most curative approach. To face the rapid spread of SARS-CoV-2 infection, deprioritization of nonemergency procedures resulted as mandatory for healthcare systems worldwide [69,70]. The European Society for Medical Oncology has proposed a structured approach for the surgical management of lung cancer based on three levels of priorities, high, medium and low [71]. A multidisciplinary approach is essential to prioritize surgical procedures with the goal of preserving the highest possible standard and ensuring a timely and adequate cancer treatment [72]. Patients with planned surgical interventions have been recommended to follow social distancing and isolation for 14 days before admission [73]. Though, a higher postoperative pulmonary complication rates has been reported, no differences in terms of both postoperative mortality and SARS-CoV-2 infection rate [74^▪]. RT-PCR test 24–72 h before operation is commonly recommended and all patients should be assessed for any symptoms on admission [75]. This affects the pre- and perioperative management of patients undergoing lung resection limiting the respiratory rehabilitation and interfering with enhanced recovery after surgery (ERAS) programs [49,76,77].

Preoperative pulmonary function assessment is mandatory for lung cancer patients suitable for surgical resection [47,78,79]. There is consensus on deferring surgical treatment when there is a COVID-19 diagnosis preoperatively. However, detrimental impact of delays on survival must be taken into account for aggressive cancers [80,81^▪,82]. Moreover, SARS-CoV-2 infection itself may be associated with poor outcomes [83^▪]. According to the first analysis of the COVID-surg cohort study including 1128 patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery, thoracic surgery had the highest mortality rate at 30 days (42%) [84]. It has been reported that independent predictors of perioperative COVID-19 included male gender, preexisting respiratory disease, open surgery, and the lack of a COVID-19 free surgical pathway. Regarding postoperative pulmonary complication, COVID-19 represented the strongest independent factor underlying the strategic importance of prevention and the containment of virus spread with safety procedures [85,86].

COVID-19 and systemic treatment for locally advanced and metastatic lung cancer

For patients with nonresectable, locally advanced or metastatic NSCLC and in patients with SCLC, different combination of chemotherapy with immune checkpoint inhibitors (ICI) have been investigated and approved [45,71,87–92]. For patients with oncogene-driven NSCLC who are treated with a TKIs, no treatment variations should be considered. However, the use of telemedicine should be included in the follow-up reassessment according the pandemic scenario and local resources [93]. Despite a potential lengthening of treatment cycle, sequential chemoradiotherapy treatment might be considered in order to reduce the toxicity profile [94]. In nononcogene addicted NSCLC, ICI alone or in combination with platinum-based regimens are the cornerstone of the treatment. However, immunotherapy is associated with potential risk of pulmonary toxicity which share clinical and radiological features of COVID-19 pneumonia. In lung cancer patients treated with ICIs who are infected with SARS-CoV2, the CD8+ T-cells overactivation promotes rapid clinical deterioration turning into an excessive immune response [94]. However, other evidences demonstrated that there is no important association between prior PD-1 blockade and the severity of COVID-19 [95]. In the radiotherapy evaluation, it is necessary to consider the volume of the target lesion to limit pneumonitis and symptoms immunosuppression related that may mimic the first sign of COVID 19 infection [92,93]. Hypofractionation of sequential radiotherapy treatment should be considered in case of paucity of resources due to pandemic. Otherwise, consensus is not to change radiotherapy practice to more hypo-fractionated regimens, except for palliative radiotherapy for NSCLC patients. In patients with SCLC, prophylactic brain radiation is regarded as standard treatment for PS 0–2 patients with stage IV SCLC who are less than 75 years old and without progression after first-line chemotherapy. Furthermore, in this patient setting, the use of oral etoposide is to be considered in order to reduce the risk of infection and the number of hospital visits.

CONCLUSION

SARS-CoV-2 infection does undoubtedly represent a challenge for care of patients with lung cancer. Since symptoms of infection may overlap with underlying condition, diagnosis must be reached and treatment should start as soon as possible. Although any cancer treatment should be procrastinated as long as infection is not cured, every choice must be pondered on individual basis, according to clinical conditions. Underdiagnosis should be avoided, and both surgical and medical treatment must be tailored to each patient. Therapeutic scenario standardization represents a major challenge for clinicians and researchers.

Acknowledgements

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Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest