Cancer Chemotherapy and Pharmacology (2020) 86:497–505

https://doi.org/10.1007/s00280-020-04142-9

ORIGINAL ARTICLE

Nivolumab increases pulmonary artery pressure in patients treated

for non‑small cell lung cancer
Ludovic Fournel1,2   · Pascaline Boudou‑Rouquette2,3 · Mathilde Prieto1 · Remi Hervochon4 · Claude Guinet4 ·
Jennifer Arrondeau2,3 · Jérôme Alexandre2,3 · Diane Damotte2,5 · Marie Wislez2,6 · Frédéric Batteux2,7 ·
Philippe Icard1,8 · François Goldwasser2,3 · Marco Alifano1,2

Received: 8 June 2020 / Accepted: 6 September 2020 / Published online: 16 September 2020
© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Purpose  The widespread use of Nivolumab results in an increasing number of side effects and adverse events. Herein, we
evaluated the impact of Nivolumab on crude and normalized pulmonary artery diameter (PAD).
Methods  We analyzed clinical, morphometric, pathological and radiological data of lung cancer patients treated by
Nivolumab in an 18-month period. Blinded radiological evaluation was performed, by three observers measuring axial
PAD and Aorta diameter (AoD) in secondarily matched pre- and post-Nivolumab CT-scans. Correlation between ΔPAD
and clinicopathological data was investigated.
Results  59 patients receiving Nivolumab for treatment of advanced lung carcinoma were identified. Pre-and post-Nivolumab
comparison of CT-scan measures revealed that mean PAD was 26.3 ± 2.8 mm versus 28.0 ± 3.0 mm (p < 0.001), and mean
PAD/AoD ratio was 0.82 ± 0.09 versus 0.87 ± 0.11 (p <  0.001), respectively. Median ΔPAD was 0.05 [0.01–0.122] was signif-
icantly higher in hypometabolic patients exhibiting low Rest Energy Expenditure (p = 0.03). Patients exhibiting ΔPAD > 1%
had significantly lower serum albumin level (p = 0.03), and higher nutritional risk (p = 0.02), compared to others. Unlike
Nivolumab therapy, there was no increase of PAD after chemotherapy in the same cohort of patients with available scans
(n = 45, 25.9 ± 2.9 mm pre-chemotherapy versus 25.7 ± 2.4 mm post-chemotherapy, p = 0.51). Anti-PD-1 treatment was
associated with immune-related adverse events in 11 (18.6%) cases including 2 cases of life-threatening acute pulmonary
hypertension, both exhibiting post-treatment PAD/AoD ratio > 1.
Conclusion  Nivolumab is associated to PAD enlargement, a potential marker of pulmonary hypertension, sometimes leading
to lethal adverse events. Careful CT-scan and echocardiographic evaluation of PAD should be part of the therapeutic work-up
of patients receiving Nivolumab, especially those suffering cancer-associated malnutrition.

Keywords  Nivolumab · Immune check-point inhibitors · Pulmonary artery hypertension · Lung cancer

5
* Ludovic Fournel Pathology Department, Cochin Hospital,
ludovic.fournel@aphp.fr AP-HP.Center-University of Paris, Paris, France
6
1 Respiratory Medicine and Thoracic Oncology Department,
Thoracic Surgery Department, Cochin Hospital, AP-
Cochin Hospital, AP-HP.Center-University of Paris, Paris,
HP.Center-University of Paris, 27 rue du Faubourg
France
Saint‑Jacques, 75014 Paris, France
7
2 Biology and Immunology Department, AP‑HP.Center,
Immunomodulatory Therapies Multidisciplinary
University of Paris, Paris, France
Study Group (CERTIM), Cochin Hospital,
8
AP-HP.Center-University of Paris, Paris, France INSERM U-119, UNICAEN, University of Caen-Normandy,
3 Caen, France
Oncology Department, Cochin Hospital,
AP-HP.Center-University of Paris, Paris, France
4
Radiology Department, Cochin Hospital,
AP-HP.Center-University of Paris, Paris, France

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Introduction
Indications of immune check-point inhibitors (ICI) and
combination therapies are constantly increasing [1–5] for
treatment of non-small cell lung carcinoma (NSCLC), as
it allows satisfactory oncological outcome with safe toxic-
ity profile [6]. Despite a relatively good tolerance, these
treatments are associated with immune-related adverse
events (IRAES), especially pulmonary and cardiovascu-
lar complications, which have been widely reported in
lung cancer [7]. A large pharmacovigilance study focused
on cardiovascular complications which occurred in more
than 30,000 patients who received ICIs [8]. The authors
found that myocarditis, pericarditis, and vasculitis were
the most frequent cardiovascular complications of these
treatments and reported 17 cases of pulmonary artery
hypertension (PAH) with associated cardiac impairment.
Similarly, we observed, in a relatively short time frame,
the occurrence of two cases of acute life-threatening PAH
following treatment by Nivolumab, a human antibody tar-
geting programmed death 1 (PD-1) receptor, the ligands
of which, PDL-1 and PDL-2, are expressed by tumor cells
to escape the immune system [9, 10]. This led our study
group, called CERTIM (Centre d’Etudes et de Recours
sur les Thérapies Immuno-Modulatrices du cancer), to
further investigate on such complications. As surrogate
of invasive investigation of PA pressure, our group pre-
viously suggested that measures of PA diameter (PAD)
could allow detection of increase PA pressure compared to
baseline, and may predict the occurrence of post-pneumo-
nectomy respiratory failure in lung cancer patients under-
going upfront or post-chemotherapy surgical treatment of
NSCLC [11].
Thus, in this study, we aimed at evaluating the impact
of Nivolumab on PAD in a well-characterized prospective
cohort of metastatic lung cancer patients, and to analyze
factors potentially associated with increased PAD, in par-
ticular metabolic variables.
Patients and methods
Clinical data collection
We analyzed the data of all patients who received
Nivolumab (3 mg/kg/dose, every 2 weeks) for treatment
of advanced-stage NSCLC, in an 18-month period (July
2015–December 2016). Clinical, pathological and survival
data were prospectively collected. Ideal weight was cal-
culated using the Lorentz formula [12] and rest energy
expenditure (REE) was determined prior to treatments,
13
Cancer Chemotherapy and Pharmacology (2020) 86:497–505
under standard resting conditions. Measured REE
(mREE, kcal/d) was determined from VO2 using Weir’s
equation [13]. The nutritional risk index (NRI) was cal-
culated at each time point using the following formula:
NRI = (1.519 × albumin (g/dl) − 1) + 41.7 (present weight/
ideal weight) [14, 15]. Patients were stratified according
to the risk of malnutrition: NRI score ≥ 100: no risk; NRI
83.5–100: mild/moderate risk; NRI < 83.5: major risk.
Radiological analysis
Computed-tomography measures were performed retro-
spectively on pre- and first post-treatment CT-imaging
which was prospectively stored in the PACS system of
our hospital. As a general rule, first CT-scan evaluation
of Nivolumab treatment was usually performed after the
4th injection and allowed classification of tumor response
according to RECIST 1.1 criteria [16]. As previously sug-
gested in COPD patients or by the American college of
radiology appropriateness criteria guidelines, CT-scan
allows a reproducible diagnosis of PAH when PAD/Aorta
Diameter (AoD) ratio is major to 1 [17, 18]. Usually, the
level of PAD measure was at the pulmonary artery bifur-
cation, in an axial plane, trying to be perpendicular to the
flow. This radiological evaluation was performed, in com-
plete blinded analysis, by three observers, including two
radiologists. Inter-observer consensus was obtained per-
forming the mean of all three measures. The variation of
PAD between matched measures was expressed as ΔPAD,
defined by the following formula: (post-Nivolumab PAD
– pre-Nivolumab PAD)/pre-Nivolumab PAD.
Ethics
The study has been submitted and approved by our Institu-
tional Review Board of oncology (Comité Local d’Ethique
en Cancérologie Clinique, approval number: 661827). It
was carried out according to the Helsinki Declaration and
to the applicable French biomedical legislation.
Statistics
Descriptive statistics were expressed as mean ± standard
deviation or median [25th–75th percentiles] for quantita-
tive variables and as frequencies (percentages) for qualita-
tive variables. Between-group comparison was performed
using Chi-square, Mann–Whitney’s or Student’s t tests,
where appropriate. Variables with a p value < 0.05 were
considered statistically significant.
Cancer Chemotherapy and Pharmacology (2020) 86:497–505 499

Results Table 1  Patients’ characteristics prior to Nivolumab therapy

Variable Mean ± SD or n (%)
Patient characteristics
Gender
We identified a total of 59 patients with available matched  Male 38 (64.4)
pre- and post-Nivolumab therapy CT-scans, in the study  Female 21 (35.6)
period. All patients were current or former smokers and Age (years) 64.2 (± 10.4)
52.5% of them received Nivolumab for treatment of an BMI (kg/m2) 24.4 (± 4.0)
advanced-stage pulmonary adenocarcinoma. Other demo- Smoking history
graphic characteristics of the cohort are summarized in  Never-smoker 0 (0.0)
Table 1. Indication for ICIs was in all the cases failure of  Former-smoker 49 (83.1)
previous systemic treatments, with most patients receiv-  Current-smoker 10 (16.9)
ing Nivolumab for disease progression or relapse follow- COPD
ing a first line of chemotherapy. First CT-scan evalua-  Yes 10 (16.9)
tion, performed after three (20.3%) or four (79.7%) cures  No 49 (83.1)
of Nivolumab, showed disease progression, stability or Cardiovascular disease (including treated arte-
rial hypertension)
regression in 82.6%, 4.3%, and 13.1% of cases, respectively,
 Yes 23 (39.0)
according to RECIST criteria.
 No 36 (61.0)
Autoimmune disease
 Yes 8 (13.6)
PAD enlargement after Nivolumab and influencing
 No 51 (86.4)
factors
Performance status
 0 6 (10.2)
Radiological analysis of the whole cohort revealed that
 1 28 (47.5)
mean pre-and post-Nivolumab PAD were 26.3 ± 2.8 mm
 2 21 (35.6)
and 28.0 ± 3.0 mm, respectively (p < 0.001, Fig. 1). In addi-
 3 4 (6.8)
tion, mean pre- and post-treatment PAD/AoD ratios were
Number of previous lines of chemotherapy
0.82 ± 0.09 and 0.87 ± 0.11, respectively (p < 0.001). Moreo-
 1 38 (64.4)
ver, the inter-observer variability was tested and Lin’s con-
 2 11 (18.6)
cordance coefficient was 0.91 for PAD measures.
 3 10 (17.0)
There was no significant change in CT-scan appearances
NRI
of lung parenchyma compared to baseline, and no observed
 No risk 40 (67.8)
distal or proximal thromboembolism, in all cases. Median
 Mild/moderate risk 13 (22.0)
and mean ΔPAD were 0.05 [0.01–0.122] and 0.06 ± 0.01,
 Severe risk 6 (10.2)
respectively. When analyzed as a continuous variable, it
Serum albumin (g/L) 39.2 (± 4.7)
was significantly higher in patients exhibiting low mREE
Serum creatinine (µMol/L) 83.8 (± 35.0)
(p = 0.03) (Table 2).
MDRD (mL/mn/1.73 m ­ 2) 86.7 (± 29.9)
Dichotomization of ΔPAD using 1% as cut-off value
C-reactive protein (mg/L) 28.4 (± 10.8)
(first quartile) showed that patients exhibiting ΔPAD > 1%
Lymphocytes (g/L) 1.35 (± 0.67)
(64.4% of the whole cohort) had significantly lower serum
Histologic type of lung carcinomas
albumin level (p = 0.03), and lower NRI status (p = 0.02).
 ADK 31 (52.5)
No other factor, including radiological tumor response to
 SCC 14 (23.7)
Nivolumab therapy and histologic type was associated with
 LCC 10 (16.9)
ΔPAD analyzed either as a continuous or a dichotomous
 LCNEC 4 (6.8)
variable (Table 3).
 PD-L1 (%) 17.7 (± 31.4)

BMI body mass index; COPD chronic obstructive pulmonary disease;

“Control” analysis of standard chemotherapy MDRD modification of diet in renal disease; ADK adenocarcinoma;
treatment SCC squamous-cell carcinoma; LCC large cell carcinoma; LCNEC
large-cell neuroendocrine carcinoma; PD-L1 percentage of PD-L1
stained tumor cells in lung primary samples
Among the same cohort of patients, available CT-scans
of those who received prior chemotherapy regimen were
analyzed to measure PA and aorta diameters and assess

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500 Cancer Chemotherapy and Pharmacology (2020) 86:497–505

***
Table 2  Risk factor analysis of ΔPAD

30 Category Mean % of ΔPAD p value

(± SEM)

28 Renal clearance (cockroft)

Mean PAD (mm)

 < 80 5.4 (2.1) 0.86

26  ≥ 80 5.9 (2.1)
C-reactive protein (mg/L)
24  < 50 6.3 (1.9) 0.91
 ≥ 50 6.8 (1.7)
22 Histological type
 ADK 5.7 (1.4) 0.77
20  Other 6.4 (2.1)
Occurrence of IRAE
t

t
en

en
 Yes 3.1 (2.3) 0.62
tm

m
at

 No 5.9 (1.5)

ea

re
tr

-t

PD-L1 (%)
e-

st
Pr

Po

 < 50 4.6 (1.5) 0.54

 ≥ 50 7.2 (5.9)
Fig. 1  Comparison of pre- and post-Nivolumab-treatment mean pul- BMI (kg/m2)
monary artery diameter; *** indicates a p value < 0.001
 < 19 1.4 (3.9) 0.35
 ≥ 19 6.5 (1.4)
mREE (kcal/d)
a potential impact of other systemic treatments than
 < 1000 20.3 (21.9) 0.03
Nivolumab. Matched scans at initiation and first radiologi-
 ≥ 1000 5.5 (1.4)
cal revaluation were compared in 45 patients and showed no
Serum albumin (g/L)
significant difference between mean PAD before and after
 < 30 8.2 (4.9) 0.76
chemotherapy (25.9 ± 2.9 mm versus 25.7 ± 2.4 mm, respec-
 ≥ 30 6.3 (1.6)
tively, p = 0.51). Similarly, paired analysis of PAD/Ao ratio
NRI
did not reveal any statistically significant effect of chemo-
 < 100 9.2 (3.2) 0.08
therapy on that parameter (0.77 ± 0.09 versus 0.77 ± 0.11,
 ≥ 100 3.8 (1.4)
p = 0.99).
Also, comparison of baseline pre-chemotherapy and pre- ADK adenocarcinoma; IRAE immune-related adverse-events; PD-L1
Nivolumab PAD measures revealed no statistical difference programmed-death ligand-1; BMI body mass index; mREE measured
with mean PAD of 25.9 mm and 26.3 mm, respectively rest energy expenditure; NRI nutritional risk index
(p = 0.55).
PAD and PAD/AoD ratio remained significantly higher after
Nivolumab treatment (both p < 0.001).
Life threatening PAH after Nivolumab

Nivolumab treatment was associated with no significant Discussion

toxicity in 48 (81.4%) patients, whereas IRAEs were diag-
nosed in the remaining 11 (18.6%) cases, including five
major complications: pneumonitis (n = 1), hypophysitis
(n = 1), myocarditis (n = 1), and life-threatening acute pul-
monary hypertension (n = 2). In these latter cases, symptoms
of acute respiratory failure required urgent ICU admission,
where pulmonary embolism, acute left ventricular dysfunc-
tion, and infectious pneumonia or acute pneumonitis were
quickly ruled out. In both patients, PAD/AoD ratio was > 1
(Fig. 2), and in one case OX40-ligand and anti-nuclear anti-
bodies’ serum levels were doubled compared to upper range
standard values (Table 4). Excluding these two cases from
the radiological comparative analysis of the whole cohort,
Relevance of PAD enlargement
In the present study, we show that Nivolumab treatment is
associated with an increase in crude and normalized PAD,
in advanced-stage NSCLC patients. This observation, which
was not found in these patients after standard chemotherapy
regimen, raises important questions as it might reflect the
occurrence of symptomatic or subclinical PAH. Although
PA pressure was not monitored by right-catheterism or
matched echocardiography in the current practice, out of a
clinical trial, an increased PAD could be relied to the eleva-
tion, even slightly, of PA pressure compared to baseline, as

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Cancer Chemotherapy and Pharmacology (2020) 86:497–505 501

Table 3  Interrelationship between dichotomized ΔPAD and patients
characteristics
Variable
Renal clearance (cockroft)
C-reactive protein (mg/L)
Rate of patients in progression
Rate of patients exhibiting
IRAEs
PD-L1 (%)
Rate of patients with
BMI < 19 kg/m2
mREE (kcal/d)
Serum albumin (g/L)
NRI
IRAE immune-related adverse-events; PD-L1 programmed-death
ligand-1; BMI body mass index; mREE measured rest energy expend-
iture; NRI nutritional risk index
PAH to life-threatening conditions. In the previously cited
study analyzing numerous cardiovascular adverse events of
Mean (± SEM) or p value ICIs, the authors reported 17 cases of PAH which were too
frequency in the two few to conclude to a reliable statistical association between
subgroups this complication and treatment, in terms of pharmacovigi-
(a) ΔPAD > 1%
(b) ΔPAD ≤ 1% lance (the related “information component value” was irrel-
evant) [8]. If the relatively high ratio (2/59 patients, 2.4%)
that we observed is probably due to statistical hazard, the
(a) 83.4 (6.0) 0.29 strong significance of PAD enlargement found in a small
(b) 73.3 (6.9) cohort suggests that this finding could be very reproducible
in larger populations.
(a) 33.0 (9.0) 0.31
(b) 20.0 (5.1) Involved mechanisms
(a) 82.8% 0.63 Beyond the potential clinical consequences of PAD enlarge-
(b) 82.4% ment, raises the question of implicated mechanisms link-
ing NSCLC patients, ICIs and PA diameter. Considering
the absence of pulmonary artery thromboembolism in these
(a) 15.8% 0.34
cancer patients, a first hypothesis could link PAD to tumor
(b) 23.8%
response and growth delay after systemic treatments, which
is likely ruled-out by the “control” analysis. One of the
(a) 17.9 (5.8) 0.97
most intuitive mechanisms leads PAD elevation to auto-
(b) 17.5 (8.2)
immunity like other IRAEs impairing the cardiovascular
system [22–24]. Biomarkers, such as OX40/OX40-ligand
or anti-nuclear antibodies [25], can theoretically be used as
(a) 5.3% 0.43
diagnostic tools in cases of IRAEs but were not routinely
(b) 10%
investigated in the serum of study patients. Thus, we should
be cautious before drawing any conclusion despite dou-
(a) 1662.9 (84.9) 0.45
(b) 1548.7 (124.9)
bling of OX40-ligand serum level in one of the two cases
of severe acute PAH. The relatively frequent occurrence of
(a) 31.8 (0.9) 0.03
pneumonitis among Nivolumab-related major IRAEs could
(b) 41.2 (0.9)
also account for PAD enlargement or pressure increase
[26]. Indeed, it could be argued that pneumonitis induces
(a) 99.2 (1.5) 0.02
secondary subclinical or clinical PAH and that Nivolumab
(b) 104.9 (1.2)
does not have any direct effect on PA, but our results do
not support this mechanism and showed no significant asso-
ciation between ΔPAD and occurrence of IRAEs including
pneumonitis.

Impact of metabolic parameters

demonstrated in many studies evaluating the performance of
non-invasive techniques for PAH diagnosis [17, 19]. Indeed,
measure of PAD (and PAD/AoD ratio) is used in COPD
patients to assess clinical PAH, thus we can extrapolate that
an increase of PAD is related to higher pulmonary artery
pressure compared to baseline [20, 21]. The absolute value
of PAD difference might seem small and little meaningful
(26.3 versus 28.0 pre- and post-treatment) but it results on
measures performed in only one axis, and these few millim-
eters could have greater physiological significance in terms
of hemodynamics, as it represents an increase of approxi-
mately 15% in surface. As seen in two patients from our
cohort, increased PA pressure could lead from subclinical
The statistical association between ΔPAD and nutritional
or metabolic characteristics, such as serum albumin level,
mREE and NRI status, suggests a possible impact of metabo-
lism in Nivolumab-associated PAD enlargement. It is known
that different types of cancers induce metabolic reprogram-
ing, for example higher REE is more frequent in patients
with pancreatic or lung cancers [27]. The inter-relationship
between metabolism and immunity, in the setting of cancer
patients, is complex and remains unclear [28, 29]. Inter-
estingly, the activation of T-lymphocytes induces a switch
from oxidative to glycolytic metabolism which theoretically
modifies lactate and pyruvate levels in cells [28]. In turn, it

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502
Fig. 2  Axial chest CT at the level of pulmonary artery trunk bifur-
cation with measurements of PAD (28.4  mm) and AoD (32.3  mm)
allowing calculation of PAD/AoD ratio (0.88), before initiation of
Nivolumab therapy (a); same measurements of PAD (36.0 mm) and
AoD (32.5  mm) after the 4th dose of Nivolumab (b) showing that
PAD/AoD ratio is increased (1.11) suggesting the occurrence of pul-
has been demonstrated that accumulation of pyruvate in the
mitochondria of some immune cells up-regulates bone mor-
phogenetic protein-4 (BMP4), a key cytokine of pulmonary
arterial circulation [30–32], part of the BMP family, which
is increasingly studied in lung cancer [33, 34] and also in
PD-L1 regulation [35]. Thus, PD-1/PD-L1 blockade could
result in BMP4 upregulation and induce a modulation of PA
via metabolic effectors impacting pulmonary endothelial and
smooth muscle cells. However, this link between ICIs and
PAH remains hypothetical and requires further mechanistic
explorations before drawing any conclusion.
Limitations
A major limitation of this analysis is related to the radiologi-
cal methodology of ΔPAD measurement as a surrogate of
invasive assessment of PA pressure. Although widely dis-
cussed and argued above, the calculation of ΔPAD variable
implies some intrinsic drawbacks such as difference in the
level of measurement between pre- and post-Nivolumab CT-
scans, inter-observer variability or absence of cardiac gating
[19, 21]. Nevertheless, we tried to minimize the impact of
these biases by performing triple-observer and blind CT-
scan measurements, possibly allowing extrapolation of
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Cancer Chemotherapy and Pharmacology (2020) 86:497–505
monary hypertension as superior to 1; sagittal chest CT at the level
of pulmonary artery trunk bifurcation with measurements of PAD
(28.8  mm) before initiation of Nivolumab therapy (c) and after the
4th dose of Nivolumab (PAD = 35.7) (d), confirming the enlargement
of PA in another axis
the results to PA pressure without invasive method (right-
catheterization). In addition, the relatively small number of
cases included in this cohort likely explains why we failed to
evidence significant impact of “intuitive” factors on ΔPAD
like PD-L1 expression by tumor cells or clinical response
to therapy. To better elucidate the mechanisms implicated
in the modulation of PAD by ICIs further preclinical and
clinical investigations are needed. In particular, perform-
ing late measures of PAD in patients receiving “long-time”
Nivolumab treatment would be of interest to evaluate
whether the observed effect is transitory or persistent.
Conclusion
The administration of Nivolumab can induce an enlargement
of pulmonary artery possibly leading to several complica-
tions ranging from subclinical PAH and presumed biological
manifestations to life-threatening right cardiogenic shock.
Careful CT-scan and echocardiographic evaluation of PAD
and pressure should be part of the pre- and post-therapeutic
work-up, especially in malnourished patients.
Cancer Chemotherapy and Pharmacology (2020) 86:497–505 503

Table 4  Characteristics of the two patients admitted for acute PAH

Patient 1 Patient 2

Gender/age (years) Male/69 Male/42

Medical history Smoking (100 pack-years) COPD, GOLD 2
Hypercholesterolemia
COPD, GOLD 2
Body mass index 29.0 kg/m2 22.6 kg/m2
Serum albumin 38 g/L 39 g/L
GFR evaluation
 Creatinine clearance (cockroft-Gault equation) 121 mL/min 106 mL/min
 Cystatin C clearance (Hoek equation) 93 mL/min 64 mL/min
Primary cancer type Lung micropapillary adenocarcinoma Lung adenocarcinoma
Previous oncologic treatments Right inferior lobectomy, Cisplatin + gemcitabine Cisplatin + pemetrexed
Pemetrexed + bevacizumab
Docetaxel + bevacizumab
Total number of Nivolumab doses received 4 doses 4 doses
(3 mg/kg/dose)
Time between diagnosis of APH since therapy 58 days 52 days
start
Treatment at ICU Oxygen, glucocorticoids, antibiotics, Mechanical Oxygen, glucocorticoids, antibiotics
ventilation, Furosemide and nitric oxide, then
inotropic agents
Status Deceased (day 10 after admission) Deceased (day 11 after admission)
Echocardiography features sPAP = 60 sPAP = 75
Right ventricular dilatation LVEF = 70%
Patent foramen ovale Paradoxical interventricular septal motion
Pre-treatment mean ± SD PAD/AoD ratio 0.88 0.99
Post treatment mean ± SD PAD/AoD ratio 1.11 1.20

COPD chronic obstructive pulmonary disease; GFR glomerular filtration rate; sPAP systolic pulmonary arterial pressure (mmHg) at echocardi-
ography evaluation; LVEF left ventricular ejection fraction (%); PAD/AoD ratio pulmonary artery (PAD): aorta (AoD) diameters Ratio, meas-
ured at the level of the pulmonary arterial bifurcation; ADK adenocarcinoma; IRAE immune-related adverse-events; PD-L1 programmed-death
ligand-1; BMI body mass index; mREE measured rest energy expenditure; NRI nutritional risk index

Acknowledgements  The authors thank Mr Graham Donlon for English References

language reviewing.
Author contributions  LF, corresponding author, is the guarantor
of the content of the manuscript. LF: study design, data collection,
manuscript writing. PBR, MP, and JAR: data collection. RH and CG:
radiological data collection and analysis. JAL, DD, MW, FB, PI: study
design, data interpretation, and manuscript review. FG and MA: study
design, data analysis and interpretation, manuscript writing and final
review.
Funding  This research has no funding source.
Data availability Available.
Compliance with ethical standards  MC, Garassino MC, KEYNOTE-189 investigators (2018) Pem-
Conflict of interest  The authors have no conflict of interest to declare.
3. Yamaguchi O, Kaira K, Hashimoto K, Mouri A, Miura Y,
1. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hell-
mann MD, Zahurak M, Yang SC, Jones DR, Broderick S, Bat-
tafarano RJ, Velez MJ, Rekhtman N, Olah Z, Naidoo J, Marrone
KA, Verde F, Guo H, Zhang J, Caushi JX, Chan HY, Sidhom J-W,
Scharpf RB, White J, Gabrielson E, Wang H, Rosner GL, Rusch
V, Wolchok JD, Merghoub T, Taube JM, Velculescu VE, Topalian
SL, Brahmer JR, Pardoll DM (2018) Neoadjuvant PD-1 blockade
in resectable lung cancer. N Engl J Med 378:1976–1986. https​://
doi.org/10.1056/NEJMo​a1716​078
2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E,
De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF,
Cheng SY-S, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck
M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S,
Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza
brolizumab plus chemotherapy in metastatic non-small-cell lung
cancer. N Engl J Med 378:2078–2092. https​://doi.org/10.1056/
NEJMo​a1801​005
Shiono A, Nishihara F, Murayama Y, Noda S-E, Kato S, Kob-
ayashi K, Kagamu H (2019) Radiotherapy is an independent
prognostic marker of favorable prognosis in non-small cell lung

13

504
cancer patients after treatment with the immune checkpoint
inhibitor, nivolumab. Thorac Cancer 10:992–1000. https​://doi.
org/10.1111/1759-7714.13044​
4. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins
M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready
N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E,
Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR,
Villaruz LC, Havel L, Krejci J, Corral JJ, Chang H, Geese WJ,
Bhagavatheeswaran P, Chen AC, Socinski MA, CheckMate 026
Investigators (2017) First-Line Nivolumab in Stage IV or recur-
rent non-small-cell lung cancer. N Engl J Med 376:2415–2426.
https​://doi.org/10.1056/NEJMo​a1613​493
5. Ando K, Kishino Y, Homma T, Kusumoto S, Yamaoka T,
Tanaka A, Ohmori T, Ohnishi T, Sagara H (2020) Nivolumab
plus ipilimumab versus existing immunotherapies in patients
with PD-L1-positive advanced non-small cell lung cancer: a
systematic review and network meta-analysis. Cancers. https​://
doi.org/10.3390/cance​rs120​71905​
6. Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi
NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Seq-
uist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck
MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, McDermott
DF, Pardoll DM, Sankar V, Ahlers CM, Salvati M, Wigginton
JM, Hellmann MD, Kollia GD, Gupta AK, Brahmer JR (2015)
Overall survival and long-term safety of Nivolumab (anti-
programmed death 1 antibody, BMS-936558, ONO-4538) in
patients with previously treated advanced non-small-cell lung
cancer. J Clin Oncol 33:2004–2012. https​://doi.org/10.1200/
JCO.2014.58.3708
7. Chitturi KR, Xu J, Araujo-Gutierrez R, Bhimaraj A, Guha A, Hus-
sain I, Kassi M, Bernicker EH, Trachtenberg BH (2019) Immune
checkpoint inhibitor-related adverse cardiovascular events in
patients with lung cancer. JACC CardioOncology 1:182–192.
https​://doi.org/10.1016/j.jacca​o.2019.11.013
8. Salem J-E, Manouchehri A, Moey M, Lebrun-Vignes B, Basta-
rache L, Pariente A, Gobert A, Spano J-P, Balko JM, Bonaca
MP, Roden DM, Johnson DB, Moslehi JJ (2018) Cardiovascular
toxicities associated with immune checkpoint inhibitors: an obser-
vational, retrospective, pharmacovigilance study. Lancet Oncol
19:1579–1589. https​://doi.org/10.1016/S1470​-2045(18)30608​-9
9. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its
ligands in tolerance and immunity. Annu Rev Immunol 26:677–
704. https​://doi.org/10.1146/annur​ev.immun​ol.26.02160​7.09033​
1 role of immune checkpoint inhibitors and their relevance for the
10. Pardoll DM (2012) The blockade of immune checkpoints in can-
cer immunotherapy. Nat Rev Cancer 12:252–264. https​://doi.
org/10.1038/nrc32​39
11. Peretti M, Hervochon R, Loi M, Blanc K, Roche N, Alifano M
(2018) Predictors of post-pneumonectomy respiratory failure and
ARDS: usefulness of normalized pulmonary artery diameter.
Intensive Care Med 44:1357–1359. https:​ //doi.org/10.1007/s0013​
4-018-5206-9
12. Lorentz FH (1929) Ein neuer Konstitutionsindex. Klinische
Wochenschr 8:348–351
13. Weir JBDB (1949) New methods for calculating metabolic rate
with special reference to protein metabolism. J Physiol 109:1–9
14. Buzby GP, Knox LS, Crosby LO, Eisenberg JM, Haakenson CM,
McNeal GE, Page CP, Peterson OL, Reinhardt GF, Williford WO
(1988) Study protocol: a randomized clinical trial of total paren-
teral nutrition in malnourished surgical patients. Am J Clin Nutr
47:366–381. https​://doi.org/10.1093/ajcn/47.2.366
15. Naber TH, de Bree A, Schermer TR, Bakkeren J, Bär B, de Wild
G, Katan MB (1997) Specificity of indexes of malnutrition when
applied to apparently healthy people: the effect of age. Am J Clin
Nutr 65:1721–1725. https​://doi.org/10.1093/ajcn/65.6.1721
13
Cancer Chemotherapy and Pharmacology (2020) 86:497–505
16. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent
D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubin-
stein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J
(2009) New response evaluation criteria in solid tumours: revised
RECIST guideline (version 1.1). Eur J Cancer Oxf Engl 45:228–
247. https​://doi.org/10.1016/j.ejca.2008.10.026
17. Expert Panel on Thoracic Imaging, Sirajuddin A, Donnelly EF,
Crabtree TP, Henry TS, Iannettoni MD, Johnson GB, Kazerooni
EA, Maldonado F, Olsen KM, Wu CC, Mohammed TL, Kanne
JP (2017) ACR appropriateness criteria® suspected pulmonary
hypertension. J Am Coll Radiol 14:S350–S361. https​://doi.
org/10.1016/j.jacr.2017.01.040
18. Cuttica MJ, Kalhan R, Shlobin OA, Ahmad S, Gladwin M,
Machado RF, Barnett SD, Nathan SD (2010) Categorization and
impact of pulmonary hypertension in patients with advanced
COPD. Respir Med 104:1877–1882. https​://doi.org/10.1016/j.
rmed.2010.05.009
19. Li M, Wang S, Lin W, Li J, Wang C, Chen H, Lu W, Yang K,
Wang J, Zeng Q (2018) Cardiovascular parameters of chest CT
scan in estimating pulmonary arterial pressure in patients with
pulmonary hypertension. Clin Respir J 12:572–579. https​://doi.
org/10.1111/crj.12564​
20. Wells JM, Washko GR, Han MK, Abbas N, Nath H, Mamary
AJ, Regan E, Bailey WC, Martinez FJ, Westfall E, Beaty TH,
Curran-Everett D, Curtis JL, Hokanson JE, Lynch DA, Make BJ,
Crapo JD, Silverman EK, Bowler RP, Dransfield MT, COPDGene
Investigators, ECLIPSE Study Investigators (2012) Pulmonary
arterial enlargement and acute exacerbations of COPD. N Engl J
Med 367:913–921. https​://doi.org/10.1056/NEJMo​a1203​830
21. Cuttica MJ, Bhatt SP, Rosenberg SR, Beussink L, Shah SJ, Smith
LJ, Dransfield MT, Kalhan R (2017) Pulmonary artery to aorta
ratio is associated with cardiac structure and functional changes
in mild-to-moderate COPD. Int J Chron Obstruct Pulmon Dis
12:1439–1446. https​://doi.org/10.2147/COPD.S1314​13
22. Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato
R, Kaneda H, Hasegawa Y, Tanaka K, Takeda M, Nakagawa
K (2018) Association of immune-related adverse events with
nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol
4:374–378. https​://doi.org/10.1001/jamao​ncol.2017.2925
23. Palmieri DJ, Carlino MS (2018) Immune checkpoint inhibitor
toxicity. Curr Oncol Rep 20:72. https​://doi.org/10.1007/s1191​
2-018-0718-6
24. Michel L, Totzeck M, Lehmann L, Finke D (2020) Emerging
cardiovascular system. Herz. https:​ //doi.org/10.1007/s00059​ -020-
04954​-8
25. Murata K, Nose M, Ndhlovu LC, Sato T, Sugamura K,
Ishii N (2002) Constitutive OX40/OX40 ligand interaction
induces autoimmune-like diseases. J Immunol Baltim Md
1950(169):4628–4636
26. Reuss JE, Suresh K, Naidoo J (2020) Checkpoint inhibitor pneu-
monitis: mechanisms, characteristics, management strategies, and
beyond. Curr Oncol Rep 22:56. https​://doi.org/10.1007/s1191​
2-020-00920​-z
27. Nguyen TYV, Batterham MJ, Edwards C (2016) Comparison of
resting energy expenditure between cancer subjects and healthy
controls: a meta-analysis. Nutr Cancer 68:374–387. https​://doi.
org/10.1080/01635​581.2016.11536​67
28. Singer K, Cheng WC, Kreutz M, Ho PC, Siska PC (2018) Immu-
nometabolism in cancer at a glance. Dis Model Mech. https​://doi.
org/10.1242/dmm.03427​2
29. Huangyang P, Simon MC (2018) Hidden features: exploring the
non-canonical functions of metabolic enzymes. Dis Model Mech.
https​://doi.org/10.1242/dmm.03336​5
30. Watanabe R, Shirai T, Namkoong H, Zhang H, Berry GJ, Wal-
lis BB, Schaefgen B, Harrison DG, Tremmel JA, Giacomini JC,
Cancer Chemotherapy and Pharmacology (2020) 86:497–505 505
Goronzy JJ, Weyand CM (2017) Pyruvate controls the checkpoint
inhibitor PD-L1 and suppresses T cell immunity. J Clin Invest
127:2725–2738. https​://doi.org/10.1172/JCI92​167
31. Csiszar A, Labinskyy N, Jo H, Ballabh P, Ungvari Z (2008) Dif-
ferential proinflammatory and prooxidant effects of bone morpho-
genetic protein-4 in coronary and pulmonary arterial endothelial
cells. Am J Physiol Heart Circ Physiol 295:H569–577. https:​ //doi.
org/10.1152/ajphe​art.00180​.2008
3 2. Cai P, Kovacs L, Dong S, Wu G, Su Y (2017) BMP4 inhibits
PDGF-induced proliferation and collagen synthesis via PKA-
mediated inhibition of calpain-2 in pulmonary artery smooth mus-
cle cells. Am J Physiol Lung Cell Mol Physiol 312:L638–L648.
https​://doi.org/10.1152/ajplu​ng.00260​.2016
33. Ju FJ, Meng FQ, Hu HL, Liu J (2019) Association between BMP4
expression and pathology, CT characteristics and prognosis of
non-small cell lung cancer. Eur Rev Med Pharmacol Sci 23:5787–
5794. https​://doi.org/10.26355​/eurre​v_20190​7_18317​
34. Bach D-H, Luu T-T-T, Kim D, An YJ, Park S, Park HJ, Lee SK
(2018) BMP4 upregulation is associated with acquired drug resist-
ance and fatty acid metabolism in egfr-mutant non-small-cell lung
cancer cells. Mol Ther Nucleic Acids 12:817–828. https​://doi.
org/10.1016/j.omtn.2018.07.016
35. Martínez VG, Hidalgo L, Valencia J, Hernández-López C, Entrena
A, del Amo BG, Zapata AG, Vicente A, Sacedón R, Varas A
(2014) Autocrine activation of canonical BMP signaling regu-
lates PD-L1 and PD-L2 expression in human dendritic cells. Eur
J Immunol 44:1031–1038. https​://doi.org/10.1002/eji.20134​3693
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