Ten-year Survival on Tyrosine-Kinase Inhibitors for Metastatic Renal Cell

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Carcinoma: A case report

Fadi Mikhael 1, Rana Irfan Mahmoud2 Rakhi Santharam3

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1. Consultant Medical Oncologist at Mediclinic City Hospital, Dubai, UAE

[email protected]

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Mobile: +971566810288

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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3940093
 ABSTRACT

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Renal cell carcinoma (RCC) contributes 3% of all cancer cases diagnosed worldwide. RCC has a

poor prognosis in advanced stages with a 5-year survival of 8% in metastatic cases. The use of

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medications targeting vascular endothelial growth factor and its receptors (VEGFR) and

mammalian target of Rapamycin (mTOR) pathway markedly increased the overall survival (OS)

and quality of life. We report a case of a 49-year-old male, diagnosed with clear cell renal cell

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carcinoma grade I, with one renal hilar node-positive, and mediastinal and lung metastasis. The

patient was treated by tyrosine kinase inhibitors (TKIs), Sunitinib and Axitinib, after left-side

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partial nephrectomy in May 2011. During the assessment in May-June 2021, his CT scans showed

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no further changes with stable disease. This case is a rare presentation of ten-year OS with an

outstanding quality of life on TKIs in a patient with metastatic RCC.

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Keywords: Renal cell carcinoma, Axitinib, Sunitinib, targeted therapy, tyrosine kinase inhibitor,

vascular endothelial growth factor receptor inhibitor

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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3940093
 INTRODUCTION

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Renal cell carcinoma (RCC) contributes 3% of all cancer cases diagnosed worldwide 1,2. There has

been a 2% annual increase in incidence during the last two decades. Many lifestyle factors

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contribute to its etiology as smoking, obesity, and hypertension 3. Having a first-degree relative

with RCC is a positive risk factor 2. Most cases remain asymptomatic till late stages 2. More than

60% of cases are incidentally diagnosed during abdominal ultrasonography (US) or computed

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tomography (CT) for other reasons 2. The wide use of US and CT in routine investigation reduced

the incidence of a classic triad of flank pain, visible hematuria, and palpable abdominal mass 2.

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RCC has a poor prognosis in advanced stages with a 5-year survival of 8% in metastatic cases 4,5.

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The use of medications targeting vascular endothelial growth factor and its receptors (VEGFR)

and mammalian target of Rapamycin (mTOR) pathway markedly increased the overall survival
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(OS) and quality of life 6,7.

Sunitinib is a first-generation tyrosine kinase inhibitor (TKI), an inhibitor of VEGFR1-3, and a

platelet-derived growth factor (PDGFR) with direct anti-tumor effects on ligands which promotes
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the proliferation and differentiation of hematopoietic cells as the FMS-like tyrosine kinase 3

(FLT3), stem-cell factor receptor (c-KIT) 6. In 2005, The Food and Drug Administration (FDA)
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approved sunitinib as a primary treatment option for mRCC 6. TKIs have unfavorable side effects

such as hypertension, fatigue, diarrhea, and hand-foot syndrome, but of mild to moderate degree
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6
. Despite being potent, the resistance is still obscuring its efficacy. To overcome this problem,

using another VEGFI is recommended 8.

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Since 2012, axitinib has been an FDA-approved second-line multi-target TKI, target in VEGFR-
6,8,9
1, 2 and 3, c-Kit and PDGFR . Its potency is 50–450 times greater than the first-generation
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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3940093
 VEGFR inhibitors. Here, we report a rare presentation of OS reached 10 years for mRCC on TKI

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preserving an outstanding quality of life and control of disease status.

CASE PRESENTATION

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We report a case of a 49-year-old male known hypertensive with recurrent hematuria and UTI.

The patient had no other significant medical, psychological, nor family history. At the time of

examination, the patient was asymptomatic with unremarkable findings except for mild mucositis.

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In April 2011, the patient was evaluated, and the workup showed bilateral kidney masses 7.4cm

on the left side and 4cm on the right with mediastinal and lung lesions. In May 2011, the patient

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underwent left side partial nephrectomy. The histopathology study revealed clear cell renal cell

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carcinoma (ccRCC) grade I with one renal hilar node-positive. His pre-operative serum creatinine

was 1.4 mg/dl and turned 1.6 mg/dl post-operatively. The patient started treatment on sunitinib
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50mg once daily in metastatic settings. Despite the good response, the patient developed acute

hepatitis, so the dose was decreased to 37.5mg daily. In October 2012, the patient was evaluated

with CT imaging showed stable disease status, and the patient continued on the same therapy dose.
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In March 2013, he underwent an imaging evaluation showing the same result seen in Figures 1-5.

Later on, his scans showed a good response, and he continued on the same therapy. Few months
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later, there was a minor disease progression but no change in his therapy plan in regards of early

suspicious progression, decided to get the maximum benefit. His last assessment in December
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2014 was stable.

At the end of March 2016, his CT scans showed disease progression in the mediastinal nodes. The
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right adrenal deposits and the right kidney lesion increased in size, but he was asymptomatic,

showing good general health. So, the patient was ready to be shifted to Axitinib. Two weeks later,
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he had coffee-ground vomits, and upper endoscopy showed ulceration, so Axitinib was stopped.

The patient was kept on conservative treatment from the gastro-side for 4-weeks. Controlled

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 gastroscopy showed a normal clear healed ulcer, and he resumed Axitinib therapy 5 mg once daily

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to be increased to 5 mg twice daily after ten days. Three months later, all labs were normal, and

the patient was asymptomatic, showing good tolerance to Axitinib. In October 2016, chest and

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pelvi-abdominal CT imaging showed central necrosis in the right adrenal mass with no other

changes except for a decrease in the left adrenal mass’s size seen in Figures 6-10.

Continued on Axitinib. In November 2016, a CT scan showed no changes in lesion sites but a

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marginal increase in the lesion. So, the dose was to be increased to 7 mg twice daily next cycle in

early December 2016. In February 2017, the tumor size reduced by 25% on CT scans. So, no

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change was employed in his therapy plan, he was on follow-up with a cardiologist. Dose 7mg BD

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x1 month was unavailable, so we continued with the same 5mg twice daily dose. An assessment

in July-August 2017 by Magnetic Resonance Imaging (MRI) showed that the patient had stable
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disease but has side effects from the medication, including diarrhea, voice issues, and weight loss.

Controlled later and treated conservatively. In August 2017, a pelvi-abdominal MRI revealed

further response. In January 2018, a chest CT scan and pelvi-abdominal MRI showed a further
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reduction in the tumor size. His laboratory investigations were normal, and creatinine was

119µmol/L. Continued on Axitinib with the same dose 5mg twice daily. He was reassessed in June
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2018 and mid-January 2019 with a chest CT-scan without contrast, and a pelvi-abdominal MRI

showed stable status with no change was observed. Status Quo. In June 2019, his assessment
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showed a remarkable ongoing response, and in December 2019, it showed stable lesions ‘status

with reduced right adrenal lesion with no other change was observed. In December 2020, His status
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was assessed with the same radiological modalities that showed stable disease with no other

changes. In May-June 2021, His chest CT and pelvi-abdominal MRI showed stable disease with
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no further changes. His CT scans are seen in Figures 11-15. The patient will be reassessed in

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3940093
 November 2021. In the current case, The overall survival (OS) reached 10 years for mRCC on

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TKI. Patient preserving good quality of life.

DISCUSSION

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Kidney cancer was the fourteenth most common malignancy worldwide in 2018 10. RCC occupies
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85% of all renal carcinomas . There are several histopathological subtypes, with ccRCC

occupying > 80% of all renal tumors 11. ccRCC is the most aggressive histological subtype of RCC

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as it is chemo-and radio-therapy-resistant neoplasm , and the metastatic cases have the worse

prognosis 13. ccRCC is a highly vascular tumor with neo-angiogenesis characteristics, labeled by

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malignant epithelial cells with clear cytoplasm 9,13. The widespread use of the imaging modalities

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in routine investigations dramatically reduced the incidence of advanced RCC cases as most cases

are incidentally diagnosed in an early asymptomatic stage 1,2

. However, The advanced disease
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incidence varies from 16.9% to 28%, according to the histopathological subtype 2.

Malignant neo-angiogenesis for ccRCC is highly associated with hereditary Von Hippel-Lindau

(VHL) disease, where the VHL tumor suppressor gene is down-regulated. This mutation reduces
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pVHL protein and pVHL-containing protein complexes, which inhibit hypoxia-inducible factor

(HIF). HIF acts as a transcription factor that up-regulates the expression of vascular endothelial
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growth factor (VEGF), platelet-derived growth factor-beta (PDGF-β), and transforming growth

factor-alpha (TGF-α) 11,14. These factors activate multiple extra-cellular TKIs, intra-cellular TKIs,
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and the mTOR pathway, which favors the angiogenesis, proliferation, differentiation, apoptosis,
9,15
and cellular mobility of malignant cells . Therefore, scientists developed several medications
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targeting VEGF, PDFG-β, TGF-α, TKIs, and mTOR pathway 9. RCC management depends on

the TNM-system staging and histopathological characteristics. T refers to the size of the Tumor,
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N refers to the regional lymph node spread, and M refers to the presence of metastasis. Surgery,

either partial or complete nephrectomy, is the first treatment option for patients with resectable

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 RCC. But in cases with unresectable or metastatic neoplasm, targeted therapy and immunotherapy

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are the treatment of choice 2,5. Interferon-α (IF-α) and Interleukin-2 (IL-2) were the main lines of

treatment of mRCC until the FDA approved the targeting agents Sorafenib and Sunitinib in 2005-

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2006 2,5. The targeting agents have a higher response, more prolonged progression-free survival,

overall survival, and less toxic effect compared to IF-α and IL-2 5. Since 2005, several targeting
9,11,12
agents have been approved and are now the standard treatment for mRCC . The patient

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presented with bilateral ccRCC grade I, with one hilar node-positive and mediastinal and lung

lesions; therefore, he was treated with a left-side partial nephrectomy and VEGFR-TKI therapy;

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started with sunitinib as a first-line treatment and followed by Axitinib as a second-line option.

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Sunitinib is an oral anti-angiogenetic, anti-lymphangiogenic, and tumor-growth inhibitor. This

targeting agent inhibits VEGFR(1,2,3), PDGFR( α, β), FLT-3, c-KIT, and rearranged during
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15
transfection (RET) . Targeting VEGFR-1,-2, and PDGFR-α, -β inhibits angiogenesis, while

down-regulating VEGFR-3 inhibits lymphangiogenesis. The down-regulation of c-KIT, FLT-3,

and RET inhibits tumor growth 15. The standard dose is either 37,5 or 50 mg daily, taken at cycles
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consist of 4-week of drug intake followed by 2-weeks of drug-free period 16. Sunitinib has ≥50%

bio-availability 17 and reaches Cmax after 6 to 12h, and T1/2 after 40-80h 18. It is metabolized in
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the liver by CYP3A4 to the active metabolite, N-des-ethyl sunitinib (SU12662), which is further

metabolized, by the same enzyme, to an inactive molecule to be eliminated through the urinary
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(16%) and fecal (61%) routes 16. Axitinib is an oral selective TKI drug, FDA-approved in 2012

as a second-line treatment for RCC 8,19. This drug selectively targets VEGFR-1, -2 and -3, PDGFR-
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α and-β and c-KIT 8,19. Sunitinib has been the standard treatment for mRCC for more than a decade,

but the secondary resistance of the tumor develops after a median 11-month period of regular
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20
intake . But, a little evidence hypothesized that the resistance is temporarily based on the

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 21
observation that the epithelial-to-mesenchymal transition is a reversible phenomenon . To

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overcome this obstacle, The scientists innovated new targeting agents such as the MET/AXL and
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VEGFR inhibitor cabozantinib, the FGF and VEGFR TKI lenvatinib , and the immune

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23
checkpoint inhibitors . Despite optimizing the outcomes in Sunitinib-resistant tumors, most
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patients will develop disease progression . Few clinical trials (CTs) support the Sunitinib-

rechallenge approach in patients who developed resistance to sunitinib after treatment break 24, or

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to various targeting agents, including mTOR inhibitors, monoclonal antibodies, cytokines, and

other TKIs 24,25. This approach might be irrelevant with the innovation of novel treatment agents,

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but the unavailability of these agents for most patients may force us to consider Sunitinib

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rechallenge as an additional option for improving the outcomes of patients with mRCC 24.

Immune checkpoint inhibitors (ICIs), including the anti-programmed death-ligand 1 (PD-L1) anti-
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body avelumab, have acceptable safety and more prolonged anti-tumor activity as first- and
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second-line treatments in patients with advanced malignancies mRCC . In addition to

antiangiogenic effects, VEGFR inhibitors enhance the tumor infiltration of immune cells and
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reduce the immunosuppressive effects of myeloid-derived suppressor cells 27. These observations

led to a hypothesis that the combination of ICIs and VEGFR inhibitors might enhance the
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outcomes in patients with mRCC through a complementary mechanism of action . But further

investigation of this hypothesis is needed.

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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3940093
 Acknowledgment: We thanks Dr Andrew Mccombe medical director of Mediclinic City

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Hospital Comprehensive cancer center. And to Maria Antoinette Palmera Oncology dedicated

nurse in the comprehensive cancer center

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Funding:

No funding

Informed Consent:

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Written informed consent was obtained from the patient for publication of this case report and

any accompanying images

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Conflict of Interest:

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The authors have no conflicts of interest to declare.

Ethical approval:
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Ethical approval was obtained from the hospital after obtaining the institutional review board

(IRB) approval for conducting this study.

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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3940093
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27. Roland CL, Lynn KD, Toombs JE, Dineen SP, Udugamasooriya DG, Brekken RA.

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 FIGURES

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Figure 1 shows paratracheal nodes coronal view (2013)
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Figure 2 shows paratracheal nodes axial view (2013)

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Figure 3 shows subcarinal nodes axial view (2013)
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Figure 4 shows subcarinal nodes coronal view (2013)

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Figure 5 shows adrenal right coronal view (2013)
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Figure 6 shows paratracheal nodes coronal view (2016)
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Figure 7 shows paratracheal nodes axial view (2016)

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Figure 8 shows subcarinal nodes axial view (2016)

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Figure 9 shows subcarinal nodes coronal view (2016)

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Figure 10 shows adrenal right coronal view (2016)
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Figure 11 shows the paratracheal node coronal view (2021)

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Figure 12 shows paratracheal nodes axial view (2021)
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Figure 13 shows subcarinal nodes axial view (2021)

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Figure 14 shows the subcarinal nodes coronal view (2021)
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Figure 15 shows the adrenal right coronal view (2021)

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