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Brain metastasis in renal cell cancer responding to sunitinib

November 2007
Anticancer Research 27(6C):4255-7

November 2007
27(6C):4255-7

Source
PubMed

Authors:

Dimitrios Krikelis

Aristotle University of Thessaloniki

Natassa Alexandrou

Ioannis Starakis

Πανεπιστημιακό Γενικό Νοσοκομείο Πατρών

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Background: Sunitinib (SU011248; Sutent) is a new small molecule that inhibits members of the split-kinase domain family of receptor tyrosine kinases (RTKs), with established antitumor activity in renal cancer. In the current report, we describe a patient with a solitary brain metastasis from renal cell carcinoma who achieved partial response of the cerebral lesion following treatment with sunitinib. To the best of our knowledge, this is the first report of sunitinib activity in brain metastases from kidney cancer. A limited number of publications support the hypothesis that small tyrosine kinase inhibitors may cross the blood-brain barrier. Although the role of sunitinib in advanced renal carcinoma has been evaluated through prospective trials, the efficacy of the drug in patients with brain metastases has not been explored, since patients with cerebral lesions were excluded in those studies. Thus, we believe that accumulating evidence from personal experience or limited reports could be useful. Moreover, in our case, sunitinib was found to be safe, leading to considerable shrinkage of the brain metastasis without any serious adverse events or central nervous system toxicities. We consider this observation to be important, given the absence of data regarding the activity of the drug in this particular clinical setting.

CT scan of the brain before the administration of sunitinib. Figure 2. CT scan of the brain after 2 cycles of treatment with sunitinib.

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CT scan of the brain before the administration of sunitinib. Figure 2. CT scan of the brain after 2 cycles of treatment with sunitinib.

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CT scan of the brain after 5 cycles of treatment with sunitinib.

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Figures - uploaded by Dimitrios Krikelis

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Content uploaded by Dimitrios Krikelis

Content may be subject to copyright.

Abstract. Background: Sunitinib (SU011248; Sutentì) is a

new small molecule that inhibits members of the split-kinase

domain family of receptor tyrosine kinases (RTKs), with

established antitumor activity in renal cancer. In the current

report, we describe a patient with a solitary brain metastasis

from renal cell carcinoma who achieved partial response of

the cerebral lesion following treatment with sunitinib. To the

best of our knowledge, this is the first report of sunitinib

activity in brain metastases from kidney cancer. A limited

number of publications support the hypothesis that small

tyrosine kinase inhibitors may cross the blood-brain barrier.

Although the role of sunitinib in advanced renal carcinoma

has been evaluated through prospective trials, the efficacy of

the drug in patients with brain metastases has not been

explored, since patients with cerebral lesions were excluded in

those studies. Thus, we believe that accumulating evidence

from personal experience or limited reports could be useful.

Moreover, in our case, sunitinib was found to be safe, leading

to considerable shrinkage of the brain metastasis without any

serious adverse events or central nervous system toxicities. We

consider this observation to be important, given the absence

of data regarding the activity of the drug in this particular

clinical setting.

Case Report

A 40-year-old woman underwent nephrectomy for a

moderately differentiated, clear cell adenocarcinoma of the

left kidney in August 2004. The pathological stage of the

disease was II (T2N0M0). In February 2006, the patient

complained of numbness of the left upper limb, focal

seizures and headache. Computed tomography (CT) and

magnetic resonance imaging revealed a solitary mass in the

right parietal-occipital lobe. The patient underwent surgical

excision of the lesion which was histopathologically

confirmed to be a metastasis from clear cell renal cancer.

Postoperatively, evaluation with CT scan did not reveal

residual disease in the brain. Moreover, evidence of the

disease elsewhere in the body was not apparent.

Immunotherapy consisting of interferon alpha (10 mU 3 x

weekly) was started in March 2006. Five months later,

repetition of imaging procedures (CT scan) demonstrated

relapse of the disease in the brain, with a lesion located in the

right parietal-occipital lobe (maximum diameter 4 cm),

together with peritumoral edema (Figure 1). Again, CT scan

of the abdomen and the lungs was negative for local relapse

and other metastatic sites. The lesion was considered

inoperable and the patient started (August 2006) sunitinib

monotherapy at a dose of 50 mg orally once daily for 4 weeks,

followed by 2 weeks off, in repeated 6-week cycles. The

patient also received methylprednisolone at a dose of 16 mg

daily, which was progressively decreased until discontinuation,

during the following months. At that time, the patient was in

a good clinical condition (Eastern Cooperative Oncology

Group Performance Status=0, lactate dehydrogenase=145

U/L, haemoglobin=10.9 g/dL, corrected calcium=9 mg/dL

and alkaline phosphatase=63 U/L). The treatment was

tolerated fairly well without serious adverse events.

The patient developed grade 1 hypertension (according to

National Cancer Institute Common Toxicity Criteria, version

3.0) after the first cycle of the treatment, which was

successfully controlled with olmesartan. Other side-effects

included anemia grade 1 and hand-foot syndrome grade 1

(according to the above mentioned criteria). Evaluation of

the patient with CT scan after 2 cycles of treatment

(November 2006), revealed a reduction of the metastatic

lesion (maximum diameter 3.2 cm), together with significant

resolution of the associated edema (Figure 2). Given the

response of the disease and the lack of considerable toxicity,

treatment was continued at the same dose. Re-evaluation of

the patient after the completion of the fifth cycle (March

2007) demonstrated further reduction of the lesion

(maximum diameter 2 cm), without any signs of disease

elsewhere (Figure 3). The patient remains on treatment

with sunitinib at the same dosage, without clinical or

radiographic evidence of disease progression.

4255

Correspondence to: H.P. Kalofonos, Division of Oncology,

Department of Medicine, University Hospital, Patras Medical

School, Rion 26504, Greece. Tel: +30 2610999535, Fax: +30

2610994645, e-mail: kalofon@med.upatras.gr

Key Words: Sunitinib, renal cell cancer, brain metastases.

ANTICANCER RESEARCH 27: 4255-4258 (2007)

Brain Metastasis in Renal Cell Cancer Responding to Sunitinib

ANGELOS K. KOUTRAS, DIMITRIOS KRIKELIS, NATASSA ALEXANDROU,

IOANNIS STARAKIS and HARALABOS P. KALOFONOS

Division of Oncology, Department of Medicine, University Hospital, Patras Medical School, Rion 26504, Greece

0250-7005/2007 $2.00+.40

Discussion

Sunitinib (SU011248; Sutentì) is a new, orally administered,

small molecule that inhibits members of the split-kinase

domain family of receptor tyrosine kinases (RTKs),

including the vascular endothelial growth factor receptors

(VEGFRs) types 1 and 2, platelet-derived growth factor

receptors (PDGFR-· and PDGFR-‚), the stem cell factor

receptor c-KIT, the FLT3 and RET kinases (1). Sunitinib

exhibits potent antiangiogenic and antitumor activity.

Considerable clinical activity has been demonstrated in

patients with advanced renal cell carcinoma (2-4).

Brain metastases are not a rare occurrence in patients

with kidney cancer (5). Whole-brain radiotherapy is the

standard treatment, although generally, renal tumors are

relatively radioresistant and more aggressive approaches

such as surgery or radiosurgery are indicated only in a

subset of patients. In the current report, we describe a

patient with a solitary brain metastasis from renal cell

carcinoma who achieved partial response of the cerebral

lesion, following treatment with sunitinib. To the best of

our knowledge, this is the first report of sunitinib activity

in brain metastases from kidney cancer. It is noteworthy

that our patient continued to respond further, seven

months after the initiation of the treatment, as was

demonstrated by CT scan in March 2007. It is also

interesting that seizures or other central nervous system

(CNS) toxicities were not observed during the treatment,

although prophylactic anticonvulsant therapy was not

administered.

A limited number of publications support the hypothesis

that small tyrosine kinase inhibitors (TKIs) may cross the

blood-brain barrier. Gefitinib, an oral selective epidermal

growth factor receptor (EGFR) tyrosine kinase inhibitor,

has shown activity in brain metastases from non-small cell

lung cancer (NSCLC) (6-8). Responses have also been

reported with erlotinib, another EGFR tyrosine kinase

ANTICANCER RESEARCH 27: 4255-4258 (2007)

4256

Figure 1. CT scan of the brain before the administration of sunitinib.

Figure 2. CT scan of the brain after 2 cycles of treatment with sunitinib.

Figure 3. CT scan of the brain after 5 cycles of treatment with sunitinib.

inhibitor, in patients with intracranial lesions from NSCLC

(9, 10). Lapatinib, another small molecule, is a dual

reversible inhibitor of the tyrosine kinase activity of EGFR

and human epidermal growth factor receptor 2 (HER-2). In

a randomized study comparing lapatinib plus capecitabine

versus capecitabine in patients with HER-2 positive

refractory advanced breast cancer, the authors reported an

advantage of the combination in terms of less CNS

progression (11). That observation suggests that the low

molecular weight TKIs may penetrate the blood-brain

barrier and may be useful in the management of patients

with brain metastases.

Although the role of sunitinib in advanced renal

carcinoma has been evaluated through prospective trials,

the efficacy of the drug in patients with brain metastases has

not been explored, since patients with cerebral lesions were

excluded in those studies (2-4). We acknowledge that trials

designed to address prospectively the feasibility of sunitinib

in these patients are difficult to conduct and hence,

accumulating evidence from personal experience or limited

reports could be useful. It might also be useful to consider

the randomized study comparing sunitinib to interferon

alpha in metastatic renal cell carcinoma (4), and assess the

proportion of patients per arm who developed progression

of the disease in the brain to identify whether there is an

advantage favoring sunitinib use.

Initial experience with sunitinib suggested a mild and

manageable adverse event profile. However, it has become

clear with additional experience that antiangiogenic agents

are associated with a distinct array of toxicities, such as

hemorrhage. Further investigation is warranted to determine

risk factors for the development of hemorrhagic events with

such agents. Hemorrhagic complications, some of them fatal,

have rarely been observed in patients receiving sunitinib for

gastrointestinal stromal tumors or squamous cell lung

carcinomas. Undoubtedly, there is a concern related to the

safety of antiangiogenic factors in patients with CNS lesions.

On the other hand, prognosis of patients with brain

metastases from renal cell carcinoma is usually dismal, since

no effective treatments are currently available. Thus,

sunitinib could be a potentially active therapeutic option in

certain patients.

In conclusion, sunitinib was found to be effective and

safe, leading to considerable shrinkage of brain metastasis

without any serious adverse events. Our case highlights the

potential of sunitinib in patients with CNS metastases from

renal cell carcinoma. We consider this observation to be

important, given the absence of data regarding the activity

of the drug in this particular clinical setting.

References

1 Chow LQ and Eckhardt SG: Sunitinib: From rational design to

clinical efficacy. J Clin Oncol 25: 884-896, 2007.

2 Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ,

Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding

G, Ginsberg MS, Bacik J, Kim ST, Baum CM and Michaelson

MD: Sunitinib in patients with metastatic renal cell carcinoma.

JAMA 295: 2516-2524, 2006.

3 Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding

G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE,

Li JZ, Bello CL, Theuer CP, George DJ and Rini BI: Activity

of SU11248, a multitargeted inhibitor of vascular endothelial

growth factor receptor and platelet-derived growth factor

receptor, in patients with metastatic renal cell carcinoma. J Clin

Oncol 24: 16-24, 2006.

4 Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski

RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I,

Bycott PW, Baum CM and Figlin RA: Sunitinib versus

interferon alfa in metastatic renal-cell carcinoma. N Engl J Med

356: 115-124, 2007.

5 Gay PC, Litchy WJ and Cascino TL: Brain metastasis in

hypernephroma. J Neurooncol 5: 51-56, 1987.

6 Villano JL, Mauer AM and Vokes EE: A case study

documenting the anticancer activity of ZD1839 (Iressa) in the

brain. Ann Oncol 14: 656-658, 2003.

7 Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crinò L and

Villa E: Gefitinib in patients with brain metastases from non-

small-cell lung cancer: a prospective trial. Ann Oncol 15: 1042-

1047, 2004.

8 Hotta K, Kiura K, Ueoka H, Tabata M, Fujiwara K, Kozuki T,

Okada T, Hisamoto A and Tanimoto M: Effect of gefitinib

(‘Iressa', ZD1839) on brain metastases in patients with

advanced non-small-cell lung cancer. Lung Cancer 46: 255-261,

2004.

9 Lai CS, Boshoff C, Falzon M and Lee SM: Complete response

to erlotinib treatment in brain metastases from recurrent

NSCLC. Thorax 61: 91, 2006.

10 Popat S, Hughes S, Papadopoulos P, Wilkins A, Moore S, Priest

K, Meehan L, Norton A and O'Brien M: Recurrent responses

to non-small cell lung cancer brain metastases with erlotinib.

Lung Cancer 56: 135-137, 2007.

11 Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG,

Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A,

Kaufman B, Skarlos D, Campone M, Davidson N, Berger M,

Oliva C, Rubin SD, Stein S and Cameron D: Lapatinib plus

capecitabine for HER2-positive advanced breast cancer. N Engl

J Med 355: 2733-2743, 2006.

Received July 12, 2007

Revised October 16, 2007

Accepted October 22, 2007

Koutras et al: Sunitinib for Brain Metastases in Renal Cell Cancer

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Jul 2006
J Am Med Assoc

Current treatment options for metastatic renal cell carcinoma (RCC) are limited and there is a need to identify novel and effective therapies. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, which has shown activity in an initial study of cytokine-refractory metastatic RCC patients. To confirm the antitumor efficacy of sunitinib as second-line treatment in patients with metastatic clear-cell RCC, the predominant cell type of this malignancy. Open-label, single-arm, multicenter clinical trial. Patients were enrolled between February and November 2004, with follow-up continuing until disease progression, unacceptable toxicity, or withdrawal of consent. The reported data apply through August 2005. Patients (N = 106) had metastatic clear-cell RCC, which had progressed despite previous cytokine therapy. Repeated 6-week cycles of sunitinib, 50 mg per day given orally for 4 consecutive weeks followed by 2 weeks off per treatment cycle. Assessment of clinical response, degree of tumor regression on imaging studies using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Primary end point was overall objective response rate (complete plus partial). Secondary end points were progression-free survival and safety. Response was evaluated by independent third-party core imaging laboratory and by treating physicians (investigator assessment). All 106 patients received sunitinib and were included in the intent-to-treat population for safety analyses. Of these, 105 patients were evaluable for efficacy analyses. The objective response rate according to an independent third-party assessment resulted in 36 patients with partial response (34%; 95% confidence interval, 25%-44%), and a median progression-free survival of 8.3 months (95% confidence interval, 7.8-14.5 months). The most common adverse events experienced by patients were fatigue in 30 (28%) and diarrhea 21 (20%). Neutropenia, elevation of lipase, and anemia were the most common laboratory abnormalities observed in 45 (42%), 30 (28%), and 27 (26%) patients, respectively. The results of this trial demonstrate the efficacy and manageable adverse-event profile of sunitinib as a single agent in second-line therapy for patients with cytokine-refractory metastatic clear-cell RCC. clinicaltrials.gov Identifier: NCT00077974.

Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer

Article

Full-text available

Dec 2006
NEW ENGL J MED

Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).

Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma

Conference Paper

Jan 2006

Purpose Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (Sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC. Patients and Methods Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off, Overall response rate was the primary end point, and time to progression and safety were secondary end points. Results Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting >= 3 months, Median time to progression in the 63 patients was 8.7 months. Dosing was generally tolerated with manageable toxicities, Conclusion SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.

Brain metastasis in hypernephroma

Article

Feb 1987

Of 926 patients with hypernephroma, 36 (3.9%) had metastasis to the brain. The median age at presentation was 61 years (range, 34 to 82). Nineteen patients had a single lesion metastatic to the brain, and 16 of these lesions were supratentorial. In 28% of the patients, computed tomography showed hyperdense lesions before contrast material was injected. All patients, except 2 with incomplete records, had evidence of widespread disease involving bone, liver, or lung. The median time interval between the initial diagnosis and the discovery of brain metastasis was 65.5 weeks (range, 0 to 462), with only 2 patients initially presenting with brain metastasis. Twenty-five of the patients who received only radiation therapy had a median survival of 13 weeks (range, 4 to 146), while 7 selected patients who underwent surgical resection and postoperative radiation had a median survival of 66 weeks (range, 18 to 260). In 5 of the 7 patients, scans demonstrated recurrent tumor from 6 to 23 weeks postoperatively. One patient had a pronounced reduction in the size of the tumor after radiation therapy only. This study shows that brain metastasis is usually a late complication of hypernephroma and is associated with a poor prognosis.

A case study documenting the anticancer activity of ZD1839 (Iressa) in the brain

Article

May 2003

Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crin?? L, Villa E. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial

Article

Aug 2004

Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer

Article

Nov 2004
LUNG CANCER

Gefitinib ('Iressa', ZD1839), an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), has shown antitumor activity in refractory patients with non-small-cell lung cancer (NSCLC) in clinical trials. We have retrospectively analyzed the efficacy and tolerability of gefitinib in patients with advanced NSCLC treated at Okayama University Hospital. We reviewed the clinical records of 57 patients with advanced NSCLC who had received 250 mg/day gefitinib at our hospital between November 2000 and May 2003. Correlations between the sensitivity of brain metastases and extracranial disease following treatment with gefitinib were also investigated. Extracranial objective responses were observed in 15 (27%; 95% confidence interval 15.8-40.3%) patients. Fourteen out of 57 patients had brain metastases; six experienced objective responses (one complete response, CR and five partial responses, PR) and eight had stable disease (SD) in the brain. Seven out of 14 patients with brain metastases experienced objective responses in their extracranial tumors and, interestingly, objective responses in the brain were observed in six (86%) of these patients. Multivariate analysis found that advanced age (> or = 70 years) and the presence of brain metastases were associated with clinical response to gefitinib (P = 0.01 and 0.05, respectively), and that female patients were more likely to respond. Median survival and median duration of response were 9.1 and 7.7 months, respectively. The majority of adverse events (AEs) were mild and reversible skin and gastrointestinal disorders, with grade 3 adverse events observed in six (11%) patients. This retrospective analysis has found that gefitinib is effective and well tolerated in patients with refractory NSCLC, confirming previous phase II trial data. Interestingly, gefitinib appeared to be effective for brain metastases as well as extracranial tumors. Further prospective trials are warranted to evaluate the efficacy of gefitinib in elderly patients and in patients with brain metastases.

Activity of SU11248, a Multitargeted Inhibitor of Vascular Endothelial Growth Factor Receptor and Platelet-Derived Growth Factor Receptor, in Patients With Metastatic Renal Cell Carcinoma

Article

Jan 2006
J CLIN ONCOL

Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC. Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off. Overall response rate was the primary end point, and time to progression and safety were secondary end points. Results Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting > or = 3 months. Median time to progression in the 63 patients was 8.7 months. Dosing was generally tolerated with manageable toxicities. SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.

Recurrent responses to non-small cell lung cancer brain metastases with erlotinib

Article

May 2007
LUNG CANCER

We report the case of a Caucasian female never smoker with erlotinib sensitive metastatic non-small cell lung cancer in the brain. Having progressed after receiving whole brain radiotherapy, her brain metastases responded both initially and on re-treatment with erlotinib. However, her extra-cranial disease remained erlotinib-resistant throughout. This case demonstrates that brain metastases may be sensitive to erlotinib and also highlights the oligoclonal nature of non-small cell lung cancer reflected by differential tyrosine kinase inhibitor tumour sensitivity. On the basis of this case we suggest that erlotinib should be considered in the treatment paradigm for patients with intra-cranial disease and propose further study into the continued use of this drug in the situation where there is a differential response.

Brain metastasis in renal cell cancer responding to sunitinib

Abstract and Figures

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