Yttrium-90 Selective Internal Radiation Therapy Research Articles

S2988 Gastric Ulcer Due to Yttrium-90 Selective Internal Radiation Therapy

S2988 Gastric Ulcer Due to Yttrium-90 Selective Internal Radiation Therapy

Deep-Learning Based Auto-Segmentation for Liver Yttrium-90 Selective Internal Radiation Therapy

In resin Yttrium-90 (Y-90) selective internal radiation therapy (SIRT), liver volume sizes are needed for Y-90 activity calculations using the body-surface-area method, which are obtained from contours that are manually delineated in 3D images. The aim was to apply a deep-learning based auto-segmentation method for liver delineation for Y-90 SIRT. A deep-learning-based liver segmentation method was applied using the U-Net3D architecture, which is a 3D convolutional neural network (CNN) extended from the original 2D U-Net architecture for 3D objects in medical imaging. The segmentation model was trained on the Liver Tumor Segmentation (LiTS) dataset. The training data set contained 130 CT scans, and the test data set contained 70 CT scans. The model was deployed in the clinic using DICOM communication. Auto-segmentation of liver in the CT images of 18 SIRT patients was studied. The CT images were exported from clinical database to the segmentation model's DICOM location, where a monitoring software detected the incoming data and automatically ran the liver segmentation. The results were then returned to the original DICOM location where the CT images were stored. Auto-segmented liver contours were compared with physician manually-delineated contours. Dice similarity coefficient (DSC), mean distance to agreement (MDA), ratio of volume (RV), and ratio of activity (RA, ratio of activity calculated using an auto-segmented liver contour to the accurate activity calculated using a manually-delineated contour), were assessed. DSC, MDA, and RV are 0.942±0.014 (range: 0.908-0.959), 1.902±0.503 mm (range: 1.043-2.956 mm), and 0.988±0.039 (range: 0.901-1.045), respectively. RA is 1.001±0.003 (range: 0.993-1.007), which indicates that the activities calculated using the auto-segmented liver contours are close to the accurate activities. The segmentation model was able to successfully identify and segment livers in the CT images, and provide accurate and reliable results. The proposed method is beneficial for clinical use as it can process large amounts of data quickly and efficiently, and can be easily deployed in a clinical environment using DICOM communication.

THU-129 - Survival outcomes of hepatocellular carcinoma after yttrium-90 selective internal radiation therapy in an Asian population stratified by tumour volume and distribution

THU-129 - Survival outcomes of hepatocellular carcinoma after yttrium-90 selective internal radiation therapy in an Asian population stratified by tumour volume and distribution

Evaluation of Atlas-based auto-segmentation of liver in MR images for Yttrium-90 selective internal radiation therapy.

The aim was to explore the feasibility of applying an atlas-based auto-segmentation tool, MIM Atlas Segment, for liver delineation in MR images in Y-90 selective internal radiation therapy (SIRT). MR images of 41 liver patients treated with resin Y-90 SIRT were included: 20 patients' images were used to create an atlas, and the other 21 patients' images were used for testing. Auto-segmentation of liver in the MR images was performed with MIM Atlas Segment, and various settings for the auto-segmentation (i.e., with and without normalized deformable registration, single atlas-match and multi-atlas match, and multi-atlas match using different finalization methods) were tested. Auto-segmented liver contours were compared with physician manually-delineated contours, using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). Ratio of volume (RV) and ratio of activity (RA) were calculated to further evaluate the auto-segmentation results. Auto-segmentations with normalized deformable registration generated better contours than those without normalized deformable registration. With normalized deformable registration, 3-atlas match using Majority Vote (MV) method generated better results than single-atlas match and 3-atlas match using STAPLE method, and generated similar results as 5-atlas match using MV method or STAPLE method. The average DSC, MDA, and RV of the contours generated with normalized deformable registration are 0.80-0.83, 0.60-0.67, and 0.91-1.00 cm, respectively. The average RA are 1.00-1.01, which indicate that the activities calculated using the auto-segmented liver contours are close to the accurate activities. The atlas-based auto-segmentation can be applied to generate initial liver contours in MR images for resin Y-90 SIRT, which can be used for activity calculations after physicians review.

Stereotactic body radiation therapy (SBRT) following Yttrium-90 (90Y) selective internal radiation therapy (SIRT): a feasibility planning study using 90Y delivered dose

Objective. 90Y selective internal radiation therapy (SIRT) treatment of hepatocellular carcinoma (HCC) can potentially underdose lesions, as identified on post-therapy PET/CT imaging. This study introduces a methodology and explores the feasibility for selectively treating SIRT-underdosed HCC lesions, or lesion subvolumes, with stereotactic body radiation therapy (SBRT) following post-SIRT dosimetry. Approach. We retrospectively analyzed post-treatment PET/CT images of 20 HCC patients after 90Y SIRT. Predicted tumor response from SIRT was quantified based on personalized post-therapy dosimetry and corresponding response models. Predicted non-responding tumor regions were then targeted with a hypothetical SBRT boost plan using a framework for selecting eligible tumors and tumor subregions. SBRT boost plans were compared to SBRT plans targeting all tumors irrespective of SIRT dose with the same prescription and organ-at-risk (OAR) objectives. The potential benefit of SIRT followed by a SBRT was evaluated based on OAR dose and predicted toxicity compared to the independent SBRT treatment. Main results. Following SIRT, 14/20 patients had at least one predicted non-responding tumor considered eligible for a SBRT boost. When comparing SBRT plans, 10/14 (71%) SBRTboost and 12/20 (60%) SBRTalone plans were within OAR dose constraints. For three patients, SBRTboost plans were within OAR constraints while SBRTalone plans were not. Across the 14 eligible patients, SBRTboost plans had significantly less dose to the healthy liver (decrease in mean dose was on average ± standard deviation, 2.09 Gy ± 1.99 Gy, ) and reduced the overall targeted PTV volume (39% ± 21%) compared with SBRTalone. Significance. A clinical methodology for treating HCC using a synergized SIRT and SBRT approach is presented, demonstrating that it could reduce normal tissue toxicity risk in a majority of our retrospectively evaluated cases. Selectively targeting SIRT underdosed HCC lesions, or lesion subvolumes, with SBRT could improve tumor control and patient outcomes post-SIRT and allow SIRT to function as a target debulking tool for cases when SBRT is not independently feasible.

Letter to the Editor From Hallanger Johnson and El-Haddad: "Yttrium-90 Selective Internal Radiation Therapy Plus Cryoablation for Recurrent Adrenocortical Carcinoma With Liver Metastases".

Letter to the Editor From Hallanger Johnson and El-Haddad: "Yttrium-90 Selective Internal Radiation Therapy Plus Cryoablation for Recurrent Adrenocortical Carcinoma With Liver Metastases".

Yttrium-90 Internal Radiation Therapy as Part of the Multimodality Treatment of Metastatic Colorectal Carcinoma

About 70% of patients with metastatic colorectal carcinoma (mCRC) have liver metastases. Hepatic failure accounts for most mCRC-related deaths. Therefore, controlling liver metastases may improve outcomes. A data overview of liver-directed treatment using yttrium-90 selective internal radiation therapy (SIRT) is provided as part of a multimodality treatment. SIRT in mCRC is discussed, and the prognostic factors for patient selection are defined. Pooled analyses of three recent trials incorporating SIRT plus chemotherapy revealed subsets of patients with mCRC who might benefit from SIRT. A multidisciplinary treatment for most mCRC patients is proposed to achieve long-term survival in this cohort of patients.

Narrative review of the role of yttrium-90 selective internal radiation therapy in the surgical management of colorectal liver metastases.

The management of colorectal liver metastasis (CRLM) is complicated and benefits from a multidisciplinary team approach. Liver-directed therapy has been emerging as a modality for better progression-free control. In its early years, selective internal radiation therapy (SIRT) with yttrium-90 (Y-90) was confined as an end-of-line therapy. However, literature has supported other roles including: a first-line treatment for CRLM alone or in combination with systemic chemotherapy; an adjunct to second or third-line chemotherapy; and a salvage treatment for chemo-refractory disease. Although future liver remnant (FLR) hypertrophy may take 3-12 months, the SIRT effect on loco-regional disease control has rendered it to be a useful tool in some pathologies with certain strategic goals. This paper reviews the use of SIRT with Y-90 in a surgical treatment pathway. This includes: (I) an element of multidisciplinary treatment of low-volume CRLMs, (II) convert an R1 to R0 resection by sterilizing the margins of tumor near critical structures, and (III) radiation lobectomy to induce contralateral hypertrophy in order to aid in a safer resection. There are many opportunities to validate the role of SIRT as a first-line therapy along with surgical resection including an umbrella clinical trial design.

Lung shunt fraction calculation using 99mTc-MAA SPECT/CT imaging for 90Y microsphere selective internal radiation therapy of liver tumors

Background99mTc-macroaggregated albumin (99mTc-MAA) scintigraphy is utilized in treatment planning for Yttrium-90 (90Y) Selective Internal Radiation Therapy (SIRT) of liver tumors to evaluate hepatopulmonary shunting by calculating the lung shunt fraction (LSF). The purpose of this study was to evaluate if LSF calculation using SPECT/CT instead of planar gamma camera imaging is more accurate and if this can potentially lead to more effective treatment planning of hepatic lesions while avoiding excessive pulmonary irradiation.ResultsLSF calculation was obtained using two different methodologies in 85 cases from consecutive patients intended to receive 90Y SIRT. The first method was based on planar gamma camera imaging in the anterior and posterior views with geometric mean calculation of the LSF from regions of interest of the liver and lungs. The second method was based on segmentation of the liver and lungs from SPECT/CT images of the thorax and abdomen. The differences in planar imaging versus SPECT/CT derived LSF values along with the estimated absorbed lung mean dose (LMD) were evaluated. The LSF values were higher in planar imaging versus SPECT/CT in 81/85 cases, with a mean value of 8.5% vs. 4.6% respectively; the difference was statistically significant using a paired t-test (alpha = 0.05). In those patients who received SIRT, the estimated absorbed LMD calculated with planar imaging was significantly higher than with SPECT/CT (t-test, P < 0.005). Repeated phantom experiments using an anthropomorphic torso phantom with variable 99mTc activity concentrations for the liver and lungs were performed with the standard patient protocol, demonstrated improved accuracy of the LSF calculation based on SPECT/CT than planar imaging (mean overestimated value of 6% vs. 26%).ConclusionsThis study demonstrates that LSF calculation using planar imaging can be significantly overestimated while calculation using SPECT/CT imaging and appropriate segmentation tools can be more accurate. Minimizing the errors in obtaining the LSF can lead to more effective 90Y SIRT treatment planning for hepatic tumors while ensuring the lung dose will not exceed the standard acceptable safety thresholds.

Clinical outcome of Yttrium-90 selective internal radiation therapy (Y-90 SIRT) in unresectable hepatocellular carcinoma: Experience from a tertiary care center

Background and aimWhereas Yttrium-90 selective internal radiation therapy (Y-90 SIRT) was shown to improve local tumor control in non-Asian population, the efficacy of this therapy for Asian population in real-world setting remains poorly detailed. We aimed to determine outcomes and identify predictors of response in hepatocellular carcinoma (HCC) patients treated by Y-90 SIRT. MethodsWe retrospectively enrolled 52 HCC patients receiving Y-90 SIRT at our tertiary center between 2014 and 2019. Overall survival (OS), progression free survival (PFS), and predictive factors were determined by Kaplan–Meier method and Cox-proportional hazard analysis. ResultsOf the 52 patients (81% male, mean age 64.9 years), 71% and 29% were classified as Barcelona Clinic Liver Cancer stage C and B HCC, respectively; 63% had portal vein thrombosis, and 35% had objective tumor response defined by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. OS and PFS were 11.0 and 2.4 months, respectively. Two patients were successfully down-staged and further underwent surgical resection. Multifocal lesion, alpha-fetoprotein (AFP) ≥200 ng/mL, and Eastern Cooperative Oncology Group (ECOG) score ≥1 were significantly associated with poor survival, with adjusted hazard ratio (95% confidence interval) of 7.7 (2.0–29.8), 5.4 (2.0–14.7), and 3.1 (1.0–9.6), respectively (all in P < 0.05). ConclusionsY-90 SIRT is an effective treatment for the local tumor control of HCC without serious adverse events. Single lesion, AFP level and ECOG status were predictors of response.

Systematic Review of Radiation-Based Therapies for Hepatocellular Carcinoma

Abstract Aim Despite the increasing trend to utilize radiation therapies for the treatment of hepatocellular carcinoma (HCC), there is limited analysis comparing treatment outcomes of various radiation-based therapies including selective internal radiation therapy (SIRT) to stereotactic body radiation therapy (SBRT) and proton beam therapy (PBT). This study aims to examine the heterogeneity of designs and outcomes in existing radiation therapy studies for the treatment of HCC. Methods A systematic review was performed to compare the radiation therapies for HCC including SBRT, PBT, and yttrium-90 (Y90) SIRT by searching through PubMed, EMBASE, Medline, and Cochrane library databases. The main outcomes analyzed were overall survival rates, median overall survival, and progression-free survival with additional analysis of baseline patient characteristics, including Barcelona Clinic Liver Cancer stage, Child–Pugh class, and tumor size. Results Eighty-seven studies comprising 7,462 patients were included. The pooled 1-year overall survival rates for the Y90 SIRT, SBRT, and PBT groups were 57.8, 83.1, and 78.7%, respectively. The rates of Barcelona Clinic Liver Cancer A, B, and C patients were 22.9, 32.2, and 42.5% in Y90 SIRT; 52.5, 20.2, and 25.1% in SBRT; and 36.3, 33.4, and 28.2% in PBT groups, respectively. The baseline intergroup differences were statistically significant (p &lt; 0.0001). The median tumor sizes were 5.8, 3.1, and 4.5 cm in the Y90 SIRT, SBRT, and PBT groups, respectively. Conclusion In the management of HCC, there is substantial heterogeneity in studies investigating Y90 SIRT, SBRT, and PBT, with Y90 SIRT patients having worse Barcelona Clinic Liver Cancer and tumor burden at baseline, which likely contributes to the observed lower survival outcome.

3D image-based dosimetry for Yttrium-90 radioembolization of hepatocellular carcinoma: Impact of imaging method on absorbed dose estimates.

To improve therapy outcome of Yttrium-90 selective internal radiation therapy (90Y SIRT), patient-specific post-therapeutic dosimetry is required. For this purpose, various dosimetric approaches based on different available imaging data have been reported. The aim of this work was to compare post-therapeutic 3D absorbed dose images using Technetium-99m (99mTc) MAA SPECT/CT, Yttrium-90 (90Y) bremsstrahlung (BRS) SPECT/CT, and 90Y PET/CT. Ten SIRTs of nine patients with unresectable hepatocellular carcinoma (HCC) were investigated. The 99mTc SPECT/CT data, obtained from 99mTc-MAA-based treatment simulation prior to 90Y SIRT, were scaled with the administered 90Y therapy activity. 3D absorbed dose images were generated by dose kernel convolution with scaled 99mTc/90Y SPECT/CT, 90Y BRS SPECT/CT, and 90Y PET/CT data of each patient. Absorbed dose estimates in tumor and healthy liver tissue obtained using the two SPECT/CT methods were compared against 90Y PET/CT. The percentage deviation of tumor absorbed dose estimates from 90Y PET/CT values was on average -2±18% for scaled 99mTc/90Y SPECT/CT, whereas estimates from 90Y BRS SPECT/CT differed on average by -50±13%. For healthy liver absorbed dose estimates, all three imaging methods revealed comparable values. The quantification capabilities of the imaging data influence 90Y SIRT tumor dosimetry, while healthy liver absorbed dose values were comparable for all investigated imaging data. When no 90Y PET/CT image data are available, the proposed scaled 99mTc/90Y SPECT/CT dosimetry method was found to be more appropriate for HCC tumor dosimetry than 90Y BRS SPECT/CT based dosimetry.

Stereotactic Inverse Dose Planning After Yttrium-90 Selective Internal Radiation Therapy in Hepatocellular Cancer

PurposeSelective internal radiation therapy (SIRT) is administered to treat tumors of the liver and is generally well tolerated. Although widely adopted for its therapeutic benefits, SIRT is rarely combined with external beam radiation therapy (EBRT) owing to the complexity of the dosimetry resulting from the combination of treatments with distinct radiobiological effects. The purpose of this study was to establish a dosimetric framework for combining SIRT and EBRT using clinical experience derived from representative patients with hepatocellular carcinoma (HCC) who received both therapies. Methods and MaterialsTreatments from 10 patients with HCC given EBRT either before or after SIRT were analyzed. The dosimetry framework used here considered differences in the radiobiological effects and fractionation schemes of SIRT versus EBRT, making use of the concepts of biological effective dose (BED) and equivalent dose (EQD). Absorbed dose from SIRT was calculated, converted to BED, and summed with BED from EBRT dose plans. Two of these patients were used in a virtual planning exercise to investigate the feasibility of combining stereotactic body radiation therapy and SIRT. ResultsThe combination of EBRT and SIRT in 10 patients with HCC showed no major toxicity. No Child-Pugh scores went above 8 and albumin-bilirubin scores from only 1 patient worsened to grade 3 (> -1.39) from treatment through 3-months follow-up. A framework with radiobiological modeling was developed to manage the combined treatments in terms of their sum BED. The exploratory SIRT plus SABR inverse dose plans for 2 patients, incorporating radiobiologically informed 90Y SIRT dosimetry, achieved dose distributions comparable to SBRT alone. ConclusionsTreatment with both EBRT and SIRT can be given safely to patients with HCC. The BED and EQD concepts should be used in combined dosimetry to account for the differing radiobiological effects of EBRT and SIRT. Inverse dose planning of EBRT after SIRT could provide improved dose distributions and flexibility to the clinical workflow. Further research into combination therapy is needed through prospective trials.

Yttrium-90 selective internal radiotherapy as bridge to curative hepatectomy for recurrent malignant solid pseudopapillary neoplasm of pancreas: case report and review of literature

Recurrent malignant solid pseudopapillary neoplasms of the pancreas (SPNP) are rare tumors with unpredictable clinical and histopathological features. There is a lack of consensus regarding utilization of adjuvant modalities in conjunction with or in lieu of curative metastatectomy. We present a remarkable case where Yttrium-90 selective internal radiation therapy (Y-90 SIRT) was successfully utilized to elucidate underlying tumor biology and aid resection of a large multifocal recurrent metastatic SPNP in the right hemi-liver of a 59-year-old female. Thus, in cases where curative metastatectomy remains the treatment goal in management of recurrent and/or metastatic SPNPs, Y-90 SIRT is a safe and effective adjunct treatment to facilitate curative resection.

Role of yttrium-90 selective internal radiation therapy in the treatment of liver-dominant metastatic colorectal cancer: an evidence-based expert consensus algorithm.

Surgical resection of colorectal liver metastases is associated with greater survival compared with non-surgical treatment, and a meaningful possibility of cure. However, the majority of patients are not eligible for resection and may require other non-surgical interventions, such as liver-directed therapies, to be converted to surgical eligibility. Given the number of available therapies, a general framework is needed that outlines the specific roles of chemotherapy, surgery, and locoregional treatments [including selective internal radiation therapy (SIRT) with Y-90 microspheres]. Using a data-driven, modified Delphi process, an expert panel of surgical oncologists, transplant surgeons, and hepatopancreatobiliary (HPB) surgeons convened to create a comprehensive, evidence-based treatment algorithm that includes appropriate treatment options for patients stratified by their eligibility for surgical treatment. The group coined a novel, more inclusive phrase for targeted locoregional tumor treatment (a blanket term for resection, ablation, and other emerging locoregional treatments): local parenchymal tumor destruction therapy. The expert panel proposed new nomenclature for 3 distinct disease categories of liver-dominant metastatic colorectal cancer that is consistent with other tumor types: (I) surgically treatable (resectable); (II) surgically untreatable (borderline resectable); (III) advanced surgically untreatable (unresectable) disease. Patients may present at any point in the algorithm and move between categories depending on their response to therapy. The broad intent of therapy is to transition patients toward individualized treatments where possible, given the survival advantage that resection offers in the context of a comprehensive treatment plan. This article reviews what is known about the role of SIRT with Y-90 as neoadjuvant, definitive, or palliative therapy in these different clinical situations and provides insight into when treatment with SIRT with Y-90 may be appropriate and useful, organized into distinct treatment algorithm steps.

Yttrium-90 selective internal radiation therapy: Are patient radiation protection contact restrictions necessary?

Yttrium-90 (90Y) microspheres are used for selective internal radiation therapies (SIRTs) to treat patients with hepatocellular carcinoma (HCC) or metastatic colon cancer to the liver, with doses of up to 150 Gy delivered per treatment. 90Y is a pure beta emitter with a decay energy of 0.94 MeV and half-life of 64.2 h. While external beta exposure from the patient is negligible, there can be a considerable associated Bremsstrahlung radiation exposure component. Previous studies in the US, towards establishing radiation dose rates from patients, have deemed radiation protection precautions post-therapy to be unnecessary in most cases; however, the question remains as to whether precautions are necessary within the EU, where more conservative dose constraints are employed. Accordingly, dose rates from 28 patients, treated over a three year period (2016–2018) were measured post therapy at distances of 0.3 m and 1 m, and in contact with the patients’ upper abdomen. Dose rates were compared with theoretical predictions and used as model inputs for calculating radiation doses received by family members and carers based on interaction patterns previously described in the literature. The work demonstrated restrictions to be advisable considering the dose constraints employed within the EU. Indeed, while this study examined dose rates for 90Y Therasphere patients, another 90Y therapeutic pharmaceutical, namely SIRSpheres, require reportedly similar treatment activities, leading to similar Bremsstrahlung radiation dose rates. Thus, in accordance with EU dose constraints, radiation protection precautions are necessary for those individuals in regular contact with patients having undergone SIRT procedures.

Evaluation of Lung Dose Using Voxel-based Dosimetry with SPECT/CT for Yttrium-90 Selective Internal Radiation Therapy of Liver Cancer

Evaluation of Lung Dose Using Voxel-based Dosimetry with SPECT/CT for Yttrium-90 Selective Internal Radiation Therapy of Liver Cancer

Yttrium-90 selective internal radiation therapy, examining dose rates and radiation protection precautions

MethodsDose rates from 30 patients, treated over a 3-year period (2016–2018) were measured post therapy in contact with the patients’ upper abdomen and at distances of 0.3 m and 1 m. Dose rates were compared with theoretical predictions and used as model inputs for calculating radiation doses received by family members and carers based on interaction patterns previously described in the literature. ResultsThe average dose rate per activity from SIRT patients were:- In contact: 29 ± 23 µSv.h−1.GBq−1; 0.3 m: 4.1 ± 2.34 µSv.h−1.GBq−1 and 1 m: 0.59 ± 0.42 µSv.h−1.GBq−1. Dose rates measured at 0.3 and 1 m followed a predictable distribution. Estimated doses based on proximity models demonstrated restrictions to be advisable, depending on the administered activity, considering the dose constraint and limit of 0.3 and 1 mSv, respectively, employed within the EU. ConclusionsIn accordance with local dose constraints, and depending on administered activities, radiation protection precautions may be necessary for those individuals in regular contact with patients who have receive 90Y SIRT. A radiation protection precautions calculator has been devised to offer personalised instructions taking into account the administered activity and proximity models.

Radical Radial: Pearls and Pitfalls in Transradial Yttrium-90 Liver-Directed Therapy

The frequency of transradial access in interventional radiology has been steadily increasing, including for yttrium-90 (Y-90) selective internal radiation therapy to treat hepatic malignancies. The aim of this article is to detail an optimized approach to transradial Y-90 (TRY-90), showing it to be a safe and feasible first-line approach to hepatic selective internal radiation therapy. Salient preprocedural considerations to enable appropriate patient selection for TRY-90 are discussed and a detailed equipment list is provided. The article will describe our approach to TRY-90 in addition to a discussion around technical pearls and pitfalls.

Current Status and Growth of Nuclear Theranostics in Singapore.

The concept of theranostics, where individual patient-level biological information is used to choose the optimal therapy for that individual, has become more popular in the modern era of 'personalised' medicine. With the growth of theranostics, nuclear medicine as a specialty is uniquely poised to grow along with the ever-increasing number of concepts combining imaging and therapy. This special report summarises the status and growth of Theranostic Nuclear Medicine in Singapore. We will cover our experience with the use of radioiodine, radioiodinated metaiodobenzylguanidine, peptide receptor radionuclide therapy, prostate specific membrane antigen radioligand therapy, radium-223 and yttrium-90 selective internal radiation therapy. We also include a section on our radiopharmacy laboratory, crucial to our implementation of theranostic principles. Radionuclide theranostics has seen tremendous growth and we hope to be able to grow alongside to continue to serve the patients in Singapore and in the region.