Radiation oncology training in Singapore - A non-Australasian RANZCR training site.

The Radiation Oncology Department at The National Cancer Institute, Singapore (NCIS) and the Royal Australian and New Zealand College of Radiology (RANZCR) has had a well-established relationship that began as a partnership to grow a pool of local radiation oncologists to meet a nation's demand for radiotherapy services. This journey has surpassed its initial aims and now has produced a generation of radiation oncologists leading a national cancer institute. We recount the history and progress of this partnership here, as well as the unique success of its product; the only RANZCR-accredited radiation oncology training site outside of Australia and New Zealand since 2002. We outline the mutual benefits through many years of collaboration and deliberate efforts to grow the partnership. We also outline the distinctive specialist training path that our trainees take to meet both the local accreditation body as well as the RANZCR requirements.

Singapore Undiagnosed Disease Program: Genomic Analysis aids Diagnosis and Clinical Management.

OBJECTIVE: Use next-generation sequencing (NGS) technology to improve our diagnostic yield in patients with suspected genetic disorders in the Asian setting. DESIGN: A diagnostic study conducted between 2014 and 2019 (and ongoing) under the Singapore Undiagnosed Disease Program. Date of last analysis was 1 July 2019. SETTING: Inpatient and outpatient genetics service at two large academic centres in Singapore. PATIENTS: Inclusion criteria: patients suspected of genetic disorders, based on abnormal antenatal ultrasound, multiple congenital anomalies and developmental delay. EXCLUSION CRITERIA: patients with known genetic disorders, either after clinical assessment or investigations (such as karyotype or chromosomal microarray). INTERVENTIONS: Use of NGS technology-whole exome sequencing (WES) or whole genome sequencing (WGS). MAIN OUTCOME MEASURES: (1) Diagnostic yield by sequencing type, (2) diagnostic yield by phenotypical categories, (3) reduction in time to diagnosis and (4) change in clinical outcomes and management. RESULTS: We demonstrate a 37.8% diagnostic yield for WES (n=172) and a 33.3% yield for WGS (n=24). The yield was higher when sequencing was conducted on trios (40.2%), as well as for certain phenotypes (neuromuscular, 54%, and skeletal dysplasia, 50%). In addition to aiding genetic counselling in 100% of the families, a positive result led to a change in treatment in 27% of patients. CONCLUSION: Genomic sequencing is an effective method for diagnosing rare disease or previous 'undiagnosed' disease. The clinical utility of WES/WGS is seen in the shortened time to diagnosis and the discovery of novel variants. Additionally, reaching a diagnosis significantly impacts families and leads to alteration in management of these patients.

Identification of KMT2D and KDM6A variants by targeted sequencing from patients with Kabuki syndrome and other congenital disorders.

Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive facies, postnatal growth deficiency, cardiac defects and skeletal anomalies. Studies have determined that pathogenic variants of the lysine-specific methyltransferase 2D (KMT2D) and lysine-specific demethylase 6A (KDM6A) genes are the major causes of KS. The two genes encode different histone-modifying enzymes that are found in the same protein complex that is critical for cell differentiation during development. Here we report the results from next-generation sequencing of genomic DNA from 13 patients who had a clinical diagnosis of KS based on facial dysmorphism and other KS-specific cardinal phenotypes. Nine of the 13 patients were confirmed to be carrying heterozygous pathogenic KMT2D variants, seven of which were truncating and two were missense substitutions. Overall, we uncovered 11 novel variants - nine in KMT2D and two in KDM6A. Seven of the novel variants (all KMT2D) were likely causative of the KS phenotype. Our study expands the number of naturally occurring KMT2D and KDM6A variants. The discovery of novel pathogenic variants will add to the knowledge on disease-causing variants and the relevance of missense variants in KS.

A review of whole brain radiotherapy outcomes in a high epidermal growth factor receptor mutation rate population: Does QUARTZ apply in Asia?

AIM: Whole brain radiotherapy (WBRT) is commonly used to treat brain metastases (BM) from nonsmall cell lung cancer (NSCLC). Its utility is increasingly being questioned after a recent randomized trial (QUARTZ) showed that its omission did not significantly impact the survival or quality of life of their patients recruited from UK and Australian centers. We report the patient characteristics and survival outcomes of our local population in comparison with theirs. METHODS: Medical records of patients who received WBRT in two tertiary hospitals over 18 months were reviewed. Characteristics and survival outcomes of patient with NSCLC receiving WBRT for the first time were evaluated. Patients with prior excision of BM or stereotactic radiotherapy were excluded. Treatment details including radiotherapy dose and use of tyrosine kinase inhibitors (TKIs) were recorded. RESULTS: Between January 2015 and June 2016, 116 patients with NSCLC received WBRT for their BM. Their median age was 65 years (range, 36-85) and median follow-up duration was 110 days (range, 14-840). A total of 102 (88%) patients had their driver mutation tested of which 59 (58%) were epidermal growth factor receptor (EGFR) mutants. Factors predicting for better survival were female gender (P < .001), EGFR mutant receiving TKIs (P = .013), prescription other than 20 Gray in five fractions (P = .003), and presence of more than four BM (P = .001). CONCLUSION: Our patients appear to be considerably different from those recruited into the QUARTZ trial. Further prospective studies should be done to evaluate the value of WBRT in our population.

The spectrum of genetic variants and phenotypic features of Southeast Asian patients with Noonan syndrome.

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant disorder that belongs to a group of developmental disorders called RASopathies with overlapping features and multiple causative genes. The aim of the study was to identify mutations underlying this disorder in patients from Southeast Asia and characterize their clinical presentations. METHODS: Patients were identified from the hospital's Genetics clinics after assessment by attending clinical geneticists. A targeted gene panel was used for next-generation sequencing on genomic DNA extracted from the blood samples of 17 patients. RESULTS: Heterozygous missense variants were identified in 13 patients: eight were in PTPN11, three in SOS1, and one each in RIT1 and KRAS. All are known variants that have been reported in patients with NS. Of the 13 patients with identified variants, 10 had short stature, the most common feature for NS. Four of the eight patients with PTPN11 variants had atrial septal defect. Only two had pulmonary stenosis which is reported to be common for PTPN11 mutation carriers. Another two had hypertrophic cardiomyopathy, a feature which is negatively associated with PTPN11 mutations. CONCLUSIONS: Our study provides the mutation and phenotypic spectrum of NS from a new population group. The molecular testing yield of 76% is similar to other studies and shows that the targeted panel approach is useful for identifying genetic mutations in NS which has multiple causative genes. The molecular basis for the phenotypes of the remaining patients remains unknown and would need to be uncovered via sequencing of additional genes or other investigative methods.

Chemoradiotherapy versus chemotherapy for locally advanced unresectable pancreatic cancer: A systematic review and meta-analysis.

PURPOSE: To determine the benefit of adding radiotherapy (RT) to chemotherapy for patients with locally advanced unresectable pancreatic cancer (LAUPC). METHODS: We searched MEDLINE for comparative studies comparing chemoradiotherapy with chemotherapy for patients with LAUPC. We performed the meta-analysis with random effects model. The primary outcome was overall survival (OS); secondary outcomes include progression-free survival (PFS) and adverse events (AE). RESULTS: We found five randomized (RCT) and three observational studies (OBS) including 830 patients. For RCTs, the addition of radiotherapy did not improve PFS (hazard ratio [HR] 0.90; 95% confidence interval [CI], 0.74-1.10; P = 0.30; I2   =  11%,) or OS (HR 0.87; 95% CI, 0.63-1.21; P = 0.41; I2 = 67%,) and was associated with increased grade 3 or 4 gastrointestinal AE. In contrast, OBS reported an improvement in PFS (HR 0.58; 95% CI, 0.37-0.92; P = 0.02; I2 = 32%) and OS (HR 0.48; 95% CI, 0.35-0.60; P < 0.0001; I2 = 6%). CONCLUSION: The addition of radiotherapy did not improve the OS and PFS in RCTs. The divergence in results seen in OBS may be due to imbalance in baseline characteristics. Further research incorporating biomarkers may help to better select patients who will benefit from RT.

Evolution of Diabetes Care in Hong Kong: From the Hong Kong Diabetes Register to JADE-PEARL Program to RAMP and PEP Program.

The rapid increase in diabetes prevalence globally has contributed to large increases in health care expenditure on diabetic complications, posing a major health burden to countries worldwide. Asians are commonly observed to have poorer ß-cell function and greater insulin resistance compared to the Caucasian population, which is attributed by their lower lean body mass and central obesity. This "double phenotype" as well as the rising prevalence of young onset diabetes in Asia has placed Asians with diabetes at high risk of cardiovascular and renal complications, with cancer emerging as an important cause of morbidity and mortality. The experience from Hong Kong had demonstrated that a multifaceted approach, involving team-based integrated care, information technological advances, and patient empowerment programs were able to reduce the incidence of diabetic complications, hospitalizations, and mortality. System change and public policies to enhance implementation of such programs may provide solutions to combat the burgeoning health problem of diabetes at a societal level.

Outcomes of neoadjuvant chemoradiotherapy followed by total mesorectal excision surgery for locally advanced rectal cancer: a single-institution experience.

INTRODUCTION: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) surgery for locally advanced rectal cancer has been shown to improve local control and reduce toxicity, as compared to adjuvant CRT. We reported the outcomes of our patients with locally advanced rectal cancer treated at National University Hospital, Singapore. METHODS: From April 2002 to December 2014, 117 patients with T3/4, N0/+, M0 rectal cancer received neoadjuvant CRT followed by TME surgery. The treatment regimen comprised a total radiotherapy dose of 50.4 Gy in 28 daily fractions delivered concurrently with 5-fluorouracil or capecitabine chemotherapy over 5.5 weeks. All patients were planned for TME surgery. Local control, disease-free survival, overall survival and treatment toxicities were analysed. RESULTS: Median follow-up was 34 (range 2-122) months. 11.5% (13/113) of patients achieved a pathological complete response (pCR) and 72.6% (85/117) had either tumour or nodal downstaging following neoadjuvant CRT. 5.2% (5/96) of patients had Grade 3 acute toxicities (dermatitis and diarrhoea) and 3.1% (3/96) had Grade 3 late toxicities (fistula and stricture). There was no Grade 4 toxicity noted. The five-year local recurrence, disease-free survival and overall survival rates were 4.5%, 65.7% and 80.6%, respectively. Multivariate analysis showed that nodal positivity was a predictor of poor disease-free survival and poor overall survival. Tumour downstaging and pCR did not improve outcomes. CONCLUSION: Our outcomes were comparable to internationally published data, and this treatment regimen remains the standard of care for locally advanced rectal cancer in our local population.

Outcomes of Asian patients with localized prostate cancer treated with combined intensity modulated radiation therapy (IMRT) and high dose rate (HDR) brachytherapy: A single institution experience.

AIM: External beam radiotherapy (EBRT) followed by high dose rate (HDR) brachytherapy boost has demonstrated minimal toxicities and improved disease control rate compared with EBRT alone in observational and randomized studies with predominantly Caucasian patients. This study aims to report the outcomes of patients treated with this approach in our predominantly Asian population. METHODS: Medical records for patients with localized prostate cancer who received combined EBRT delivered via intensity modulated radiotherapy (IMRT) technique followed by HDR brachytherapy boost were retrospectively reviewed. Outcomes evaluated included 5-year biochemical recurrence-free survival (per Phoenix definition), overall survival and treatment toxicities. RESULTS: From June 2009 to March 2015, 75 patients were treated with IMRT followed by HDR brachytherapy boost. Twenty patients (27%) had intermediate risk, 55 (74%) had high-risk disease. Median follow up was 64 months. All patients received IMRT to a median dose of 45 Gy to the pelvis followed by HDR brachytherapy boost. Sixty, 10 and 5 patients received boost of 21 Gy in two fractions, 19 Gy in two fractions and 15 Gy in a single fraction, respectively. All patients met the planning criteria adapted from RTOG 0815. The 5-year prostate-specific antigen (PSA) control was 85.2% (80.3% and 100% for high-risk and intermediate-risk group, respectively). Cancer-specific survival and overall survival are 97.3% and 92.0%, respectively. Eleven (15%) patients developed biochemical failure, six of which had distant metastasis. Three (4%) developed grade 3 genitourinary toxicity (urethral stricture and/or cystitis) and none developed grade 3 radiation proctitis. CONCLUSION: Our outcomes are comparable to internationally published data and demonstrate reproducibility of this approach in our population.

Rapidly Fatal Radiation-induced Glioblastoma.

Glioblastoma (GBM) typically occurs as a primary tumour (i.e., primary GBM) and predominantly affects elderly patients. The remaining ~10% occur as a result of malignant progression from lower grade astrocytic tumours (i.e., secondary GBM). Although there are no certain causative environmental agents, prior radiation exposure may play a role. We report on a patient who had been treated six years prior for a vestibular schwannoma with high-dose conventional radiotherapy and subsequently developed a rapidly fatal glioblastoma at the same location. The diagnosis was confirmed by routine histopathology as well as more advanced techniques, such as whole genome copy number analysis.

Long-term remission after low dose radiotherapy in patient with extensive squamous cell carcinoma of the hand: A case report.

RATIONALE FOR CASE REPORT: Cutaneous Squamous Cell Carcinoma (cSCC) of the hand is uncommon and tends to have poorer outcomes. Surgical resection with wide margins around the tumor is recommended as the treatment of choice, and radiotherapy is considered second-line treatment. Nodal evaluation involves dissection necessitating some morbidity. The role of less invasive modalities of nodal evaluation is not well established. CASE PRESENTATION: We report a case of locally advanced case of hand cSCC. Positron emission tomography-computed tomography (PET-CT) showed disease involving full thickness of the hand as well as the ipsilateral axillary node. To achieve adequate surgical margins would have necessitated amputation at the wrist, which the patient did not consent to. Instead, he was given a two-and-a-half week course radiotherapy to the hand without axillary radiation. With the radiotherapy treatment, he managed to achieve complete remission of disease while retaining full function of the hand, which was maintained at 22 months post-treatment. MAIN LESSONS: CSCC of the hand is uncommon and challenging to treat. Radiotherapy is a highly effective treatment modality which is able to achieve functional preservation. Care should be taken when evaluating nodal status using PET-CT.

Use of deferiprone for iron chelation in patients with transfusion-dependent thalassaemia.

AIM: To conduct a retrospective case analysis of the clinical efficacy and adverse effects of deferiprone in our population. METHODS: All patients with transfusion-dependent thalassaemia at KK Hospital who have been on deferiprone were included in the study. Outcomes measured include the change in ferritin levels and cardiac T2* values during deferiprone therapy, and incidence of side effects. RESULTS: Thirty-three (47.1%) of the total cohort of 70 patients have been on deferiprone, out of which 26 were on combination therapy with desferrioxamine. Majority of the patients (76%) had stable cardiac iron load during deferiprone therapy, and four patients with moderate to severe cardiac iron load showed improvement. Ten patients (30.3%) had improvement in their ferritin levels. Three patients (9.1%) developed mild neutropenia at 3, 18 and 26 months, respectively, and two patients (6.1%) had agranulocytosis at 4 and 10 months, respectively. Their neutrophil counts improved spontaneously after cessation of deferiprone. Thrombocytopenia developed in 27.3% of the patients and was transient in majority (77.8%) of the patients. Five patients (15.2%) developed arthritis that improved after cessation of deferiprone therapy, and one patient had transient arthralgia that resolved spontaneously. Three patients (9.1%) had nausea and abdominal pain. CONCLUSION: Deferiprone effectively reduced or stabilised cardiac iron load in our patients. Thrombocytopenia, arthropathy, neutropenia and agranulocytosis are the most important side effects. It is recommended that patients on deferiprone have their full blood counts monitored weekly for the first year of therapy and subsequently fortnightly as long as they are on deferiprone.

International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers.

PURPOSE: To examine the reproducibility of the single breathhold T2* technique from different scanners, after installation of standard methodology in five international centers. MATERIALS AND METHODS: Up to 10 patients from each center were scanned twice locally for local interstudy reproducibility of heart and liver T2*, and then flown to a central MR facility to be rescanned on a reference scanner for intercenter reproducibility. Interobserver reproducibility for all scans was also assessed. RESULTS: Of the 49 patients scanned, the intercenter reproducibility for T2* was 5.9% for the heart and 5.8% for the liver. Local interstudy reproducibility for T2* was 7.4% for the heart and 4.6% for the liver. Interobserver reproducibility for T2* was 5.4% for the heart and 4.4% for the liver. CONCLUSION: These data indicate that T2* MR may be developed into a widespread test for tissue siderosis providing that well-defined and approved imaging and analysis techniques are used.

Amelioration of oxidative stress in red blood cells from patients with beta-thalassemia major and intermedia and E-beta-thalassemia following administration of a fermented papaya preparation.

In beta-hemoglobinopathies, such as beta-thalassemia (thal) and sickle cell anemia, the primary defects are mutations in the beta-globin gene. However, many aspects of the pathophysiology are mediated by oxidative stress. Fermented papaya preparation (FPP), a natural health food product obtained by biofermentation of carica papaya, has been shown to limit oxidative stress both in vitro and in vivo. We studied the effect of FPP on two groups of beta-thal patients: beta-thal, major and intermedia, (in Israel) and E-beta-thal (in Singapore). The results indicated that in both groups FPP treatment increased the content of reduced glutathione (GSH) in red blood cells (RBC), and decreased their reactive oxygen species (ROS) generation, membrane lipid peroxidation, and externalization of phosphatidylserine (PS), indicating amelioration of their oxidative status, without a significant change in the hematological parameters. Since the turnover of the erythron is relatively slow, it is possible that longer duration of treatment, probably with the addition of an iron chelator, is required in order to achieve the latter goals.

Multi-center transferability of a breath-hold T2 technique for myocardial iron assessment.

BACKGROUND: Cardiac iron overload is the leading cause of death in thalassemia major and is usually assessed using myocardial T2* measurements. Recently a cardiovascular magnetic resonance (CMR) breath-hold T2 sequence has been developed as a possible alternative. This cardiac T2 technique has good interstudy reproducibility, but its transferability to different centres has not yet been investigated. METHODS AND RESULTS: The breath-hold black blood spin echo T2 sequence was installed and validated on 1.5T Siemens MR scanners at 4 different centres across the world. Using this sequence, 5-10 thalassemia patients from each centre were scanned twice locally within a week for local interstudy reproducibility (n = 34) and all were rescanned within one month at the standardization centre in London (intersite reproducibility). The local interstudy reproducibility (coefficient of variance) and mean difference were 4.4% and -0.06 ms. The intersite reproducibility and mean difference between scanners were 5.2% and -0.07 ms. CONCLUSION: The breath-hold myocardial T2 technique is transferable between Siemens scanners with good intersite and local interstudy reproducibility. This technique may have value in the diagnosis and management of patients with iron overload conditions such as thalassemia.

MS analysis of single-nucleotide differences in circulating nucleic acids: Application to noninvasive prenatal diagnosis.

The analysis of circulating nucleic acids has revealed applications in the noninvasive diagnosis, monitoring, and prognostication of many clinical conditions. Circulating fetal-specific sequences have been detected and constitute a fraction of the total DNA in maternal plasma. The diagnostic reliability of circulating DNA analysis depends on the fractional concentration of the targeted sequence, the analytical sensitivity, and the specificity. The robust discrimination of single-nucleotide differences between circulating DNA species is technically challenging and demands the adoption of highly sensitive and specific analytical systems. We have developed a method based on single-allele base extension reaction and MS, which allows for the reliable detection of fetal-specific alleles, including point mutations and single-nucleotide polymorphisms, in maternal plasma. The approach was applied to exclude the fetal inheritance of the four most common Southeast Asian beta-thalassemia mutations in at-risk pregnancies between weeks 7 and 21 of gestation. Fetal genotypes were correctly predicted in all cases studied. Fetal haplotype analysis based on a single-nucleotide polymorphism linked to the beta-globin locus, HBB, in maternal plasma also was achieved. Consequently, noninvasive prenatal diagnosis in a mother and father carrying identical beta-thalassemia mutations was accomplished. These advances will help in catalyzing the clinical applications of fetal nucleic acids in maternal plasma. This analytical approach also will have implications for many other applications of circulating nucleic acids in areas such as oncology and transplantation.