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Background Gastrointestinal stromal tumours (GISTs) represent the most common mesenchymal tumour of the gastrointestinal tract. Although the efficacy of targeted therapy cannot be over-emphasized, surgery remains the only curative primary treatment for patients with localized disease. The median size of GIST at diagnosis is approximately 5–7 cm; however, it is not uncommon for tumours to be as large as 30–40 cm and involving multiple viscera. Methods Data were retrospectively collected from patients with GISTs treated at the Singapore General Hospital and the National Cancer Centre Singapore over a 15-year period. Standard resection of GIST without any additional organ removal was termed as a single organ resection (SOR). If the tumour was adjacent to another organ, necessitating the removal of more than one organ, the procedure was defined as a multivisceral resection (MVR). We aim to evaluate the role of MVR in the management of large GISTs. Results A total of 187 patients underwent curative surgery for GIST between January 2000 and January 2014. Of the 187 patients, 40 (21%) underwent MVR whereas 147 (79%) had SOR. Patients in the MVR group had significantly larger tumour sizes (P

Background Gastrointestinal stromal tumours (GISTs), despite complete surgical cytoreduction, are associated with recurrence rates of up to 50% at 2 years. At recurrence, tyrosine kinase inhibitor (TKI) therapy is recommended, conferring a survival of up to 55 months. Several studies have shown that patients with TKI-responsive recurrent GIST benefit from surgery. However, no studies have compared upfront surgery versus TKI alone. Methods Data were retrospectively collected from patients with recurrent GIST treated at Singapore General Hospital and National Cancer Centre Singapore over a 12-year period. Our primary end points were disease-free and overall survival (OS). Results A total of 186 patients underwent curative surgery for GIST between January 2000 and June 2012. Fifty-six (30%) patients experienced recurrence, of which 30 (54%) had resectable recurrent disease. Twenty-four patients underwent upfront surgery for their recurrence while the remaining six patients opted for non-surgical management. The median OS for all patients with recurrent GIST was 5.3 years (95% confidence interval (CI) 3.2–8.4). It was not reached for patients who underwent curative surgery for their recurrence, and was 3.9 years (95% CI 2.4–7.0) for patients who had palliative TKI and conservative management. There were significant differences in OS and disease-specific survival between patients who underwent curative surgery for recurrence compared with those who had not. Conclusion Our study shows that upfront surgery is a reasonable treatment strategy for selected patients with recurrent GIST.

BackgroundMucinous epithelial ovarian cancers (mEOCs) respond poorly to conventional chemotherapy and have a poor prognosis in advanced stages. The genomic landscape for mEOC in the Asian settings is ill defined. We seek to identify various mutational aberrations present in mEOC and correlate them with clinical outcomes.MethodsA total of 199 cases of mEOC were identified from a prospectively maintained gynecologic oncology tumor database. DNA was extracted and analyzed for KRAS mutations by using Sanger sequencing. Further MassArray sequencing was performed on 45 samples. Clinicopathologic correlation was performed with the results obtained.FindingsKRAS mutation status was evaluable in 124 cases. Fifty-five percent (68/124) were KRAS negative, whereas 45% (56/124) harbored a KRAS mutation, lower than that in Western populations. Successful ascertainment of both KRAS and HER2 statuses by Sanger sequencing occurred for 105 cases. The proportion of the double-positive subtype (HER2+ and KRAS positive) was 8% (8/105); double-negative subtype (HER2− and KRAS negative), 34% (36/105); and cases with mutation in either KRAS or HER2, 58% (61/105). The KRAS mutation rate was 44%, 50%, and 29% among Chinese, Indians, and Malays, respectively. There was no significant difference in overall survival (P = 0.952) or progression-free survival (P = 0.635) between KRAS-positive and KRAS-negative patients. Similar results were observed for progression-free survival (P = 0.206) and overall survival (P = 0.440) when outcomes were examined between the 4 groups based on KRAS and HER2 mutation. Patients in the double-negative mutation subgroup had higher risk for death/progression compared with patients in the other 3 mutation subgroups. Further MassARRAY multiplexed profiling was performed in patients with sufficient DNA material (n = 45) and yielded KRAS mutations (n = 16), PDGFRA mutations (n = 3), PIK3CA (n = 1) and KIT (n = 1), and HRAS, FGFR, MET, and NRAS (n = 1 each).ConclusionsOur study provides further knowledge about the mutational aberrations in mEOC in Asian populations. Neither the presence of KRAS mutation nor their correlation with HER2 mutations influenced outcomes.

Objectives/Hypothesis The purpose of this study was to report the outcomes of a retrospective consecutive cohort study of patients with T1N0M0 glottic carcinoma treated with 4-MV or 6-MV radiotherapy. Study Design Retrospective case–control study. Methods This was a retrospective review of all patients with T1N0M0 glottic carcinoma treated with radiotherapy between January 2000 and December 2012 in the Department of Radiation Oncology at National Cancer Center Singapore. A total of 124 patients were included. Clinical endpoints of interest were: local control (LC), overall survival (OS), and disease-specific survival (DSS). Other prognostic factors for LC were also analyzed: age, gender, smoking status, T substage, dose fraction, field size, anterior commissure involvement, total dose, and overall treatment time. Results Six-megavolt photon radiotherapy was used in 73 patients and 4-MV photon radiotherapy in 51 patients. Median follow-up was 4.9 years. The 5-year LC and OS were as follows: 4 MV, 91.6% and 83.4%; 6 MV, 88.8% and 82.8%; and the 5-year LC, OS, and DSS for all patients were 90.4%, 83.3%, and 98.3%. There was no significant difference in LR and OS between 4-MV and 6-MV radiotherapy (P = .92, P = .16, respectively). In the univariate analysis of LC, none of the prognostic factors was statistically significant. Twenty patients (23%) developed second primary cancers, the majority in the lungs. Conclusions Six-megavolt photon radiotherapy yields comparable results to 4-MV photons. Bolus and computed tomographic simulation are useful to ensure adequate dose coverage of target volume. Follow-up postradiotherapy should incorporate chest imaging, smoking cessation advice, and thyroid function test. Level of Evidence 4 Laryngoscope, 2016

Gastrointestinal stromal tumours (GISTs) represent the most common mesenchymal tumour of the gastrointestinal tract. Although the efficacy of targeted therapy cannot be over-emphasized, surgery remains the only curative primary treatment for patients with localized disease. The median size of GIST at diagnosis is approximately 5-7 cm; however, it is not uncommon for tumours to be as large as 30-40 cm and involving multiple viscera.Data were retrospectively collected from patients with GISTs treated at the Singapore General Hospital and the National Cancer Centre Singapore over a 15-year period. Standard resection of GIST without any additional organ removal was termed as a single organ resection (SOR). If the tumour was adjacent to another organ, necessitating the removal of more than one organ, the procedure was defined as a multivisceral resection (MVR). We aim to evaluate the role of MVR in the management of large GISTs.A total of 187 patients underwent curative surgery for GIST between January 2000 and January 2014. Of the 187 patients, 40 (21%) underwent MVR whereas 147 (79%) had SOR. Patients in the MVR group had significantly larger tumour sizes (P 0.001) yet R0 and R1 resection was achieved in all patients, and no intra-peritoneal rupture was reported. On comparison of MVR versus SOR groups, there was no significant difference in in-hospital morbidity and mortality.MVR may be required to achieve negative margins in patients with large GISTs, and can be performed with acceptable morbidity and mortality.

Importance Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm ( P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance ( P −8 ), including a novel DPYD variant (rs75267292; P = 1.57 × 10 −10 ), and variants in the MACF1 (rs183324967, P = 4.80 × 10 −11 ;rs148221738, P = 5.73 × 10 −10 ) and SPRY2 (rs117876855, P −8 ;rs139544515, P = 1.30 × 10 −8 ) genes involved in wound healing. Conclusions and Relevance Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. Trial Registration clinicaltrials.gov Identifier:NCT00486213

Aims: Emerging evidence in viral-associated oro- and naso-pharynx cancers supports the concept of radiotherapy (RT) dose de-intensification in these radiosensitive tumours. This notion is particularly relevant in the background that a majority of head and neck cancer patients develop severe late toxicities despite modern precision RT. A reasonable strategy could thus entail stratifying patients at risk of late toxicities to dose de-intensification. Here, we investigated the utility of a lymphocyte apoptosis (RILA) assay to predict for late toxicities in EBV-positive nasopharynx cancer patients. We also test if a multi-modal approach incorporating DNA damage induction and repair improves the prediction of clinical radiosensitivity. Methods: Assays were assessed retrospectively among survivors of a randomised controlled trial (NCC-0902), where patients were assigned to weekly cisplatin-RT with or without neoadjuvant gemcitabine, carboplatin, and paclitaxel. Late toxicities were assessed by CTCAE v.2 at the following intervals - 2-mo year 1, 4-mo year 2, 6-mo years 3-5, and annually thereafter; and considered severe if CTCAE v.2 ≥Grade 2. RILA was based on a fluorogenic inhibitor of caspases assay (48 h post-8 Gy). DNA damage induction and repair were assessed by semi-automated scoring of ϒH2AX foci at 30 min post-1 Gy and 24 h post-4 Gy, respectively. Results: Median follow-up of patients was 5.7 (range 4.6-7.4) years. Clinical and treatment indices, including assigned study arm and RT dosimetry to normal tissue structures, were balanced between patients with and without late toxicities (p >0.05). We observed a trend between decreasing RILA scores and increased risks of late toxicities; odds ratio (OR) 1.27 (95% CI = 0.92-1.72) for lowest quartile cut-off, corresponding to an AUC of 0.608 for prediction accuracy (p = 0.049). A multi-modal approach incorporating DNA damage induction and repair did not improve upon the predictive accuracy of RILA for clinical radiosensitivity. Independently, DNA damage induction and repair were not associated with risks of late toxicities; OR 1.03 (95% CI = 0.69-1.53, p = 0.901) and 1.04 (95% CI = 0.73-1.49, p = 0.829), respectively. Interestingly, onset of late toxicities was correlated to an improved disease-free survival in our cohort (5-y DFS = 94.1% vs 73.3%, no late toxicity, p = 0.003), which suggests a common mechanism underlying tumour and normal tissue radiosensitivity in EBV-positive nasopharynx cancer. Conclusions: Herein, we report on the potential utility of a RILA assay in stratifying for patients at risk of late RT-induced toxicities. The clinical implication of this assay is further exemplified by the observation of a superior survival in these sensitive individuals, which supports the approach of selecting this subgroup for treatment de-intensification. Citation Format: Kevin L.M. Chua, Shihabuddeen Waseem Ahamed, Ma Than Than Shwe, Li-lian Kwok, Joseph T.S. Wee, Terence W.K. Tan, Prakash M. Hande, Kai Rothkamm, Melvin L.K. Chua. Lymphocyte apoptosis as a predictive biomarker for radiotherapy de-intensification in EBV-associated nasopharynx cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1794. doi:10.1158/1538-7445.AM2017-1794

Purpose This study was undertaken to examine the impact of screening and race on breast cancer outcomes in Singapore. Methods An institutional database was reviewed, and invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS) data were analyzed separately. Overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were assessed. Results The study included 6,180 IDC and 1,031 DCIS patients. The median follow-up time was 4.1 years. Among IDC patients, Malay women were the youngest when first diagnosed, and were more likely to present with advanced stage disease. Malay women also had the highest proportion of T3 and T4 tumors at 14.2%, compared with Chinese women at 8.7% and Indian women at 9.6% (p

BACKGROUND: Valproic acid (VPA), other than its seizure activity, has shown potential benefit as a chemosensitizing agent due to its histone deacetylase inhibitor activity in the management of patients with high grade glioma. On the other hand, VPA could also potentially increase the toxicity of chemotherapeutic agents. We aim to study the use of VPA on the outcomes of patients with high grade gliomas. METHODS: All patients with high grade glioma seen at the Neuro-oncology clinic in National Cancer Centre Singapore between 2006 to 2008 were analyzed retrospectively. Patients with high grade glioma, defined as World Health Organization (WHO) grade III or IV astrocytic, oligodendroglial, oligoastrocytic tumors were included in the study. RESULTS: A total of 122 patients were analyzed. Median age of diagnosis for the cohort was 49.6 years. 87 patients (71.3%) underwent surgical resection, while 33 patients (27%) had a biopsy performed. In the cohort, 60 patients (49.2%) had concurrent temozolomide and radiotherapy thereafter. Median follow up time for the cohort was 1.5 years. Median overall survival (OS) was comparable for VPA users and non-users (VPA users: 25.2 months (95% CI: 18.0, 48.0) versus non-VPA users: 33.6 months (95% CI: 20.4, 67.2), p = 0.348). Among the 60 patients who underwent concurrent temozolomide and radiotherapy, the use of VPA conferred a marginal worsening of OS (VPA users: 25.2 months (95% CI: 18.0, 38.4) versus non-VPA users: 33.6 months (95% CI: 20.4, 67.2), p = 0.083). CONCLUSIONS: In our study, high grade glioma patients on VPA have similar median OS compared to those who were not on VPA. However, there is a trend towards decreased overall survival in those patients who had concurrent temozolomide and radiotherapy with VPA use. This could be related to increased treatment toxicity. The role of VPA in high grade glioma will need to be clarified in further studies.