Repurposing Proton Beam Therapy through Novel Insights into Tumour Radioresistance.

Despite improvements in radiotherapy, radioresistance remains an important clinical challenge. Radioresistance can be mediated through enhanced DNA damage response mechanisms within the tumour or through selective pressures exerted by the tumour microenvironment (TME). The effects of the TME have in recent times gained increased attention, in part due to the success of immune modulating strategies, but also through improved understanding of the downstream effects of hypoxia and dysregulated wound healing processes on mediating radioresistance. Although we have a better appreciation of these molecular mechanisms, efforts to address them through novel combination approaches have been scarce, owing to limitations of photon therapy and concerns over toxicity. At the same time, proton beam therapy (PBT) represents an advancement in radiotherapy technologies. However, early clinical results have been mixed and the clinical strategies around optimal use and patient selection for PBT remain unclear. Here we highlight the role that PBT can play in addressing radioresistance, through better patient selection, and by providing an improved toxicity profile for integration with novel agents. We will also describe the developments around FLASH PBT. Through close examination of its normal tissue-sparing effects, we will highlight how FLASH PBT can facilitate combination strategies to tackle radioresistance by further improving toxicity profiles and by directly mediating the mechanisms of radioresistance.

Disseminated Melioidosis with Spinal Intraosseous Abscess.

Melioidosis is endemic in the State of Sabah, Malaysia. We report a case of a 34-year-old man with one-week history of fever and cough, three days history of diarrhoea and vomiting, which was associated with a loss of appetite and loss of weight for one-month. Clinically, he had hepatosplenomegaly and crepitation over his right lower zone of lung. Chest radiograph showed right lower lobe consolidation. Ultrasound abdomen showed liver and splenic abscesses. Ultrasound guided drainage of splenic abscess yielded Burkholderia pseudomallei. Magnetic resonance imaging (MRI) lumbosacral confirmed right sacral intraosseous abscess after he developed back pain a week later. He received 6 weeks of intravenous antibiotics and oral co-trimoxazole, followed by 6 months oral co-trimoxazole and had full recovery.

Mutational Signatures in Mandibular Ameloblastoma Correlate with Smoking.

Ameloblastoma is a rare tumor of odontogenic epithelium, the low incidence rate of which precludes statistical determination of its molecular characterizations. Despite recent genomic and transcriptomic profiling, the etiology of ameloblastomas remains poorly understood. Risk factors of ameloblastoma development are also largely unknown. Whole exome sequencing was performed on 11 mandibular ameloblastoma samples. We identified 2 convergent mutational signatures in ameloblastoma: 1) a signature found in multiple types of lung cancers with probable etiology of tobacco carcinogens (COSMIC signature 4) and 2) a signature present in gingivobuccal oral squamous cell carcinoma and correlated with tobacco-chewing habits (COSMIC signature 29). These mutational signatures highlight tobacco usage or related mutagens as one possible risk factor of ameloblastoma, since the association of BRAF mutations and smoking was demonstrated in multiple studies. In addition to BRAF hotspot mutations (V600E), we observed clear inter- and intratumor heterogeneities. Interestingly, prior to BRAF mutation, important genes regulating odontogenesis mutated (e.g., corepressor BCOR), possibly playing important roles in tumorigenesis. Furthermore, recurrent mutations in the CDC73 gene, the germline mutations of which predispose patients to the development of jaw tumors, were found in 2 patients, which may lead to recurrence if not targeted by therapeutic drugs. Our unbiased profiling of coding regions of ameloblastoma genomes provides insights to the possible etiology of mandibular ameloblastoma and highlights potential disease risk factors for screening and prevention, especially for Asian patients. Because of the limited sample size and incomplete habitual, dietary, and occupational data, a causal link between tobacco usage and ameloblastoma still requires further investigations.

Cost Effectiveness of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Management of Colorectal Peritoneal Carcinomatosis.

BACKGROUND: Peritoneal carcinomatosis from colorectal cancer is a stage 4 disease for which palliative chemotherapy has traditionally been considered the mainstay of treatment. Since the development of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by Sugarbaker, this combined method treatment has resulted in improved survival outcomes with acceptable morbidity for selected patients with peritoneal carcinomatosis. This study examined the cost effectiveness of CRS and HIPEC compared with palliative chemotherapy for patients with peritoneal carcinomatosis from colorectal cancer within the context of the Singaporean health care system. METHODS: A retrospective review of patients with peritoneal carcinomatosis from histologically proven colorectal cancer treated at the National Cancer Centre Singapore (NCCS) was conducted. RESULTS: The average cost of CRS and HIPEC per patient was S$83,680.26, and the median overall survival period was 47 months. The calculated cost per life year attained for a patient who underwent CRS and HIPEC was S$21,365.19 per life year. In comparison, the average cost of palliative chemotherapy was S$44,478.87, with a median overall survival of 9 months, and the calculated cost per life year attained for a patient in this treatment group was S$59,305.16 per life year. CONCLUSION: The findings show that CRS and HIPEC results in prolonged survival for selected patients with colorectal peritoneal carcinomatosis and a lower cost per life year attained than for the traditionally used palliative chemotherapy. It should logically be the preferred treatment of choice for selected patients with colorectal peritoneal metastasis.

Repeat Cytoreductive Surgery and HIPEC for Peritoneal Surface Malignancy and Peritoneal Carcinomatosis.

BACKGROUND: Peritoneal-based malignancy (PBM), especially peritoneal carcinomatosis from gastrointestinal malignancies traditionally carries a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC) have been shown to attain long median survival of 34-92 months and 5 year survival of 29-59% in patients with favorable histopathological subtypes. Recurrence after CRS and HIPEC poses a management dilemma. This paper evaluates our institution's experience with repeat CRS and HIPEC, its associated morbidity and outcomes. METHODS: One-hundred and thirty underwent CRS and HIPEC for PBM from April 2001 to June 2013. 49 had peritoneal recurrences, of which 24 had peritoneal only recurrence. 7 out of the 24 underwent a second CRS and HIPEC. RESULTS: Five females and two males with median age of 51 (37-63), underwent a second CRS and HIPEC. The primary malignancies were: 1 peritoneal mesothelioma, 3 appendiceal, 2 ovarian, and 1 colorectal cancers. Median peritoneal cancer indices for the initial and second CRS were 19 and 12, respectively. Completeness of cytoreduction score of 0 was achieved for all patients. Median hospitalization after second CRS and HIPEC was 12 days (7-60). 1 out of 7 (14%) experienced grade 3 or 4 post-operative complications. There was no 30-day or inpatient mortality. Median follow-up was 13 months (1-97). Median disease-free interval between the first CRS and HIPEC to peritoneal recurrence was 20 months (14-87). Median disease-free survival of 6 months (1-97) was achieved after the second CRS and HIPEC. Six patients remained alive without disease and one passed away with disease. Two had recurrences at 12 and 71 months after second CRS and HIPEC, 1 died and the other, still alive, went on to have a third CRS. CONCLUSION: Repeat CRS and HIPEC can achieve prolonged survival in selected patients with peritoneal-based malignancies, and can be performed with acceptable morbidity and mortality.

Quality of life in patients with peritoneal surface malignancies after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: An increasing number of patients are presenting with peritoneal carcinomatosis and more centers are performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). While morbidity and mortality are shown to be acceptable, quality of life after surgery should be assessed. METHODS: 63 patients who had CRS and HIPEC from 2001 to 2012 and who were still alive and on follow up were included. The EORTC-QLQ-C30 was administered to the patients. RESULTS: Median age was 53 years (14-71). 44% had ovarian primaries, 21% had appendicael primaries and 19% had colorectal primaries. Median follow-up was 1.08 years (0.06-9.8). The median time from surgery to the questionnaire was 1.3 years (0.24-10.18). There was no statistical difference in scores when comparing by age, gender, recurrence, gender, PCI score, presence of a complication and type of primary cancer. Scores were highest less than 6 months after surgery, dropped subsequently but rose again after 2 years. Our patients had better scores compared to a control group of outpatient cancer patients at our institution as well as the reference EORTC group. CONCLUSIONS: In keeping with previous quality of life studies done for CRS and HIPEC patients, we have shown that our patients can achieve a good quality of life after CRS and HIPEC even with recurrent disease.

Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial.

BACKGROUND: The purpose of the present study was to determine whether intrahepatic injection of (131)I-lipiodol (Lipiodol) is effective against recurrence of surgically resected hepatocellular carcinoma (HCC). METHODS: From June 2001 through March 2007, this nationwide multi-center prospective randomized controlled trial enrolled 103 patients 4-6 weeks after curative resection of HCC with complete recovery (52: Lipiodol, 51: Control). Follow-up was every 3 months for 1 year, then every 6 months. Primary and secondary endpoints were recurrence-free survival (RFS) and overall survival (OS), respectively, both of which were evaluated by the Kaplan-Meier technique and summarized by the hazard ratio (HR). The design was based on information obtained from a similar trial that had been conducted in Hong Kong. RESULTS: The Lipiodol group showed a small, and nonsignificant, improvement over control in RFS (HR = 0.75; 95 % confidence interval [95 % CI] 0.46-1.23; p = 0.25) and OS (HR = 0.88; 95 % CI 0.51-1.51; p = 0.64). Only two serious adverse events were reported, both with hypothyroidism caused by (131)I-lipiodol and hepatic artery dissection during angiography. CONCLUSIONS: The randomized trial provides insufficient evidence to recommend the routine use of (131)I-lipiodol in these patients.

Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.

BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.

Comparing the efficacy of sunitinib with sorafenib in xenograft models of human hepatocellular carcinoma: mechanistic explanation.

Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest malignancy. Sorafenib has demonstrated 44% survival advantage over placebo and has emerged as a standard of care in advanced HCC. The therapeutic effects of sorafenib are however transient and hence additional treatment options are warranted. In this study, we aimed to compare the efficacy of sunitinib relative to sorafenib, two potent inhibitors of protein tyrosine kinases involved in tumor growth, metastasis, or angiogenesis. We reported that sorafenib and sunitinib suppressed tumor growth, angiogenesis, cell proliferation, and induced apoptosis in both orthotopic and ectopic models of HCC. However, the antitumor effect of 50 mg/kg sorafenib was greater than that of 40 mg/kg sunitinib. Sorafenib inhibited p-eIF4E Ser209, p-p38 Thr180/Tyr182 and reduced survivin expression. This was not seen with sunitinib. In addition, the antitumor and apoptotic effects of sorafenib, which are associated with upregulation of fast migrating Bim and ASK1 and downregulation of survivin, were greater than that of sunitinib. These observations explained in part the apparent superior anti-tumor activity of sorafenib compared to sunitinib. In conclusion, sunitinib demonstrated an inferior anti-tumor activity compared to sorafenib in ectopic and orthotopic models of human HCC. It remains to be seen whether such observations would be recapitulated in humans.

Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. We tested megestrol acetate (MA) against placebo in the treatment of advanced HCC. METHODS: From 2002 through 2007, this randomised double-blind trial enrolled 204 patients with treatment-naive advanced HCC (Eastern Cooperative Oncology Group (ECOG) performance rating of 0-3) from specialist care centres in six Asia-Pacific nations. Patients received placebo or MA (320 mg day(-1)). End points were overall survival (OS) and quality of life. RESULTS: An adverse but not statistically significant difference in OS was found for MA vs placebo: median values 1.88 and 2.14 months, respectively (hazard ratio (HR)=1.25, 95% CI=0.92-1.71, P=0.16). However, OS was similar among patients of good functional status (Child-Pugh A and ECOG 0, 1 or 2) (44.3%) in both treatment groups, with the adverse effect of MA confined to those of poor status. Megestrol acetate patients had a worse global health status (not statistically significant) but reduced levels of appetite loss and nausea/vomiting. CONCLUSION: Megestrol acetate has no role in prolonging OS in advanced treatment-naive HCC. Overall survival with placebo differed markedly from that in similar trials conducted elsewhere, suggesting therapeutic outcomes may be strongly dependent on ECOG status and Child-Pugh score.

Clinical application of fluorescence endoscopic imaging using hypericin for the diagnosis of human oral cavity lesions.

BACKGROUND: Diagnosis of oral cancer is conventionally carried out using white light endoscopy and histopathology of biopsy samples. However, oral tumours are mostly superficial and the lesion and its margins can be difficult to visualise under white light. We present clinical data on fluorescence diagnostic imaging of oral lesions using hypericin, a plant-based photosensitiser. METHODS: Fluorescence images of lesions and normal tissue were captured using an endoscope after hypericin administration. The images were analysed to extract their colour parameters, which, along with the red-to-blue intensity ratios, were analysed and used to discriminate between tissue types. The results were correlated with those from histopathology. RESULTS: The red-to-blue intensity ratio increased from normal to hyperplastic to cancerous tissue and was a good parameter to discriminate between these tissue types, with sensitivity and specificity levels of 90% and above. CONCLUSION: Our results show that hypericin fluorescence imaging has the potential to be used for the clinical diagnosis of oral cancer. Further study to enhance the clinical potential of this technique includes the development of a real-time image processing and analysis system interfaced to the endoscope to enable same-day cancer diagnosis and demarcation of lesion margins in a clinical setting.

Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest primary neoplasm. Since HCC is a particularly vascular solid tumor, we determined the antitumor and antiangiogenic activities of sunitinib malate, a potent inhibitor of two receptors involved in angiogenesis - vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In the present study, we reported that treatment of HepG2 and SK-Hep-1 cells with sunitinib led to growth inhibition and apoptosis in a dose-dependent fashion. Sunitinib inhibited phosphorylation of VEGFR-2 at Tyr951 and PDGFR-beta at Tyr1021 both in vitro and in vivo. Sunitinib also suppressed tumor growth of five patient-derived xenografts. Sunitinib-induced tumor growth inhibition was associated with increased apoptosis, reduced microvessel density and inhibition of cell proliferation. This study provides a strong rationale for further clinical investigation of sunitinib in patients with hepatocellular carcinoma.

Risk-stratified management of well-differentiated thyroid cancers: a review of experience from a single institution, 1990-2003.

INTRODUCTION: Controversy persists regarding ideal management strategies in well-differentiated thyroid cancers (WDTC). This retrospective study reviews the utilization of a modified AMES risk stratification in the management of our institution's patients. METHODS: A total of 352 patients (median follow-up of 5.5 years) were reviewed and were risk stratified. Surgical resection was performed, and patients with clinically palpable lymph nodes were subjected to radical neck dissection. Patients were referred for adjuvant therapy if necessary. RESULTS: Of the 352 patients, 264 (75%) were females and 276 (78%) had papillary thyroid cancer (PTC). For those with lymph nodes (50%), 95% had PTC. In this series, 72% of the patients underwent total thyroidectomy; 5-year disease-free survival probability was 100% in low-risk patients, 92% in intermediate-risk patients, and 64% in high-risk patients. The 5-year overall survival probability was 100% in low-risk patients, 96% in intermediate-risk patients, and 69% in high-risk patients, respectively (both logrank trend p<0.001). CONCLUSIONS: Management of WDTC requires multimodal treatment and should be based on patient risk classifications. We recommend aggressive surgical resection for all gross disease in high-risk and intermediate-risk patients. Adjuvant therapy is recommended in high-risk patients, but should be individualized for intermediate-risk patients. Total thyroidectomy may not be necessary in low-risk patients.

Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells.

Although Kruppel-like factor 5 (KLF5) is a transcription factor that has been implicated in pathways critical to carcinogenesis, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Here, we describe a novel role for KLF5 in a p53-independent apoptotic pathway. Using RNA-interference technology, we show that cells deficient in KLF5 have increased sensitivity to DNA damage, regardless of p53 status. Both p53 and p53-dependent factors are unaffected by KLF5 depletion. Instead, the apoptotic phenotype consequent to damage is associated with reduced bad phosphorylation, and downregulation of Pim1. Consistently, transfection of wild-type Pim1 is sufficient to rescue this phenotype. Previous data have shown a number of putative Sp1-binding consensus sequences on the Pim1 promoter. Remarkably, chromatin immunoprecipitation studies show that KLF5 binds to the Pim1 promoter, and that binding increases soon after damage. These results identify a novel, p53-independent apoptotic pathway through which KLF5 functions in response to DNA damage. Therapeutic deregulation of this pathway could be used to modulate chemosensitivity.

Follicular thyroid carcinoma presenting as axial skeletal metastases.

INTRODUCTION: Common modes of presentation of follicular thyroid carcinoma include a solitary thyroid nodule and cervical lymphadenopathy. We report four patients who presented with axial skeletal metastases rather than the usual neck lumps. METHODS: A review of a database of 389 cases of thyroid cancer, managed by our department from 1990 to 2003, was perfomed. Based on each patient's presenting clinical feature, patients for the case series were selected. RESULTS: Four of the 389 patients presented with axial skeletal metastases - three were in the scalp while the fourth was in the sacral region. The histology of all four cases was that of follicular thyroid carcinoma. Despite widespread metastases at presentation, the overall survival rates of these patients remained relatively good. CONCLUSION: Patients presenting with lesions suspicious of secondary malignancy in the axial skeleton should be clinically evaluated for thyroid cancer. This is especially important if the patient belongs to a high risk age group and has highly vascular lesions.

Clinical spectrum and surgical management of acute mesenteric ischaemia in Singapore.

INTRODUCTION: Acute mesenteric ischaemia (AMI) is a surgical emergency with a dismal prognosis. Much of the literature concerning this condition is from the West. This study aims to present a single-centre Asian experience of management of patients with AMI and the immediate outcome following surgical treatment. METHODS: This is a retrospective study of patients managed for AMI in our department between 1990 and 2003. The data was obtained from a prospectively-collected surgical data base as well as from clinical case records. RESULTS: 65 patients were managed by our department for AMI over 14 years. The median age of this patient group was 69 years, with a high prevalence of cardiovascular diseases. The majority of patients presented with abdominal pain, distension and vomiting. The commonest subtype of AMI was caused by mesenteric arterial occlusion; this subtype also had the highest in-hospital mortality. Our overall in-hospital mortality for all 65 patients was 55.4 percent. CONCLUSION: Clinical suspicion, especially in a patient with the relevant risk factors, remains the mainstay of appropriate early management of AMI. Our patient demographics, coexistent diseases and commonest subtype of AMI were similar to that reported in the Western literature. In this paper, we also suggest a management algorithm for patients with suspected AMI.

Lessons learned from initial experience with peritonectomy and intra-peritoneal chemotherapy infusion.

INTRODUCTION: Patients diagnosed with peritoneal carcinomatous usually survive for less than 6 months. Cytoreductive surgery allows relief of the obstruction and improvement in functional status, while intraperitoneal chemotherapy infusion provides high local concentrations of chemotherapeutic agents. Our institutional experience is reviewed to assess the selection criteria, peri-operative complications, and outcomes. MATERIALS AND METHODS: We carried out a retrospective review of nine patients who had undergone aggressive cytoreductive surgery and hyperthermic intra- and early post-operative chemotherapy by a single surgeon between April 2000 and October 2004. The inclusion criteria were: (1) a demonstrated absence of extra-peritoneal and hepatic spread, (2) fitness of the patient and ability to tolerate cytoreductive surgery and intra-operative chemotherapy, and (3) the presence of a primary tumor originating form the gastro-intestinal tract (colonic, appendiceal, and gastric primaries). RESULTS: Seven women and two men, with a median age of 55 years, were treated. The median duration of the operation was 12 hours and 55 minutes. Seven of the nine patients required the insertion of at least one chest tube. All patients were monitored in the surgical intensive care unit (SICU) for a median of 1 day, started on feeds after a median of 6 days, and were hospitalized for a median of 16 days (range:11-18 days). There was no peri-operative mortality and only one major peri-operative complication (11.1%). At the time of analysis, the median follow-up was 16 months (range: 2-40 months), and the median disease-free survival was 8 months, with four of the nine patients showing no evidence of recurrence. To date, all of the patients are still alive. A 1-year survival rate of 100% is also documented. CONCLUSIONS: This article describes our initial experience with peritonectomy and intra-operative, intra-peritoneal chemotherapy infusion. Our initial problems included difficulty with leakage of the chemotherapeutic agents into the thoracic cavity that had to be overcome by the early insertion of chest-tubes. With appropriate patient selection, cytoreductive surgery with the infusion of intra-operative chemotherapy can be considered to be a therapeutic option for some patients with diffuse peritoneal metastases, and good disease-free and overall survival can be achieved with minimal morbidity.

Concurrent chemoradiotherapy followed by surgery in locally advanced squamous cell carcinoma of the oesophagus: a single centre experience.

INTRODUCTION: Data on combined modality treatment for locally advanced squamous cell carcinoma of the oesophagus involving Asian patients are limited. MATERIALS AND METHODS: A retrospective study of 56 consecutive patients with this condition treated with concurrent chemoradiotherapy followed by surgery in a single tertiary institution in Singapore was performed. RESULTS: The median overall survival of the entire cohort was 14.1 months [95% confidence interval (CI); range, 8.6 to 19.6 months]. In patients who underwent successful oesophagectomy after chemoradiotherapy (n = 17), the median survival was 27.8 months compared to 9.8 months for those who did not have surgery (n = 39) (P = 0.046, log-rank test). The median time to first relapse for the entire cohort was 16.1 months (95% CI, 7.7 to 24.5 months). The time to first relapse was 23.9 months in the subgroup of patients with successful surgery and 12.1 months in the group which did not (P = 0.147, log-rank test). The high proportion of patients who were medically unfit for surgery or declined surgery may have conferred a selection bias. CONCLUSION: Concurrent chemoradiotherapy followed by surgery is feasible in selected patients. The benefit of adding of surgery to chemoradiotherapy is still controversial and we await the results of randomised controlled trials comparing chemoradiotherapy with surgery versus chemoradiotherapy alone.

Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison.

We compared concurrent combination chemotherapy and radiotherapy with surgery and adjuvant radiotherapy in patients with stage III/IV nonmetastatic squamous cell head and neck cancer. Patients with non-nasopharyngeal and nonsalivary resectable squamous cell head and neck cancer were randomised to receive either surgery followed by adjuvant radiotherapy (60 Gy over 30 fractions) or concurrent combination chemotherapy and radiotherapy (66 Gy in 33 fractions). Combination chemotherapy comprised two cycles of i.v. cisplatin 20 mg m(-2) day(-1) and i.v. 5-fluorouracil 1000 mg m(-2) day(-1), both to run over 96 h given on days 1 and 28 of the radiotherapy. A total of 119 patients were randomised. At a median follow-up of 6 years, there was no significant difference in the 3-year disease-free survival rate between the surgery and concurrent chemoradiotherapy (50 vs 40% respectively). The overall organ preservation rate or avoidance of surgery to primary site was 45%. Those with laryngeal/hypopharyngeal disease subsite had a higher organ-preservation rate than the rest (68 vs 30%). Combination chemotherapy and concurrent irradiation with salvage surgery was not superior to conventional surgery and postoperative radiotherapy for resectable advanced squamous cell head and neck cancer. However, this form of treatment schedule with a view to organ-preservation can be attempted especially for those with laryngeal/hypopharyngeal and possibly oropharyngeal disease subsites.

Singapore's proposed graduate medical school--an expensive medical tutorial college or an opportunity for transforming Singapore medicine?

The proposed Graduate Medical School at the Outram Campus will open in 2007. The main value of this medical school is the transformation of the medical institutions in the campus and SingHealth into Academic Medical Centres. Such centres will train and host quality physicians and physician-scientists. It will help push the development of translational research, complementing the country's investment in Biopolis. It will also underpin Singapore's push into regional medical tourism and its development as an educational hub in the biomedical sciences.