Background: Genomic profiling of ctDNA has proven to be an effective alternative to repeat invasive biopsy in patients (pts) with advanced cancers. There is also the advantage of a more comprehensive approach over tissue-based assays with the ability to provide a summary of tumour heterogeneity. Methods: We performed a retrospective review of Hong Kong pts with advanced/metastatic NSCLC whose physician requested ctDNA-based genomic profiling utilizing the Guardant360 platform between Jan 2016 - Jun 2017. Guardant360 includes all four major types of genomic alterations (point mutations, and selected indels, fusions, and amplifications) and completely sequences exons in 73 target genes. Results: ctDNA testing was performed in 76 pts over this 18-month period (Median Age: 59.5 years (range 42-87), M:F 41:35). Histologies, as reported by the ordering physician, include squamous (SqCC) (n = 7), adenocarcinoma (Adeno) (n = 10), and NSCLC-not otherwise specified (NSCLC-NOS) (n = 58). In SqCC, all 7 pts had multiple detectable variants identified (range: 2-20 variants, median = 6), including FGFR1 amplification (n = 3), ERBB2 (HER2) amplification (n = 2). PIK3CA amplification occurred in combination with either FGFR1 or ERBB2 (HER2) amplification (n = 1 each), or alone (n = 1). In the Adeno and NSCLC-NOS groups combined, 91% of pts (61/68) had variants identified (range: 1-12 variants, median = 3), of which 42% (26/62) had at least one of the seven NCCN recommended lung adenocarcinoma genomic targets (EGFR (21%), EML4-ALK (8.1%), ERBB2 exon 20 insertion (6%), MET Amp (3.2%), ROS1 (2%), BRAF V600E (2%)). Concurrent detection of driver and resistance mutations were identified in 6/13 patients with EGFR driver mutations (T790M (n = 1), T790M/C797S (n = 1), MET amp (n = 2), T790M/MET amp (n = 1) and ERBB2 amp (n = 1)) and in 3/5 patients with EML4-ALK fusion (MET exon 14 skipping (n = 1) and the ALK L1196M gatekeeper mutation (n = 2)). Conclusions: Genomic profiling utilizing ctDNA analysis detected alterations in majority of advanced NSCLC pts, with targetable aberrations and resistance mechanisms identified. This approach has prompted changes in matched therapy in selected pts, and has demonstrated its feasibility in Asia. Legal entity responsible for the study: The Chinese University of Hong Kong Funding: None Disclosure: H. Loong: Advisory Board: Celgene, Novartis, Roche Travel Support: BMS, MSD, Novartis, Roche, TaiHo Speakers' Bureau: Abbvie, Novartis Research Funding: MSD, Mundipharma, V. Raymond: Employee of Guardant Health. T. Yung: Employee of Sanomics Limited. R.B. Lanman: Employee and shareholder of Guardant Health. S. Skrzypczak: Employee of Guardant Health, T.S.K. Mok: Shareholder of Sanomics Limited. All other authors have declared no conflicts of interest.

To assess the association between higher-than-normal BMI and incidence of premenopausal ovarian and breast cancers.This prospective cohort study included 461,646 women registered in the Danish Medical Birth Registry with self-reported early adulthood BMI ≥18.5 kg/m2, without a history of cancer. We used Cox proportional hazards regression models to estimate the hazard ratios (HRs) with 95% confidence intervals (95% CIs) of premenopausal epithelial ovarian cancer, breast cancer, estrogen receptor positive and negative, HER2 positive and negative breast cancers according to BMI.Compared with normal weight, obesity was associated with higher rates of premenopausal ovarian cancer (HR = 1.95, 95% CI 1.19–3.21) when adjusted for parity, use of hormonal contraception, family history of ovarian and/or breast cancer, other cancer, and calendar year.Obesity was associated with lower rates of premenopausal breast cancer (HR = 0.77, 95% CI 0.68–0.87) when adjusted for parity, use of hormonal contraception, family history of ovarian and/or breast cancer, any other cancer, calendar year, smoking, and highest achieved education. The associations were strongest with estrogen receptor positive premenopausal breast cancers. Results according to HER2 status were similar to overall results for premenopausal breast cancer.Obesity was associated with higher incidence of premenopausal ovarian cancer and lower incidence of premenopausal breast cancer.

Accurate target localization is always challenging in Intensity Modulated Radiation Therapy (IMRT). The use of multi-modality imaging tools is believed to improve the accuracy of target localization. The application of PET images for target localization is still preliminary and lacking consensus. In this study, we compare the tumor volumes of the primary site and neck nodes of NPC contoured on PET, CT and MRI images independently. 32 patients with newly diagnosed NPC treated with IMRT underwent incorporated PET/CT scan in the treatment position in a single session for planning purposes. 18F-fluorodeoxyglucose (FDG) and intravenous contrast were injected during PET and CT scans, respectively. MRI scan was also performed without cast but with the position of the head and neck simulating the actual treatment position. The MRI images were then co-registered with the PET/CT images. Gross tumor volumes (GTV) of both the primary site (GTV-P) and the neck nodes (GTV-N) were contoured on the images of PET, CT and MRI independently by the same oncologist without cross-referencing. The window settings of PET images were fixed at 10000Bq/mL (width) and 0Bq/mL (length). The GTVs contoured on PET, CT, PET combined with CT (PET+CT) and MRI were analyzed and compared. The mean volumes of GTV-P contoured on CT, PET, PET+CT and MRI were 22.81cm3, 24.49cm3, 30.30cm3 and 26.81cm3, respectively. The mean volumes of GTV-N on CT, PET, PET+CT and MRI were 20.37cm3, 22.50cm3, 29.09cm3 and 26.22cm3, respectively. Taking MRI as the gold standard, Pearson correlation revealed a strong correlation in the localization of GTV-P by different imaging tools: (1) MRI vs. CT (r = 0.990, p = 0.000), (2) MRI vs. PET (r = 0.964, p = 0.000) and (3) MRI vs. PET+CT (r = 0.979, p = 0.000). Subgroup analysis stratified into advanced (T3 & T4, AJCC 2002) and early T-Stage (T1, T2a & T2b, AJCC 2002) showed that high degrees of correlation for GTV-P were still maintained (MR vs. CT, r = 0.992, p = 0.000; MR vs. PET, r = 0.969, p = 0.000; and MR vs. PET+CT, r = 0.979, p= 0.000). A high degree of correlation was also noted in GTV-N (MRI vs. CT, r = 0.976, p= 0.000), (MRI vs. PET, r = 0.909, p = 0.000) and (MR vs. PET+CT, r = 0.975, p = 0.000). The minimum concentration of FDG in localizing both GTV-P (from 6800 to 7300 Bq/mL) and GTV-N (from 6800 to 7500 Bq/mL) were highly consistent and reproducible. The incorporation of PET scan into the standard MRI and CT co-registration is definitely feasible and helpful in tumor localization. Future efforts should be made to derive the most appropriate algorithm in contouring the GTV on PET images.

A reliable and novel synthetic route for the preparation of prop-1-ene-1,3-sultone (1) has been developed. An overall yield of 34% could be achieved for this five-step synthesis. The Diels-Alder reactions of 1 with a variety of dienes were investigated for the first time and achieved with good chemical yield and excellent endo-selectivity. The subsequent transformations of the Diels-Alder cycloadducts were also explored.

Epstein-Barr Virus latent infection is associated with malignancies including B cell lymphoma and nasopharyngeal carcinoma (NPC). The oncogenic EBV latent membrane protein-1, LMP1, induces cellular proteins including cytokines and matrix metalloproteinases (MMP-1, 2 and 9). After demonstrating the presence of LMP1 DNA in NPC tissues, the gene was cloned from the tissue and transiently expressed in human fibroblast MRC5 cells. Following transfection, there was MMP3 mRNA induction started at 24h and reached maximum at 32h compared to mock-transfected cells. Consistent to the transcriptional activation, there was a significant increased expression of MMP3 proteins in LMP1-expressing cells at 48h post-transfection. Our results suggest that LMP1 may contribute to invasiveness of NPC cells through the induction of MMP3 in fibroblasts.

BackgroundA previous meta-analysis investigated the role of chemotherapy in head and neck locally advanced carcinoma. This work had not been performed on nasopharyngeal carcinoma.ObjectivesThe aim of the project was to study the effect of adding chemotherapy to radiotherapy on overall survival (OS) and event-free survival (EFS) in patients with nasopharyngeal carcinoma.Search strategyWe searched MEDLINE (1966 to October 2003), EMBASE (1980 to October 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 3, 2003) and trial registers. Handsearches of meeting abstracts, references in review articles and of the Chinese medical literature were carried out. Experts and pharmaceutical companies were asked to identify trials.Selection criteriaRandomised trials comparing chemotherapy plus radiotherapy to radiotherapy alone in locally advanced nasopharyngeal carcinoma were included.Data collection and analysisThe meta-analysis was based on updated individual patient data. The log rank test, stratified by trial, was used for comparisons and the hazard ratios (HR) of death and failure (loco-regional/distant failure or death) were calculated.Main resultsEight trials with 1753 patients were included. One trial with a 2 x 2 design was counted twice in the analysis. The analysis was performed including 11 comparisons based on 1975 patients. The median follow up was six years. The pooled hazard ratio of death was 0.82 (95% confidence interval (CI) 0.71 to 0.95; P = 0.006) corresponding to an absolute survival benefit of 6% at five years from chemotherapy (from 56% to 62%). The pooled hazard ratio of tumour failure or death was 0.76 (95% CI 0.67 to 0.86; P < 0.00001) corresponding to an absolute event-free survival benefit of 10% at five years from chemotherapy (from 42% to 52%). A significant interaction was observed between chemotherapy timings and overall survival (P = 0.005), explaining the heterogeneity observed in the treatment effect (P = 0.03) with the highest benefit from concomitant chemotherapy.Authors' conclusionsChemotherapy led to a small but significant benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with radiotherapy.