Optimal time for early therapeutic response prediction in nasopharyngeal carcinoma with functional magnetic resonance imaging.

Background and Purpose: Physiological changes in tumour occur much earlier than morphological changes. They can potentially be used as biomarkers for therapeutic response prediction. This study aimed to investigate the optimal time for early therapeutic response prediction with multi-parametric magnetic resonance imaging (MRI) in patients with nasopharyngeal carcinoma (NPC) receiving concurrent chemo-radiotherapy (CCRT). Material and Methods: Twenty-seven NPC patients were divided into the responder (N = 23) and the poor-responder (N = 4) groups by their primary tumour post-treatment shrinkages. Single-voxel proton MR spectroscopy (1H-MRS), diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI were scanned at baseline, weekly during CCRT and post-CCRT. The median choline peak in 1H-MRS, the median apparent diffusion coefficient (ADC) in DW-MRI, the median influx rate constant (Ktrans), reflux rate constant (Kep), volume of extravascular-extracellular space per unit volume (Ve), and initial area under the time-intensity curve for the first 60 s (iAUC60) in DCE-MRI were compared between the two groups with the Mann-Whitney tests for any significant difference at different time points. Results: In DW-MRI, the percentage increase in ADC from baseline to week-1 for the responders (median = 11.39%, IQR = 18.13%) was higher than the poor-responders (median = 4.91%, IQR = 7.86%) (p = 0.027). In DCE-MRI, the iAUC60 on week-2 was found significantly higher in the poor-responders (median = 0.398, IQR = 0.051) than the responders (median = 0.192, IQR = 0.111) (p = 0.012). No significant difference was found in median choline peaks in 1H-MRS at all time points. Conclusion: Early perfusion and diffusion changes occurred in primary tumours of NPC patients treated with CCRT. The DW-MRI on week-1 and the DCE-MRI on week-2 were the optimal time points for early therapeutic response prediction.

Corrigendum: Compassionate use of ripretinib for patients with metastatic gastrointestinal stromal tumors: Taiwan and Hong Kong experience.

[This corrects the article DOI: 10.3389/fonc.2022.883399.].

Correlations of tumour permeability parameters with apparent diffusion coefficient in nasopharyngeal carcinoma.

Background and Purpose: Functional imaging has an established role in therapeutic monitoring of cancer treatments. This study evaluated the correlations of tumour permeability parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and tumour cellularity derived from apparent diffusion coefficient (ADC) in nasopharyngeal carcinoma (NPC). Material and Methods: Twenty NPC patients were examined with DCE-MRI and RESOLVE diffusion-weighted MRI (DW-MRI). Tumour permeability parameters were quantitatively measured with Tofts compartment model. Volume transfer constant (Ktrans), volume of extravascular extracellular space (EES) per unit volume of tissue (Ve), and the flux rate constant between EES and plasma (Kep) from DCE-MRI scan were measured. The time-intensity curve was plotted from the 60 dynamic phases of DCE-MRI. The initial area under the curve for the first 60 s of the contrast agent arrival (iAUC60) was also calculated. They were compared with the ADC value derived from DW-MRI with Pearson correlation analyses. Results: Among the DCE-MRI permeability parameters, Kep had higher linearity in inverse correlation with ADC value (r = -0.69, p = <0.05). Ktrans (r = -0.60, p=<0.05) and iAUC60 (r = -0.64, p = <0.05) also had significant inverse correlations with ADC. Ve showed a significant positive correlation with ADC (r = 0.63, p = <0.05). Conclusions: Nasopharyngeal tumour vascular permeability parameters derived from DCE-MRI scan were correlated linearly with tumour cellularity measured by free water diffusability with ADC. The clinical implementations of these linear correlations in the quantitative assessments of therapeutic response for NPC patients may be worth to further explore.

Compassionate Use of Ripretinib for Patients With Metastatic Gastrointestinal Stromal Tumors: Taiwan and Hong Kong Experience.

Background: Ripretinib was recently approved for the fourth-line targeted therapy for advanced gastrointestinal stromal tumor (GIST) refractory to imatinib, sunitinib, and regorafenib based on the pivotal INVICTUS phase III study. The INVICTUS study demonstrated significantly improved median progression-free survival (PFS) of 6.3 months and an overall survival (OS) insignificant benefit of ripretinib of 15.1 months as compared with placebo in 85 patients with advanced metastatic GIST. However, treatment outcome for the Chinese population, including in Taiwan and Hong Kong, was lacking. Material and Method: A compassionate study regarding ripretinib use for patients with advanced/metastatic GIST was conducted from March 2020 to March 2021 to assess the treatment efficacy and safety in Taiwan and Hong Kong patients. Result: Twenty evaluable patients (16 men and 4 women) with heavily pretreated metastatic GIST receiving ripretinib from March 2020 to March 2021 were enrolled to evaluate the treatment outcome. The response and clinical benefit rates to ripretinib were 25% (5/20) and 60% (12/20), respectively. The median PFS and OS in this compassionate cohort receiving ripretinib were 6.1 months and not reachable, respectively. Albumin less than 3.5 and disease progression after ripretinib use were the two independent unfavorable factors for PFS. There were 14 out of 20 (70%) experiencing any grade adverse event (AE). Loss of hair is the most common grade I to II AE with an incidence of 55%. Grade III AEs included diarrhea, skin rash, and anemia with one patient (5%) for each AE. Conclusions: Late-line ripretinib use in pretreated Taiwan and Hong Kong patients with advanced GIST showed efficacy consistent with the INVICTUS study. Albumin less than 3.5 and disease progression after ripretinib use were the two independent unfavorable factors for PFS. Ripretinib is generally tolerable, with loss of hair being the most common AE.

The changing landscape of general surgery in the elderly - trends over a decade in a tertiary centre in Singapore.

An ageing population with higher rates of helping seeking behaviour and treatment utilization is a worldwide phenomenon with no exception to Singapore. As elderly patients are fast becoming an increasing large part of our surgical practice, their long term outcomes are particularly important. OBJECTIVE: We take stock of our local experience in a high volume tertiary centre in Singapore, Tan Tock Seng Hospital by reviewing the number of surgical procedures performed for elderly patients (65 years old and above) across a decade and reviewing their post-operative outcomes. METHODS: This retrospective cohort study included elderly patients (>= aged 65) who underwent surgical procedures under general anaesthesia from January 2008 to December 2019. Demographic data, nature of operation, preoperative American Society of Anaesthesiologists (ASA) status of patients and surrogate markers of outcome including average length of stay (ALOS), 30 and 90-day mortality were retrospectively analysed. RESULTS: Across a 12-year period, we observed a nearly overall two-fold increase in the number of surgical procedures for elderly patients from 1,129 cases in 2008 to 2,118 cases in 2019. The ALOS for elderly surgical patients trended downwards from an average of 12.3 days in 2008 to 9.0 days in 2019. All cause 30-day mortality rate of elderly patients dropped from 5.8% in 2008 to 2.7% in 2019. CONCLUSION: The landscape for general surgery in the elderly is changing in the context of advances in health care and a paradigm shift in treatment beliefs and perspectives. Ultimately, informed decision making, patient engagement and empowerment by the surgeon are keys to better outcomes and improved patient experience.

Prognostic and therapeutic evaluation of nasopharyngeal carcinoma by dynamic contrast-enhanced (DCE), diffusion-weighted (DW) magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS).

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck malignancy, and radiotherapy (with or without chemotherapy) is the primary treatment modality. Reliable tumour assessment during the treatment phase, which can portend the efficacy of radiotherapy and early identification of potential treatment failure in radioresistant disease, has been implicit for better cancer management. Technological advancement in the last decade has fostered the development of functional magnetic resonance imaging (fMRI) techniques into a promising tool for diagnostic and therapeutic assessments in head and neck cancer. Apart from conventional morphological assessment, early detection of the physiological environment by fMRI allows a more thorough investigation in monitoring tumour response. This article discusses the relevant fMRI utilities in NPC as an early prognostic and monitoring tool for treatment. Challenges and future developments of fMRI in radiation oncology are also discussed.

Modified manual small incision cataract surgery technique for phacoemulsification-trained surgeons.

PURPOSE: To present the technique and outcomes of a modified manual small incision cataract surgery designed for the phacoemulsification surgeons who are learning to perform manual small incision cataract surgery. METHODS: This was a retrospective, single-centred, comparative study. We included all the patients who underwent the modified manual small incision cataract surgery for visually significant cataract at Singapore National Eye Centre. All surgeries were performed by either a senior phaco-trained surgeon (M.A.) who had performed more than 500 manual small incision cataract surgery or a junior phaco-trained surgeon (D.C.) who had performed around 500 phacoemulsification but never performed any manual small incision cataract surgery. The main modification of this technique lies in the creation of an additional phaco-like main wound at 90° to the scleral tunnel wound, with most surgical steps performed through this additional wound. The outcomes were analysed and compared between the senior and junior surgeons. The main outcome measures were visual outcome and major intraoperative complications such as posterior capsular rupture and zonular dialysis. RESULTS: A total of 132 cases were included; 102 (77.3%) and 30 (22.7%) cases were performed by the senior and junior surgeons, respectively. Pre-operatively, 85.6% eyes had best-corrected visual acuity of counting fingers or worse. Postoperatively, the visual outcome at 1 month was similar between the senior and junior surgeons, with 68.7% eyes achieving a best-corrected visual acuity of ⩾6/12 (p = 0.17). No posterior capsular rupture, zonular dialysis or endophthalmitis was observed during the study period. CONCLUSIONS: This modified technique may serve as a useful transition technique for the phaco-trained surgeons to develop skills in manual small incision cataract surgery, with demonstrable good visual outcome and safety.

Corneal Inlay Damage After Cosmetic Laser Treatment of the Eyelid With Long-Pulsed Nd:YAG Laser.

Importance: Protective eyewear or corneal shields are recommended during cosmetic facial laser treatment. Objective: To describe the occurrence of corneal inlay damage following treatment to the eyelids and face with an Nd:YAG laser. Design, Setting, and Participants: This observational case report includes a single incident case cared for at a tertiary care center. A 58-year-old man who had undergone bilateral uncomplicated myopic laser in situ keratomileusis surgery in 2003 and corneal inlay implant in the nondominant left eye in 2013 experienced decreased visual acuity (VA) and pain in the left eye after the application of 2 passes of the Nd:YAG laser to his face and both eyelids for facial tightening. At presentation, the uncorrected VA was counting fingers OS and 20/20 OD. Slitlamp biomicroscopy showed a corneal epithelial defect overlying a deformed corneal inlay, peripheral scattered pigmentary deposits, corneal haze, and brown discoloration of the lamellar pocket of the inlay. He underwent explant of the inlay and debridement 48 hours later because of deteriorating VA and increasing corneal haze. Exposure: Application of long-pulsed Nd:YAG laser at 1064 nm to the middle one-third of both upper eyelids and the periorbital region in a man with a corneal inlay implant. Corneal shields were not worn during the procedure. The peak penetration depth of this laser system is approximately 4 mm. The mean (SD) thickness of the upper eyelid in Asian eyes is 1.127 (0.238) mm. Main Outcomes and Measures: Improvement of corneal inlay damage. Results: In this 58-year-old man, 3 months after the inlay explant, the intrastromal discoloration had resolved. There was still residual corneal haze, but the patient was able to achieve a best-corrected VA of 20/25 OS for distance and J3 (Snellen equivalent, 20/30) OS for near. Conclusions and Relevance: Although the exact cause and effect cannot be determined from a single case, our findings suggest that a history of corneal inlay implant should be asked about prior to any long-pulsed Nd:YAG laser treatment to the periorbital skin and eyelids. Furthermore, these findings suggest that laser treatment to the eyelids should be avoided and that protective eyewear or corneal shields are recommended during cosmetic facial laser treatment in all patients.

Simultaneous Accelerated Corneal Crosslinking and Laser In situ Keratomileusis for the Treatment of High Myopia in Asian Eyes.

BACKGROUND: LASIK Xtra is a recently described technique which combines LASIK and accelerated corneal cross-linking(CXL) in the same setting. Its long-term outcome in Asians with high myopia is not well described. OBJECTIVES: To compare the efficacy, predictability and safety of LASIK Xtra with LASIK in patients with high myopia. METHOD: This is a retrospective study comparing 50 consecutive eyes undergoing LASIK Xtra for the correction of high myopia and/or myopic astigmatism (-6.63 to -15.50 D manifest spherical equivalent) with a matched control group of 50 eyes undergoing LASIK alone for correction of high myopia (-6.00 to -12.25 D manifest spherical equivalent). Mean follow-up was 5.7 months (range, 1.5-13.3 months) for LASIK Xtra and 3.6 months (range, 1.7-4.2 months) for LASIK only. Outcome measures included Uncorrected Distance Visual Acuity (UDVA), Corrected Distance Visual Acuity (CDVA), refraction and intraoperative and postoperative complications. RESULTS: At post-operative 3 months, all eyes achieved UDVA of 20/40 or better, and 80.0% of LASIK Xtra eyes achieved UDVA of 20/20 or better, compared to 66.0% of LASIK only eyes (p = 0.115). Efficacy indices were 0.99±0.17 for LASIK Xtra and 0.94±0.17 for LASIK only (p = 0.164). The proportion of eyes within ±0.50 D of attempted correction was 84% in the LASIK only group and 72% in the LASIK Xtra group at post-operative 3 months (p = 0.148). Safety indices were 1.11±0.19 and 1.11±0.18 in the LASIK Xtra and LASIK only groups, respectively (p = 0.735). CONCLUSION: LASIK Xtra achieved comparable safety, predictability and efficacy as LASIK in patients with high myopia. Good refractive stability was attained at 6-12 months. Further long term studies are required to determine whether simultaneous CXL is able to reduce postoperative LASIK keratectasia in high-risk individuals.

Analysis of cases and accuracy of 3 risk scoring systems in predicting ectasia after laser in situ keratomileusis.

PURPOSE: To identify risk factors for ectasia after laser in situ keratomileusis (LASIK) by comparing the accuracy of the Ectasia Risk Score System (ERSS), Screening Corneal Objective Risk of Ectasia (SCORE) Analyzer, and percentage of tissue altered (PTA) in predicting the occurrence of ectasia. SETTING: Multiple centers in 8 countries. DESIGN: Retrospective case series. METHODS: Previously unpublished post-LASIK ectasia cases were analyzed. Consecutive patients who had LASIK performed at least 5 years previously with no resultant ectasia were used as controls. Axial maps from preoperative Orbscan IIz topographies were analyzed in a masked fashion, and examination files tested with the SCORE Analyzer. The PTA values and ERSS scores were generated using available preoperative and perioperative data. Only eyes with subjectively identified normal preoperative topography were tested with the PTA. Threshold values for the SCORE, ERSS, and PTA were more than or equal to 0, 4, and 40, respectively. RESULTS: Ectasia occurred in 31 eyes (22 patients); 79 eyes (44 patients) were used as controls. In all eyes, the sensitivity and specificity for predicting ectasia, respectively, were 67.7% and 79.7% for the ERSS and 64.5% and 100% for the SCORE. In eyes with normal topography (ectasia group, 12 eyes; controls, 64 eyes), the PTA yielded sensitivity of 33.3% and specificity of 85.9%. The area under the receiver operating characteristic curve was highest for SCORE (0.911) followed by the ERSS (0.844) and PTA (0.557). CONCLUSIONS: The SCORE was most predictive of ectasia, achieving the best specificity; the ERSS had the best sensitivity. Further studies are required to validate the PTA as a screening metric for ectasia.

Clinical Application of Genomic Profiling With Circulating Tumor DNA for Management of Advanced Non-Small-cell Lung Cancer in Asia.

BACKGROUND: Genomic profiling of cell-free circulating tumor DNA (ctDNA) is a potential alternative to repeat invasive biopsy in patients with advanced cancer. We report the first real-world cohort of comprehensive genomic assessments of patients with non-small-cell lung cancer (NSCLC) in a Chinese population. PATIENTS AND METHODS: We performed a retrospective analysis of patients with advanced or metastatic NSCLC whose physician requested ctDNA-based genomic profiling using the Guardant360 platform from January 2016 to June 2017. Guardant360 includes all 4 major types of genomic alterations (point mutations, insertion-deletion alterations, fusions, and amplifications) in 73 genes. RESULTS: Genomic profiling was performed in 76 patients from Hong Kong during the 18-month study period (median age, 59.5 years; 41 men and 35 women). The histologic types included adenocarcinoma (n = 10), NSCLC, not otherwise specified (n = 58), and squamous cell carcinoma (n = 8). In the adenocarcinoma and NSCLC, not otherwise specified, combined group, 62 of the 68 patients (91%) had variants identified (range, 1-12; median, 3), of whom, 26 (42%) had ≥ 1 of the 7 National Comprehensive Cancer Network-recommended lung adenocarcinoma genomic targets. Concurrent detection of driver and resistance mutations were identified in 6 of 13 patients with EGFR driver mutations and in 3 of 5 patients with EML4-ALK fusions. All 8 patients with squamous cell carcinoma had multiple variants identified (range, 1-20; median, 6), including FGFR1 amplification and ERBB2 (HER2) amplification. PIK3CA amplification occurred in combination with either FGFR1 or ERBB2 (HER2) amplification or alone. CONCLUSION: Genomic profiling using ctDNA analysis detected alterations in most patients with advanced-stage NSCLC, with targetable aberrations and resistance mechanisms identified. This approach has demonstrated its feasibility in Asia.

Pre-emptive and therapeutic adoptive immunotherapy for nasopharyngeal carcinoma: Phenotype and effector function of T cells impact on clinical response.

Adoptive T cell therapy has emerged as a powerful strategy to treat human cancers especially haematological malignancies. Extension of these therapies to solid cancers remains a significant challenge especially in the context of defining immunological correlates of clinical responses. Here we describe results from a clinical study investigating autologous Epstein-Barr virus (EBV)-specific T cells generated using a novel AdE1-LMPpoly vector to treat patients with nasopharyngeal carcinoma (NPC) either pre-emptively in at-risk patients with no or minimal residual disease (N/MRD) or therapeutically in patients with active recurrent/metastatic disease (ARMD). Tolerability, safety and efficacy, including progression-free survival (PFS) and overall survival (OS), were evaluated following adoptive T-cell immunotherapy. Twenty-nine patients, including 20 with ARMD and nine with N/MRD, successfully completed T-cell therapy. After a median follow-up of 18.5 months, the median PFS was 5.5 months (95% CI 2.1 to 9.0 months) and the median OS was 38.1 months (95% CI 17.2 months to not reached). Post-immunotherapy analyses revealed that disease stabilization in ARMD patients was significantly associated with the functional and phenotypic composition of in vitro-expanded T cell immunotherapy. These included a higher proportion of effector CD8+ T-cells and an increased number of EBV-specific T-cells with broader antigen specificity. These observations indicate that adoptive immunotherapy with AdE1-LMPpoly-expanded T cells stabilizes relapsed, refractory NPC without significant toxicity. Promising clinical outcomes in N/MRD patients further suggest a potential role for this approach as a consolidation treatment following first-line chemotherapy.

Surrogate End Points for Overall Survival in Loco-Regionally Advanced Nasopharyngeal Carcinoma: An Individual Patient Data Meta-analysis.

Background: Our objective was to evaluate progression-free survival (PFS) and distant metastasis-free survival (DMFS) as surrogate end points for overall survival (OS) in randomized trials of chemotherapy in loco-regionally advanced nasopharyngeal carcinomas (NPCs). Methods: Individual patient data were obtained from 19 trials of the updated Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) plus one additional trial (total = 5144 patients). Surrogacy was evaluated at the individual level using a rank correlation coefficient ρ and at the trial level using a correlation coefficient R2 between treatment effects on the surrogate end point and OS. A sensitivity analysis was performed with two-year PFS/DMFS and five-year OS. Results: PFS was strongly correlated with OS at the individual level (ρ = 0.93, 95% confidence interval [CI] = 0.93 to 0.94) and at the trial level (R2 = 0.95, 95% CI = 0.47 to 1.00). For DMFS, too, the individual-level correlation with OS was strong (ρ = 0.98, 95% CI = 0.98 to 0.98); at trial level, the correlation was high but the regression adjusted for measurement error could not be computed (unadjusted R2 = 0.96, 95% CI = 0.94 to 0.99). In the sensitivity analysis, two-year PFS was highly correlated with five-year OS at the individual level (ρ = 0.89, 95% CI = 0.88 to 0.90) and at the trial level (R2 = 0.85, 95% CI = 0.46 to 1.00); two-year DMFS was highly correlated with five-year OS at the individual level (ρ = 0.95, 95% CI = 0.94 to 0.95) and at the trial level (R2 = 0.78, 95% CI = 0.33 to 1.00). Conclusions: PFS and DMFS are valid surrogate end points for OS to assess treatment effect of chemotherapy in loco-regionally advanced NPC, while PFS can be measured earlier.

What Is the Best Treatment of Locally Advanced Nasopharyngeal Carcinoma? An Individual Patient Data Network Meta-Analysis.

Purpose The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments. Methods All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were included. Treatments were grouped into seven categories: RT alone (RT), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). P-score was used to rank the treatments. Fixed- and random-effects frequentist network meta-analysis models were applied. Results The three treatments with the highest probability of benefit on overall survival (OS) were CRT-AC, followed by CRT and IC-CRT, with respective hazard ratios (HRs [95% CIs]) compared with RT alone of 0.65 (0.56 to 0.75), 0.77 (0.64 to 0.92), and 0.81 (0.63 to 1.04). HRs (95% CIs) of CRT-AC compared with CRT for OS, progression-free survival (PFS), locoregional control, and distant control (DC) were, respectively, 0.85 (0.68 to 1.05), 0.81 (0.66 to 0.98), 0.70 (0.48 to 1.02), and 0.87 (0.61 to 1.25). IC-CRT ranked second for PFS and the best for DC. CRT never ranked first. HRs of CRT compared with IC-CRT for OS, PFS, locoregional control, and DC were, respectively, 0.95 (0.72 to 1.25), 1.13 (0.88 to 1.46), 1.05 (0.70 to 1.59), and 1.55 (0.94 to 2.56). Regimens with more chemotherapy were associated with increased risk of acute toxicity. Conclusion The addition of AC to CRT achieved the highest survival benefit and consistent improvement for all end points. The addition of IC to CRT achieved the highest effect on DC.

Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis.

BACKGROUND: A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy. METHODS: We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis. FINDINGS: We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2-11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73-0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5-9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56-0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70-0·93) but not adjuvant chemotherapy alone (0·87, 0·68-1·12) or induction chemotherapy alone (0·96, 0·80-1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69-0·81), locoregional control (0·73, 0·64-0·83), distant control (0·67, 0·59-0·75), and cancer mortality (0·76, 0·69-0·84). INTERPRETATION: Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed. FUNDING: French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC).

PURPOSE: Rolapitant is a novel, long-acting neurokinin-1 (NK-1) receptor antagonist. This study evaluated the safety and efficacy of four different doses of rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). METHODS: This randomized, double-blind, active-controlled, global study was conducted in patients receiving cisplatin-based chemotherapy ≥70 mg/m(2). Patients received a 9, 22.5, 90, or 180 mg oral dose of rolapitant or placebo with ondansetron and dexamethasone on day 1 of chemotherapy. The primary end point was complete response (CR; no emesis and no use of rescue medication) in the overall (0 to 120 h) phase of cycle 1. Other assessments were CR in delayed (24-120 h) and acute (0-24 h) phases, no emesis, no significant nausea, and no nausea. RESULTS: Four hundred fifty-four patients were randomized. All doses of rolapitant improved CR with the greatest benefit observed with rolapitant 180 mg vs. active control in the overall phase (62.5 and 46.7 %, p = 0.032) and in the acute (87.6 vs. 66.7 %, p = 0.001) and delayed (63.6 vs. 48.9 %, p = 0.045) phases. Rates for no emesis and no significant nausea were significantly (p < 0.05) higher with rolapitant 180 mg vs. active control in the overall, acute, and delayed phases. Treatment-related adverse events were largely considered related to the chemotherapy and included constipation, headache, fatigue, and dizziness which were mostly mild or moderate and were similar across treatment groups. CONCLUSION: All doses of rolapitant were well tolerated and showed greater CR rates than active control. Rolapitant 180 mg demonstrated significant clinical efficacy for preventing CINV in the overall, delayed, and acute phases for patients receiving HEC.

Circulating microRNAs as specific biomarkers for breast cancer detection.

BACKGROUND: We previously showed microRNAs (miRNAs) in plasma are potential biomarkers for colorectal cancer detection. Here, we aimed to develop specific blood-based miRNA assay for breast cancer detection. METHODOLOGY/PRINCIPAL FINDINGS: TaqMan-based miRNA profiling was performed in tumor, adjacent non-tumor, corresponding plasma from breast cancer patients, and plasma from matched healthy controls. All putative markers identified were verified in a training set of breast cancer patients. Selected markers were validated in a case-control cohort of 170 breast cancer patients, 100 controls, and 95 other types of cancers and then blindly validated in an independent set of 70 breast cancer patients and 50 healthy controls. Profiling results showed 8 miRNAs were concordantly up-regulated and 1 miRNA was concordantly down-regulated in both plasma and tumor tissue of breast cancer patients. Of the 8 up-regulated miRNAs, only 3 were significantly elevated (p<0.0001) before surgery and reduced after surgery in the training set. Results from the validation cohort showed that a combination of miR-145 and miR-451 was the best biomarker (p<0.0001) in discriminating breast cancer from healthy controls and all other types of cancers. In the blind validation, these plasma markers yielded Receiver Operating Characteristic (ROC) curve area of 0.931. The positive predictive value was 88% and the negative predictive value was 92%. Altered levels of these miRNAs in plasma have been detected not only in advanced stages but also early stages of tumors. The positive predictive value for ductal carcinoma in situ (DCIS) cases was 96%. CONCLUSIONS: These results suggested that these circulating miRNAs could be a potential specific biomarker for breast cancer screening.

Expression of MMP-1 and TIMP-1 in irradiated mandibles during distraction osteogenesis.

OBJECTIVES: The study aimed to evaluate the expression of MMP-1 and TIMP-1 in irradiated mandibles during distraction osteogenesis. STUDY DESIGN: Rabbits in the experimental group received preoperative radiation of 9 Gy for 5 fractions. After 1 month, all rabbits underwent osteotomy and distraction osteogenesis with 7 days of latency. Three rabbits in the control and experimental groups were killed at days 7, 12, 18, and 25. Specimens were subjected to immunohistochemical examination and real-time polymerase chain reaction analysis. RESULTS: At day 7, expression of MMP-1 and TIMP-1 was significantly suppressed in the radiotherapy group in contrast to the control group. At day 12, expression of MMP-1 was significantly higher in the control group. At day 18, expression of MMP-1 and TIMP-1 was significantly higher in the control than in the radiotherapy group. CONCLUSIONS: Radiotherapy changes the expression pattern of MMP-1 and TIMP-1.

LTBP-2 confers pleiotropic suppression and promotes dormancy in a growth factor permissive microenvironment in nasopharyngeal carcinoma.

This study identified LTBP-2 as a pleiotropic tumor suppressor in nasopharyngeal carcinoma, which safeguards against critical malignant behaviors of tumor cells. LTBP-2 expression was significantly decreased or lost in up to 100% of NPC cell lines (7/7) and 80% of biopsies (24/30). Promoter hypermethylation was found to be involved in LTBP-2 silencing. Using a tetracycline-regulated inducible expression system, we unveiled functional roles of LTBP-2 in suppressing colony formation, anchorage-independent growth, cell migration, angiogenesis, VEGF secretion, and tumorigenicity. Three-dimensional culture studies suggested the involvement of LTBP-2 in maintenance of tumor cell dormancy in a growth factor favorable microenvironment.

Treatment of irradiated mandibles with mesenchymal stem cells transfected with bone morphogenetic protein 2/7.

PURPOSE: The study aimed to evaluate whether mesenchymal stem cells transfected with bone morphogenetic protein (BMP) 2/7 could increase bone regeneration after radiotherapy using a rabbit model of mandibular distraction osteogenesis. MATERIALS AND METHODS: Twelve rabbits were randomly assigned to the sham control, radiotherapy control, nontransfected mesenchymal stem cells (MSCs), and MSCs transfected with BMP-2/7 groups. All rabbits, except those in the sham control group, received preoperative radiation of 9 Gy for 5 fractions. One month after radiotherapy, all rabbits underwent unilateral mandibular distraction at a rate of 0.9 mm/d for 11 days. At the end of active distraction, MSCs combined with bovine collagen were injected into the distraction zone. After 4 weeks of consolidation, the mandibular samples were collected and subjected to radiographic, microcomputed tomographic, and histologic examinations. RESULTS: By radiographic examination, animals injected with nontransfected MSCs or MSCs encoding BMP-2/7 exhibited more bone formation than the control groups. Histologic examination showed that the group with MSCs encoding BMP-2/7 had a more mature medullary cavity than the nontransfected MSCs group. CONCLUSIONS: MSCs encoding BMP-2/7 can increase bone healing in irradiated mandibular bone.