Weak expression of cyclooxygenase-2 is associated with poorer outcome in endemic nasopharyngeal carcinoma: analysis of data from randomized trial between radiation alone versus concurrent chemo-radiation (SQNP-01)

<p>Abstract</p> <p>Background</p> <p>Over-expression of cyclooxygenase-2 (COX-2) enzyme has been reported in nasopharyngeal carcinoma (NPC). However, the prognostic significance of this has yet to be conclusively determined. Thus, from our randomized trial of radiation versus concurrent chemoradiation in endemic NPC, we analyzed a cohort of tumour samples collected from participants from one referral hospital.</p> <p>Methods</p> <p>58 out of 88 patients from this institution had samples available for analysis. COX-2 expression levels were stratified by immunohistochemistry, into negligible, weak, moderate and strong, and correlated with overall and disease specific survivals.</p> <p>Results</p> <p>58% had negligible or weak COX-2 expression, while 14% and 28% had moderate and strong expression respectively. Weak COX-2 expression conferred a poorer median overall survival, 1.3 years for weak versus 6.3 years for negligible, 7.8 years, strong and not reached for moderate. There was a similar trend for disease specific survival.</p> <p>Conclusion</p> <p>Contrary to literature published on other malignancies, our findings seemed to indicate that over-expression of COX-2 confer a better prognosis in patients with endemic NPC. Larger studies are required to conclusively determine the significance of COX-2 expression in these patients.</p

Recommendation for a contouring method and atlas of organs at risk in nasopharyngeal carcinoma patients receiving intensity-modulated radiotherapy

Background and purpose To recommend contouring methods and atlas of organs at risk (OARs) for nasopharyngeal carcinoma (NPC) patients receiving intensity-modulated radiotherapy, in order to help reach a consensus on interpretations of OARs delineation. Methods and materials Two to four contouring methods for the middle ear, inner ear, temporal lobe, parotid gland and spinal cord were identified via systematic literature review; their volumes and dosimetric parameters were compared in 41 patients. Areas under the receiver operating characteristic curves for temporal lobe contouring were compared in 21 patients with unilateral temporal lobe necrosis (TLN). Results Various contouring methods for the temporal lobe, middle ear, inner ear, parotid gland and spinal cord lead to different volumes and dosimetric parameters (P < 0.05). For TLN, D1 of PRV was the most relevant dosimetric parameter and 64 Gy was the critical point. We suggest contouring for the temporal lobe, middle ear, inner ear, parotid gland and spinal cord. A CT-MRI fusion atlas comprising 33 OARs was developed. Conclusions Different dosimetric parameters may hinder the dosimetric research. The present recommendation and atlas, may help reach a consensus on subjective interpretation of OARs delineation to reduce inter-institutional differences in NPC patients. © 2013 Elsevier Ireland Ltd. All rights reserved.published_or_final_versio

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

High incidence of nasopharyngeal cancer: similarity for 60% of mitochondrial DNA signatures between the Bidayuhs of Borneo and the Bai-yue of Southern China

Populations in Southern China (Bai-yue) and Borneo (Bidayuh) with high incidence of nasopharyngeal cancer(NPC) share similar mitochondrial DNA signatures, supporting the hypothesis that these two populations may share the same genetic predisposition for NPC, which may have first appeared in a common ancestral reference population before the sea levels rose after the last ice age

Is nasopharyngeal cancer really a Cantonese cancer ?

Nasopharyngeal cancer (NPC) is endemic in Southern China, with Guandong province and Hong Kong reporting some of the highest incidences in the world. The journal Science has called it a Cantonese cancer . We propose that in fact NPC is a cancer that originated in the Bai Yue ( proto Tai Kadai or proto Austronesian or proto Zhuang ) peoples and was transmitted to the Han Chinese in southern China through intermarriage. However, the work by John Ho raised the profile of NPC, and because of the high incidence of NPC in Hong Kong and Guangzhou, NPC became known as a Cantonese cancer. We searched historical articles, articles cited in PubMed, Google, monographs, books and Internet articles relating to genetics of the peoples with high populations of NPC. The migration history of these various peoples was extensively researched, and where possible, their genetic fingerprint identified to corroborate with historical accounts. Genetic and anthropological evidence suggest there are a lot of similarities between the Bai Yue and the aboriginal peoples of Borneo and Northeast India; between Inuit of Greenland, Austronesian Mayalo Polynesians of Southeast Asia and Polynesians of Oceania, suggesting some common ancestry. Genetic studies also suggest the present Cantonese, Minnans and Hakkas are probably an admixture of northern Han and southern Bai Yue. All these populations have a high incidence of NPC. Very early contact between southern Chinese and peoples of East Africa and Arabia can also account for the intermediate incidence of NPC in these regions

Treatment of nasopharyngeal carcinoma using intensity-modulated radiotherapy - the national cancer centre Singapore experience

Purpose: The aim of this study was to determine the efficacy and acute toxicity of our early experience with treating nasopharyngeal carcinoma (NPC) patients with intensity-modulated radiotherapy (IMRT). Methods and materials: A review was conducted on case records of 195 patients with histologically proven, nonmetastatic NPC treated with IMRT between 2002 and 2005. MRI of the head and neck was fused with CT simulation images. All plans had target volumes at three dose levels, with a prescribed dose of 70 Gy to the gross disease, in 2.0–2.12 Gy/fraction over 33–35 fractions. Cisplatin-based chemotherapy was offered to Stage III/IV patients. Results: Median patient age was 52 years, and 69% were male. Median follow-up was 36.5 months. One hundred and twenty-three patients had Stage III/IV disease (63%); 50 (26%) had T4 disease. One hundred and eighty-eight (96%) had complete response; 7 (4%) had partial response. Of the complete responders, 10 (5.3%) had local recurrence, giving a 3-year local recurrence-free survival estimate of 93.1% and a 3-year disease-free survival of 82.1%. Fifty-one patients (26%) had at least one Grade 3 toxicity. Conclusions: Results from our series are comparable to those reported by other centers. Acute toxicity is common. Local failure or persistent disease, especially in patients with bulky T4 disease, are issues that must be addressed in future trials

An assessment of the magnitude of intra-fraction movement of head-and-neck IMRT cases and its implication on the action-level of the imaging protocol.

BACKGROUND AND PURPOSE: A planning margin ⩽3mm is employed in some head-and-neck IMRT cases due to the proximity of critical structures. This study aims to explore the need to redefine the action-level in the head-and-neck imaging protocol in consideration of the intra-fraction movement. MATERIAL AND METHODS: This is a local study of 18 patients treated using the same immobilisation system and setup protocol. Post-treatment orthogonal pair of kilovoltage X-ray images was acquired on the first three days of treatment. 106 sets of pre- and post-treatment kV X-ray images acquired over 53 fractions were analysed against the treatment planning DRR for calculation of intra-fraction movement. RESULTS: Individual mean intra-fraction movement in all directions ranged from -1.8 to 1.1mm. Population mean (median) intra-fraction movement in the x-, y-, and z-planes were -0.1mm (0mm), -0.3mm (-0.3mm) and -0.2mm (-0.2mm) respectively. Intra-fraction movement in all three dimensions, x-, y- and z-planes were considered statistically significant (p<0.05). 7 out of 53 fractions (13.2%) were highlighted as the combined magnitude of the intra-fraction motion with the uncorrected pre-treatment setup errors had exceeded the boundaries of given margins. CONCLUSIONS: 3mm-AL was not adequate to account for intra-fraction movement when the CTV-PTV margin was ⩽3mm and should be excluded from the routine imaging protocol and daily image-guided radiotherapy should be employed. Adjusting the action-level to 2mm would allow a more confident approach in delivery of the prescribed dose in head-and-neck IMRT cases

Intra-patient and inter-patient comparisons of DNA damage response biomarkers in Nasopharynx Cancer (NPC): analysis of NCC0901 randomised controlled trial of induction chemotherapy in locally advanced NPC

Abstract Background Inter-patient heterogeneity in radiation-induced DNA damage responses is proposed to reflect intrinsic variations in tumour and normal tissue radiation sensitivity, but the prediction of phenotype by a molecular biomarker is influenced by clinical confounders and assay reproducibility. Here, we characterised the intrapatient and inter-patient heterogeneity in biomarkers of DNA damage and repair and radiation-induced apoptosis. Methods We enrolled 85 of 172 patients with locally advanced nasopharynx cancer from a randomised controlled phase II/III trial of induction chemotherapy added to chemo-radiotherapy. G0 blood lymphocytes were harvested from these patients, and irradiated with 1, 4, and 8 Gy ex vivo. DNA damage induction (1 Gy 0.5 h) and repair (4 Gy 24 h) were assessed by duplicate γH2AX foci assays in 50–100 cells. Duplicate FLICA assays performed at 48 h post-8 Gy were employed as surrogate of radiation-induced apoptosis; %FLICA-positive cells were quantified by flow cytometry. Results We observed limited intrapatient variation in γH2AX foci and %FLICA readouts; median difference of duplicate foci scores was − 0.37 (IQR = − 1.256-0.800) for 1 Gy 0.5 h and 0.09 (IQR = − 0.685-0.792) for 4 Gy 24 h; ICC of ≥0.80 was observed for duplicate %FLICA0Gy and %FLICA8Gy assays of CD4+ and CD8+ T lymphocytes. As expected, we observed wide inter-patient heterogeneity in both assays that was independent of intrapatient variation and clinical covariates, with the exception of age, which was inversely correlated with %FLICAbackground-corrected (Spearman R = − 0.406, P < 0.001 [CD4+]; R = − 0.220, P = 0.04 [CD8+]). Lastly, an exploratory case-control analysis indicates increased levels of γH2AX foci at 4 Gy 24 h in patients with severe late radiotherapy-induced xerostomia (P = 0.05). Conclusion Here, we confirmed the technical reproducibility of DNA damage response assays for clinical implementation as biomarkers of clinical radiosensitivity in nasopharynx cancer patients