Prevalence of chronic rhinosinusitis in the general population based on sinus radiology and symptomatology.

BACKGROUND: The prevalence of chronic rhinosinusitis (CRS) measured in epidemiologic studies is 5% to 12%. This might be an overestimation because of overlap with other diseases, such as allergic rhinitis. OBJECTIVE: We aimed to calculate the prevalence of CRS using a combination of epidemiologically based CRS according to the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) together with sinonasal opacification on imaging. METHODS: Subjects who underwent a computed tomographic or magnetic resonance imaging scan of the head for any nonrhinologic indication were asked to fill in the Global Allergy and Asthma European Network survey containing EPOS symptom criteria. The scans were evaluated according to the Lund-Mackay (LM) scoring system. Epidemiologically based CRS is based on nasal symptoms according to EPOS; clinically based CRS also encompasses endoscopy and/or CT scanning. RESULTS: Eight hundred thirty-four subjects were included. One hundred seven (12.8%) had epidemiologically based CRS according to EPOS. Of these subjects, 50% had an LM score of 0, 26% had an LM score of 1 to 3, and 23% had an LM score of 4 or greater. Twenty-five (3.0%) subjects had clinically based CRS (based on LM score ≥4), and 53 (6.4%) subjects had clinically based CRS (based on LM score >0). Allergic rhinitis was reported by 167 (20%) subjects. In subjects who did not report upper airway symptoms, 57% had an LM score of 0, 30% had an LM score of 1 to 3, and 12% had an LM score of 4 or greater. CONCLUSION: We found a prevalence of 3.0% to 6.4% of clinically based CRS (depending on an LM cutoff point; ie, LM ≥ 4 or LM > 0, respectively) in a relatively randomly selected group of subjects.

Can Epstein-Barr virus DNA load in nasopharyngeal brushings or whole blood predict recurrent nasopharyngeal carcinoma in a non-endemic region? A prospective nationwide study of the Dutch Head and Neck Oncology Cooperative Group.

This study estimated the value of quantitative measurements of EBV markers in the clinical management of nasopharyngeal carcinoma in a non-endemic area. The aim was to predict prognosis and detect recurrent and residual disease. In 72 patients, EBV DNA load in blood and nasopharyngeal brushes, and IgA VCA-p18 and EBNA1 in plasma were measured at different time points. At diagnosis and post-treatment, a cut-off value was used for detecting disease [positive (PPV) and negative (NPV) predictive value]. The markers were correlated as a continuous variable with tumor stage, disease-free survival (DFS) and overall survival (OS). The Cox hazard ratio model assessed hazard ratios. At diagnosis, the markers were above the COV in 45, 92, 85 and 83 % of the patients, respectively. Post-treatment, DNA load test in blood and brush had the best discriminating power (blood DNA load test: PPV 39 % and NPV 97 %, brush for local disease: PPV 75 % and NPV 99 %). Post-treatment, DNA load in blood was the best predictor for OS and DFS [hazard ratio 3.2 (95 % CI 1.51-3.5) and 2.3 (95 % CI 1.72-5.8)]. Assessing the EBV DNA load in blood has significant prognostic value, although the clinical value is for discussion. The EBV DNA load in the brush might improve early detection of local failures post-treatment.

A matched cohort comparison of mTHPC-mediated photodynamic therapy and trans-oral surgery of early stage oral cavity squamous cell cancer.

Photodynamic therapy (PDT) of early stage oral cavity tumors have been thoroughly reported. However, statistical comparison of PDT to the surgical treatment is not available in published literature. We have identified and matched cohorts of patients with early stage oral cavity cancers undergoing surgery (n = 43) and PDT (n = 55) from a single institute experience. The groups are matched demographically and had the same pre-treatment screening and follow-up schedule. Both groups consisted only of tumors thinner than 5 mm to ensure comparability. The endpoints were local disease free survival, disease free survival, overall survival and response to initial treatment. Local disease free survival at 5 years were 67 and 74 % for PDT and surgery groups, respectively [univariate HR = 1.9 (p = 0.26), multivariable HR = 2.7 (p = 0.13)]. Disease free survival at 5 years are 47 and 53 % for PDT and surgery groups, respectively [univariate HR = 0.8 (p = 0.52), multivariable HR = 0.75 (p = 0.45)]. Overall survival was 83 and 75 % for PDT and surgery groups, respectively [(univariate HR = 0.5 (p = 0.19), multivariable HR = 0.5 (p = 0.17)]. In the PDT group, six patients (11 %) and in the surgery group 11 patients (26 %) had to receive additional treatments after the initial. All of the tested parameters did not have statistical significant difference. Although there is probably a selection bias due to the non-randomized design, this study shows that PDT of early stage oral cavity cancer is comparable in terms of disease control and survival to trans-oral resection and can be offered as an alternative to surgical treatment.

Knowledge of general practitioners about nasopharyngeal cancer at the Puskesmas in Yogyakarta, Indonesia.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the leading causes of cancer death in Indonesia. At initial diagnosis, 80% of the patients present with advanced stage disease. In Indonesia, primary medical care is generally provided by the health care centres; named Puskesmas. The lack of knowledge of various aspects of NPC of the General practitioners (GPs) working in these centers might contribute to the diagnostic delay. The aim of this study was to assess the knowledge of these GPs on different aspects of NPC including symptoms, risk factors and incidence. METHODS: One hundred six GPs in the Puskesmas in the Yogyakarta province were subjected to a questionnaire on different aspects of NPC based on literature and interviews with Head and Neck Surgeons. RESULTS: All GPs approached participated and in total 106 questionnaires were filled in. All participants were aware of NPC as a disease and 89% confirmed that it is a serious problem in Indonesia. However, 50% of the participants believed NPC has a low incidence in their region. The question on early symptoms gave a mean 4.2 answers of which 50% were incorrect.The GPs provided a total of 318 answers when asked for the risk factors of NPC, 75% of which were incorrect. Fifty seven GPs (54%) stated that they did not receive sufficient education on NPC at the university and insufficient knowledge was gained during daily practice. Ninety-two percent of the GPs were interested in additional education, preferably in form of lectures, meetings or folders. CONCLUSION: This study revealed that GPs in the Puskesmas in Yogyakarta lack knowledge on all aspects of NPC. This is an important finding as NPC is endemic in Indonesia and the Puskesmas are the institutions which provide primary medical health care in the country. Further education of the GPs in these endemic areas could be a first step to increase the rate of early detection. Therefore, we suggest 1) to conduct a medical awareness campaign for GPs on the most important subjects concerning NPC, and 2) as soon as NPC awareness among GPs has risen, provide further education on the risk factors, the early symptoms and the incidence, education to the community. We propose to extend this study to other areas in Indonesia (i.e. Jakarta, Surabaya, Central Java), using models that have been developed in Yogyakarta.

Effectiveness of a multicentre nasopharyngeal carcinoma awareness programme in Indonesia.

OBJECTIVE: To evaluate the effectiveness of a nasopharyngeal carcinoma (NPC) awareness programme on the short-term and long-term improvement of knowledge and referral of patients with NPC by primary healthcare centres (PHCCs) staff in Indonesia. DESIGN: The NPC awareness programme consisted of 12 symposia including a Train-The-Trainer component, containing lectures about early symptoms and risk factors of NPC, practical examination and the referral system for NPC suspects. Before and after training participants completed a questionnaire. The Indonesian Doctors Association accredited all activities. PARTICIPANTS: 1 representative general practitioner (GP) from each PHCC attended an NPC awareness symposium. On the basis of the Train-The-Trainer principle, GPs received training material and were obligated to train their colleagues in the PHCC. RESULTS: 703 GPs attended the symposia and trained 1349 staff members: 314 other GPs, 685 nurses and 350 midwives. After the training, respondents' average score regarding the knowledge of NPC symptoms increased from 47 points (of the 100) to 74 points (p<0.001); this increase was similar between symposium and Train-The-Trainer component (p=0.88). At 1½ years after the training, this knowledge remained significantly increased at 59 points (p<0.001). CONCLUSIONS: The initial results of this NPC awareness programme indicate that the programme effectively increases NPC knowledge in the short and long term and therefore should be continued. Effects of the improved knowledge on the stage at diagnoses of the patients with NPC will still need to be scrutinised. This awareness programme can serve as a blueprint for other cancer types in Indonesia and for other developing countries.

Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma.

PURPOSE: Despite successful primary treatment of nasopharyngeal carcinoma (NPC), the incidence of distant metastasis remains 25-34 %. Treatment options are limited, and survival is poor. Intratumoural Epstein-Barr virus (EBV) was used as treatment target. In NPC, EBV is present in a latent state, expressing only few non-immunogenic viral products. Gemcitabine and valproic acid can trigger EBV to the lytic state, wherein viral kinases are expressed, making EBV-positive tumour cells susceptible for antiviral therapy with, i.e. valganciclovir, and inducing an EBV-specific immune response. METHODS: This drug combination was applied in eight patients with EBV-positive NPC, refractory to conventional treatment. The primary endpoints were safety, tolerability and clinical response. Secondary endpoint was to get proof of concept based on biomarkers, i.e. pharmacokinetics, EBV-DNA load in whole blood and nasopharyngeal brushes, EBV-RNA profiling for proof of lytic induction, EBV-IgG and EBV-IgA levels and diversity and EBV-specific T cell response. RESULTS: The best observed clinical response was partial in two patients (25 %) and stable disease in three patients (37.5 %). The median survival was 9 months (95 % confidence interval 7-17 months). Effective dose levels were reached. Peaking of EBV-DNA loads in blood and brush proved the biological effect on EBV during most treatment cycles. In one patient, RNA profiling confirmed lytic EBV induction. EBV-IgG and EBV-IgA antibody levels were already high before treatment and did not change during treatment. No changes in EBV-specific T cell response were detected. CONCLUSION: The treatment was safe with manageable side effects, clinical response was observed, and viral activation corroborated.

A prospective study: current problems in radiotherapy for nasopharyngeal carcinoma in yogyakarta, indonesia.

INTRODUCTION: Nasopharyngeal carcinoma (NPC) has a high incidence in Indonesia. Previous study in Yogyakarta revealed a complete response of 29% and a median overall survival of less than 2 years. These poor treatment outcome are influenced by the long diagnose-to-treatment interval to radiotherapy (DTI) and the extended overall treatment time of radiotherapy (OTT). This study reveals insight why the OTT and DTI are prolonged. METHOD: All patients treated with curative intent radiotherapy for NPC between July 2011 until October 2012 were included. During radiotherapy a daily diary was kept, containing information on DTI, missed radiotherapy days, the reason for missing and length of OTT. RESULTS: Sixty-eight patients were included. The median DTI was 106 days (95% CI: 98-170). Fifty-nine patients (87%) finished the treatment. The median OTT for radiotherapy was 57 days (95% CI: 57-65). The main reason for missing days was an inoperative radiotherapy machine (36%). Other reasons were patient's poor condition (21%), public holidays (14%), adjustment of the radiation field (7%), power blackout (3%), inoperative treatment planning system (2%) and patient related reasons (9%). Patient's insurance type was correlated to DTI in disadvantage for poor people. CONCLUSION: Yogyakarta has a lack of sufficient radiotherapy units which causes a delay of 3-4 months, besides the OTT is extended by 10-12 days. This influences treatment outcome to a great extend. The best solution would be creating sufficient radiotherapy units and better management in health care for poor patients. The growing economy in Indonesia will expectantly in time enable these solutions, but in the meantime solutions are needed. Solutions can consist of radiation outside office hours, better maintenance of the facilities and more effort from patient, doctor and nurse to finish treatment in time. These results are valuable when improving cancer care in low and middle income countries.

Current status of cancer care for young patients with nasopharyngeal carcinoma in Jakarta, Indonesia.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is endemic in Indonesia and 20% of the patients are diagnosed before the age of 31. This study evaluates presentation and treatment outcome of young patients in Jakarta, in a tertiary referral centre. METHODS: Forty-nine patients under the age of 31, diagnosed with NPC between July 2004 and January 2007, were evaluated. Baseline data included histological type, stage of disease and presenting symptoms. We intended to follow all patients after diagnosis to reveal treatment outcome and overall survival (OS). RESULTS: All but two patients had advanced stage disease (94%), 7 (14%) had distant metastasis. The median interval between start of complaints and diagnosis was 9 months. Forty-two patients were planned for curative intent treatment. Eleven patients (26%) never started treatment, 2 patients did not complete treatment and 3 patients did not return after finishing treatment. Four patients died before radiation could start. Three patients died within 4 months after treatment. Nine patients (21%) had a complete response. Due to the high number of patients who were lost to follow-up (LFU), OS was analyzed as follows: a best-case (patients censored at last contact) and a worst-case scenario (assuming that patients who did not finish treatment or had disease at last contact would have died). The 2-year OS for patients without distant metastases was 39-71%. CONCLUSION: Treatment outcome for young patients with NPC in this institute was poor. Improvement can be achieved when NPC is diagnosed at an earlier stage and when there is better treatment compliance.

Lower mortality from nasopharyngeal cancer in The Netherlands since 1970 with differential incidence trends in histopathology.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is rare in western countries albeit affected by common and unrelated phenomena: smoking less in men, more in women and immigration from China and North Africa. We studied trends in NPC incidence, tumour morphology, survival and mortality in order to assess progress against this cancer. MATERIALS AND METHODS: A trend analysis was performed with nationwide incidence and survival data (from The Netherlands Cancer registry in 1989-2009), followed by analysis of mortality (data from Statistics Netherlands) covering the period 1970-2009, and calculating estimated percentages of change (EAPC) in both. According to the WHO classification we distinguished keratinizing SCC (WHO-I), differentiated (WHO-IIA) and undifferentiated (WHO-IIB) non-keratinizing carcinoma. RESULTS: NPC incidence significantly decreased since 1989, especially in males (EAPC 1989-2009: -1.3; 95% CI: -2.5, -0.2) and in patients with keratinizing SCC (WHO-I) (EAPC: -3.6; 95% CI: -5.3, -1.8). By contrast, the incidence of differentiated non-keratinizing tumours (WHO-IIA) significantly increased in the same period (EAPC: 9.6; 95% CI: 5.6, 13.5). One- and three-year relative survival, as an indicator of disease-specific survival increased slightly from 79% to 81% and from 57% to 65% since 1989. NPC mortality significantly decreased since 1970 (EAPC: -1.2; 95% CI: -1.8, -0.5) and more pronounced since 1989 (EAPC: -3.0; 95% CI: -4.3, -1.6). CONCLUSION: During the past two decades, the incidence of NPC in The Netherlands decreased mainly by less keratinizing, supposedly smoking-related NPC (WHO-I). However, the incidence of non-keratinizing NPC (WHO-IIA, B) increased, most likely due to EBV infection and thus related to higher immigration levels of people from high-incidence areas.

Local control in advanced cancer of the nasopharynx: is a boost dose by endocavitary brachytherapy of prognostic significance?

PURPOSE: To analyze whether local tumor control in advanced nasopharyngeal cancer (NPC) can be optimized by boosting the primary dose by endocavitary brachytherapy (EBT). METHODS AND MATERIALS: To study the role of EBT, three data sets on NPC, that is, the "Vienna", "Rotterdam," and "Amsterdam" series, with a total number of 411 advanced NPC patients, were available. The Rotterdam series consisted of 72 patients (34 T1,2N+ and 38 T3,4N0,+) and were treated with neoadjuvant chemotherapy followed by external beam radiotherapy (dose 70/2Gy). After 70/2Gy, a boost was applied by EBT (in case of T1,2N+) or stereotactic radiation (in case of T3,4 tumors). The Amsterdam (Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute) series consisted of 76 patients (40 T1,2N+ and 36 T3,4N0,+) and were irradiated to a dose of 70/2Gy with concomitant chemotherapy. No second boost by EBT was applied. RESULTS: In the case of T1,2N+ tumors, the local relapse rate (LRR) was significantly smaller if a boost was applied, that is, 0% (0/34, EBT boost) vs. 14% (14/102, no EBT boost) (p=0.023). For the T3,4 tumors, an LRR of 10% (4/38, EBT or stereotactic radiation boost) vs. 15% (17/111, no boost) was found (p=0.463). CONCLUSIONS: In the case of advanced NPC (T1,2N+ vs. T3,4N+,0), for early T-stages (T1,2N+), an EBT boost seems an excellent way to deliver highly conformal high doses of radiation to the nasopharynx, with high local control rates. For advanced T-stages (T3,4N+,0), the reduction in LRR (10% vs. 15%) was not significant (p=0.463).

Primary treatment results of Nasopharyngeal Carcinoma (NPC) in Yogyakarta, Indonesia.

INTRODUCTION: Nasopharyngeal Carcinoma (NPC) is a major health problem in southern and eastern Asia. In Indonesia NPC is the most frequent cancer in the head and neck area. NPC is very sensitive to radiotherapy resulting in 3-year disease-free and overall survival of approximately 70% and 80%, respectively. Here we present routine treatment results in a prospective study on NPC in a top referral; university hospital in Indonesia. METHODS: All NPC patients presenting from September 2008 till January 2011 at the ear, nose and throat (ENT) department of the Dr. Sardjito General Hospital, Universitas Gadjah Mada, Yogyakarta, Indonesia, were possible candidates. Patients were included if the biopsy was a histological proven NPC without distant metastasis and were assessed during counselling sessions prior to treatment, as being able to complete the entire treatment. RESULTS: In total 78 patients were included for treatment analysis. The median time between diagnosis and start of radiotherapy is 120 days. Forty-eight (62%) patients eventually finished all fractions of radiotherapy. The median duration of the radiotherapy is 62 days for 66 Gy. Median overall survival is 21 months (95% CI 18-35) from day of diagnosis. CONCLUSION: The results presented here reveal that currently the treatment of NPC at an Indonesian hospital is not sufficient and cannot be compared to the treatment results in literature. Main reasons for these poor treatment results are (1) a long waiting time prior to the start of radiotherapy, (2) the extended overall duration of radiotherapy and (3) the advanced stage of disease at presentation.

Cytolytic virus activation therapy for Epstein-Barr virus-driven tumors.

PURPOSE: Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV) infection. Because all tumor cells carry EBV, the virus itself is a potential target for therapy. In these tumor cells, EBV hides in a latent state and expresses only a few non-immunogenic proteins for EBV maintenance and contributes to tumor growth. We developed a cytolytic virus activation (CLVA) therapy for NPC treatment, reactivating latent EBV, triggering immune recognition, and inducing susceptibility to antiviral therapy. EXPERIMENTAL DESIGN: CLVA therapy combines gemcitabine (GCb) and valproic acid (VPA) for virus activation and tumor clearance with (val)ganciclovir (GCV) as the antiviral drug to block virus replication and kill proliferating virus-infected cells. CLVA treatment was optimized and validated in NPC cell lines and subsequently tested in 3 Dutch patients with NPC that was refractory to conventional treatment. RESULTS: In NPC cell lines, both GCb and VPA can induce the lytic cycle of EBV. Their combination resulted in a strong synergistic effect. The addition of GCV resulted in higher cytotoxicity compared with chemotherapy alone, which was not observed in EBV-negative cells. CLVA therapy was analyzed in 3 patients with end-stage NPC. Patients developed increased levels of viral DNA in the circulation originating from apoptotic tumor cells, had disease stabilization, and experienced improved quality of life. CONCLUSIONS: Our results in the initial CLVA-treated patients indicate that the therapy had a biological effect and was well tolerated with only moderate transient toxicity. This new virus-specific therapy could open a generic approach for treatment of multiple EBV-associated malignancies.

Short-term effect of different teaching methods on nasopharyngeal carcinoma for general practitioners in Jakarta, Indonesia.

UNLABELLED: In Indonesia, Nasopharyngeal Carcinoma (NPC) is the most frequent cancer of the head and neck region. At first presentation in the hospital most patients already have advanced NPC. Our previous study showed that general practitioners (GPs) working in Yogyakarta, Indonesia lack the knowledge necessary for early detection of NPC. By providing training on early symptoms of NPC we hope that the diagnosis and referral will occur at an earlier stage. Here we assess the current NPC knowledge levels of GPs in Jakarta, evaluate improvement after training, compare the effectiveness of two training formats, and estimate the loss of recall over a two week period. METHODS: Two Indonesian GPs visited 31 Primary Health Care Centres (PHCCs) and provided a lecture on NPC. The alternative format consisted of a symposium at the Universitas Indonesia, Jakarta, presented by local head and neck surgeons, with all GPs in the region being invited. To evaluate the effect of both formats a questionnaire was conducted before and after. RESULTS: The lecture in the PHCCs was attended by 130 GPs. Sixty-six GPs attended the training in the university hospital and 40 GPs attended both. Pre training the NPC knowledge level was poor with an average of 1.6 symptoms being correctly identified out of a potential maximum of 12, this was increased to 4.9 post training (p<0.0001). GPs attending the PHCC course recorded a greater increase in correct symptoms than those attending the symposium (3.8 vs. 2.8; p = 0.01). After a two week period the knowledge levels had declined slightly from 5.5 correctly identified symptoms to 4.2 (p = 0.25). CONCLUSION: These results confirm our findings regarding GPs insufficient knowledge of NPC. Lectures in the PHCC and a symposium have both been proven to be effective training tools in the education of GPs.

Can an online clinical data management service help in improving data collection and data quality in a developing country setting?

BACKGROUND: Data collection by electronic medical record (EMR) systems have been proven to be helpful in data collection for scientific research and in improving healthcare. For a multi-centre trial in Indonesia and the Netherlands a web based system was selected to enable all participating centres to easily access data. This study assesses whether the introduction of a clinical trial data management service (CTDMS) composed of electronic case report forms (eCRF) can result in effective data collection and treatment monitoring. METHODS: Data items entered were checked for inconsistencies automatically when submitted online. The data were divided into primary and secondary data items. We analysed both the total number of errors and the change in error rate, for both primary and secondary items, over the first five month of the trial. RESULTS: In the first five months 51 patients were entered. The primary data error rate was 1.6%, whilst that for secondary data was 2.7% against acceptable error rates for analysis of 1% and 2.5% respectively. CONCLUSION: The presented analysis shows that after five months since the introduction of the CTDMS the primary and secondary data error rates reflect acceptable levels of data quality. Furthermore, these error rates were decreasing over time. The digital nature of the CTDMS, as well as the online availability of that data, gives fast and easy insight in adherence to treatment protocols. As such, the CTDMS can serve as a tool to train and educate medical doctors and can improve treatment protocols.

Photodynamic therapy in the therapy for recurrent/persistent nasopharyngeal cancer.

To determine the efficacy of Photodynamic therapy of patients with recurrent Nasopharyngeal Carcinoma we reviewed all available literature. Since the treatment options for recurrent or persistent Nasopharyngeal Carcinoma are limited, the survival rates poor and the complications severe; there is definitely a place for alternative treatment modalities with more efficacy and less morbidity. Photodynamic therapy (PDT) has the potential to be a very effective local treatment modality for recurrent or persistent nasopharyngeal cancer, without the severe side effects seen with re-irradiation. This review shows all reported results of Photodynamic therapy in the treatment for Nasopharyngeal Carcinoma.

Radiotherapy in laryngeal carcinoma: can a panel of 13 markers predict response?

OBJECTIVES/HYPOTHESIS: To find biomarkers associated with response to radiotherapy in laryngeal cancer that can be used together with clinical parameters to improve outcome prediction. METHODS: In this study, 26 patients irradiated for laryngeal carcinomas with a local recurrence within two years (cases) and 33 patients without recurrence (controls) were included. All pretreatment biopsies were arrayed onto a tissue array. Immunohistochemistry was performed for 13 biomarkers that were selected from the literature as potential predictors for radioresponse in head and neck (HN) cancer: Bcl-2, Bcl-xL, p16, p21, p27, p53, cyclin D1, HIF-1alpha, CA9, COX-2, EGFR, ki-67, and pRB. RESULTS: Univariate logistic regression models showed borderline statistically significant increased relative risks, with positivity for CA9, COX-2, and p53. Goeman's global testing revealed an overall association between outcome and the 13 markers together with clinical variables. The most important markers were CA9 and COX-2. CONCLUSIONS: In laryngeal carcinoma, hypoxia and COX-2 overexpression provide a stronger contribution to an increased risk of local recurrence after radiotherapy compared with the well-known candidate markers p53, Bcl-2, and cyclin D1. However, no robust expression profile for the prediction of radioresistance was found.