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  Cervical cancer incidence in young women: a historical andgeographic controlled UK regional population study  A Patel 1 , K Galaal 1 , C Burnley 2 , K Faulkner  2 , P Martin-Hirsch 3 , MJ Bland 4 , S Leeson 5 , H Beer  6 , S Paranjothy 6,7 ,P Sasieni 8 and R Naik  1 1 Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Sheriff Hill, Gateshead Tyne and Wear NE9 6SX, UK;  2 The North East, Yorkshireand Humber Quality Assurance Reference Centre, Leeds, UK;  3 Preston Royal Infirmary, Preston, UK;  4 Department of Health Sciences, University of York,York, UK;  5 Department of Obstetrics and Gynaecology, Betsi Cadwaladr University Health Board, North Wales, UK;  6 Screening Division, Public HealthWales NHS Trust, Wales, UK;  7 Department of Primary Care and Public Health, Cardiff University, Wales, UK;  8 Centre for Cancer Prevention,Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK  BACKGROUND :  The commencing age of cervical screening in England was raised from 20 to 25 years in 2004. Cervical cancer incidencein young women of England is increasing. It is not clear if this is due to either greater exposure to population risk factors or reducedcervical screening. METHODS :  We measured if the relative risk of cervical cancer in younger women (20–29 years) of the north-east of England (NE)differed to that of women aged 30yrs and above since 2004. We also measured average annual percentage change (AAPC) in the3yr moving average incidence for all age-groups. Regional screening coverage rate and population risk factors were reviewed.Comparisons were made with Wales where screening continues to commence from the age of 20yrs. RESULTS :  Cervical cancer incidence in women aged 20–29 increased annually by an average of 10.3% between 2000 and 2009.The rise in women aged 30–39 was less steep (3.5%/year) but no significant rise was observed in women aged 40–49.Socioeconomic factors remained stable or improved during the time period except for the incidence of chlamydia, herpes simplexand in particular, genital warts, which increased significantly in young women. Data from Wales show similar results. CONCLUSION :  The incidence of cervical cancers in young women of the NE is increasing. The rise in incidence is unrelated to thechange in screening policy in 2004. Close monitoring of incidence in young women and a greater attempt to reverse the currentdecline in screening coverage of women aged 25–29 years are recommended. British Journal of Cancer   (2012)  106,  1753–1759. doi:10.1038/bjc.2012.148 www.bjcancer.comPublished online 24 April 2012 &  2012 Cancer Research UK  Keywords:  cervical cancer; incidence; screening; cervical intra-epithelial neoplasia; human papilloma virus; sexually transmitted disease  Recently published analyses of trends in cervical cancer incidencein England suggest a rise in incidence in young women,particularly in the north-east of England (NE) (Foley   et al  , 2011;NCIN, 2011). Although wide variability in completeness of cancerregistration (Swerdlow   et al  , 1993; Bullard  et al  , 2000; Bernays  et al  ,2002) limits interpretation, these results are alarming and of significant public health interest. Whether the rise in incidence isdue to either greater exposure to risk factors or reduced cervicalscreening activity remains unclear.The National Health Service Cervical Screening Programme(NHSCSP) has achieved remarkable success in the reduction of incidence of cervical cancer. An estimate of lives saved per year by screening in the United Kingdom varies between 1100 and 4500according to the mathematical models used (Sasieni  et al  , 1996;Peto  et al  , 2004b). Despite such successes, commencing age of screening in England was raised from 20 to 25 years in 2004(NHSCSP, 2003). This was in response to a study that concludedthat the protection offered by negative cytology improves with age(Sasieni  et al  , 2003). Following this policy change, the value andsensitivity of cervical screening in young women has been thesubject of considerable debate. Although proponents have arguedfor the potential life years saved, opponents have raised concernsof physical and psychological harm to women and cost to society.In June 2009, an independent Advisory Committee for CervicalScreening in England reviewed the evidence and upheld thedecision of cervical screening policy change of 2004 (ACCS, 2009).Analyses of an extended data set in 2009 also reported thatscreening of women aged 20–24 years had little or no impact oncancer incidence under the age of 30 years (Sasieni  et al  , 2009).In 2011, the cervical screening programme of Northern Ireland wasamended with policy changes similar to England (NICSP, 2010).Scotland and Wales continue to offer the cervical screening fromthe age of 20 years.The International Agency for Research on Cancer (IARC) in1986 reported that the sensitivity of cervical cytology or thesojourn time period of a premalignant disease is not age dependent(IARC, 1986). More recent evidence from Wales (Rieck  et al  , 2006)and Sweden (Andrae  et al  , 2008) showed cytological screening tobe effective in young women. Similar conclusions were reached by Peto  et al   (2004b) and Sigurdsson and Sigvaldason (2007) in theirreview of invasive and preinvasive cervical disease in England and *Correspondence: R Naik; E-mail: raj.naik@ghnt.nhs.uk Received 11 November 2011; revised 21 March 2012; accepted 22March 2012; published online 24 April 2012 British Journal of Cancer (2012) 106,  1753–1759 &  2012 Cancer Research UK All rights reserved 0007– 0920/12 www.bjcancer.com      C     l     i    n     i    c    a     l     S     t    u     d     i    e    s  Iceland, respectively. However, the relevance of these findings hasbeen called into question (Sasieni  et al  , 2010).The withdrawal of cervical screening from 20 to 24 years inEngland is the first occasion globally, where a population cancerscreening programme has been cut back. Any subsequent increasein cancer incidence in young women will naturally be attributed tothe policy change. However, the true and full effect can only be revealed by prospectively following the birth cohort (born in1985 or after) directly affected by the change in policy. Suchwomen will only turn 30 years in 2014 and cancer incidence datamay not be available until 2017. Alternatively, a thorough review of multisource cancer registrations, screening coverage and popula-tion risk factors in the years immediately prior to and after thechange in policy, particularly if compared with other nations of theUnited Kingdom, may clarify the causative factors responsible forthe rise in cervical cancer incidence in young women.In this study, we describe the trends in incidence of cervicalcancer in young women within a well-defined geographical regionof the NE between 2000 and 2009, and compare our results withthat of Wales where women continued to be offered screening fromthe age of 20 years. MATERIALS AND METHODS All cervical cancer cases diagnosed between 2000 and 2009 withinfive predefined postcodes (NE, CA, DH, SR and TD) wereidentified from a regional cancer registry, cancer centres, cancerunits and pathology laboratories of the NE and Cumbria. Duplicatecases were removed. Age at diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, year of diagnosis andprior screening history were collected for each case. High-gradeintra-epithelial neoplasia (HG-CIN, ICD10 code D06) registrationsbetween 2000 and 2009 for the North-East Cancer Network(NECN) were obtained from the regional cancer registry. Mid-year population estimates were obtained from the Office of National Statistics (ONS).We first confirmed if the relative risks for all and FIGO stage 1Bor higher cases in three age groups (20–24, 25–29 and 30 years andabove) differed between two calendar periods, 2000–2004 and2005–2009. We then assessed if relative risk in younger age groups(20–24 and 25–29 years) differed compared with 30 years andabove between these two calendar periods. For this analysis weused Poisson regression, with number of cases as an outcome,adjusting for the populations’ size as an exposure and using agegroup, calendar period and the interaction between age group andcalendar period as predictors. A similar analysis was performed forHG-CIN registrations for the NECN.We then measured an average annual percentage change(AAPC) in the 3-year moving average incidence rate for variousage groups by fitting a regression line to the natural logarithm of the rates using calendar year as a regressor variable and allowingfor significant trend changes between 2000 and 2009. The AAPC isa weighted average measure of all episodes of differing trend incancer incidence over a fix time period. The weighted averageincorporates an annual percentage change (APC) in incidence,the slope coefficients of regression trend line and the duration(in years) of each episode (NCI, 2011a). This analysis wasperformed for all, FIGO stage 1B or higher, FIGO stage 1A cancercases and HG-CIN cases. This enabled us to measure if the rise inrisk was steady or if there were any significant point changes in thetrend of cervical cancer incidence.As women born prior to 1984 would have been invited forscreening from the age of 20 years, and those born in 1985 or afterwould not have been invited until age 25 years (in 2009), it is thenof interest, that we compare cervical cancer incidence at ages 20–24years in women invited from the age of 20 years with those notinvited until the age of 25 years keeping an equal number atdifferent ages. Similar analyses for women aged 25–29 years wouldnot be possible for a further few years as the cohort enteredscreening in 2009.To determine route to diagnosis of cervical cancer (symptom  vs screen detected) and screen category, we reviewed cervicalscreening histories of women aged 20–29 years. Comparisonswere made between the two calendar periods. The screeningcoverage rates for the NE were obtained from The North East,Yorkshire and Humber Quality Assurance Reference Centre(NEYHQARC). The regional and national population trends onvarious risk factors for cervical cancer (e.g., socioeconomic factors,smoking, sexually transmitted diseases, teenage conceptions andterminations, and migration) during the 10-year study period wereanalysed. Data for these factors were obtained from the ONS,Health Protection Agency and the Department of Health.A quality assured registration of cervical cancer cases along withHG-CIN registration, population statistics, screening coveragerates and trends in various risk factors for the Wales populationwere obtained from the Welsh Cancer Intelligence and SurveillanceUnit, ONS, Cervical Screening Wales and Public Health Wales NHSTrust, respectively. Similar statistical analyses and comparisonswere made with the NE data.All statistical analyses were two-sided.  P  -value  o 0.05 wasconsidered significant. Statistical analyses were performed usingStata 10 (Stata Corp., College Station, TX, USA) except for theAAPC analysis that was performed using the ‘JoinPoint’ softwarefrom the Surveillance Research Program of the US National CancerInstitute (NCI, 2011b). RESULTS A total of 1061 cervical cancer cases were diagnosed between 2000and 2009 in the defined geographical region of the NE: 512 casesbetween the years 2000 and 2004, and 549 cases between 2005 and2009 with overall incidences of 8.4 and 8.9 per 100000 women-years, respectively. There were 152 (14%) cases in women agedbetween 20–29 years between 2000 and 2009, of which 39 (26%)were aged 20–24 years. Overall, 54 out of 940 cases (5.7%) of cervical cancers were not registered with the regional cancerregistry. These missing cases showed no obvious trends in age,FIGO stage or geographical distribution (Supplementary Table S1).In addition, 14% of cases registered at regional cancer registry either had missing or erroneous FIGO stage.Table 1 and Supplementary Figure S1 show the Poisson regressionanalysis and differences between the two calendar periods (2000–2004and 2005–2009) in cervical cancer and HG-CIN incidence in the NE.There is strong evidence for all cancers (* P  ¼ 0.001) and Stage 1Band higher cancers (* P  ¼ 0.005) that the relative risks among thethree age groups differed between two time periods. The interactionalso gave sufficient evidence (* P  ¼ 0.04) for women aged 20–24years, and strong evidence (* P  ¼ 0.004) for women aged 25–29years that their relative risk has increased compared with womenaged 30 years and above since 2004. Similar analyses limited toFIGO Stage 1B and higher returned significance values of 0.068and 0.021 for women aged 20–24 and 25–29 years, respectively.When Poisson regression was performed with four age groups(20–24, 25–29, 30–34 and 35 years and above) we found similarresults for 20–24 and 25–29 age groups (Table 1b). In addition, wefound that the relative risk was higher in the 30–34 years age groupsince 2004 compared with 35 years and above. However, whenthe analysis was performed excluding cases from 2009 (data notshown) to eliminate the effect of media coverage following thediagnosis and death of a UK celebrity from cervical cancer (JadeGoody effect), the relative risk remained higher for the 20–24 and25–29 age groups, but not for women aged 30–34 years. Analysis of HG-CIN, expectedly, showed significant reduction in incidence inthe 20–24 years age group since the withdrawal of screening Cervical cancer incidence in young women A Patel  et al 1754 British Journal of Cancer (2012)  106 (11), 1753–1759  &  2012 Cancer Research UK   Cl   i   ni    c al    S  t   u d i    e s   (difference of 201 per 100000). However, an equivalent andconsiderable rise in incidence (difference of 131 per 100000) wasobserved in the 25–29 years age group.Table 2 presents an AAPC in 3-year moving average incidence of cervical cancer and HG-CIN to assess whether the change inincidence was steady over time in the different age groups of theNE. The rise in AAPC for age groups 20–24 and 25–29 years wassteady, similar and significant from public health perspective(Supplementary Figure S2). Combining these two groups to 20–29years (and adjusting for age group), the AAPC in all stages, stage1B and higher and stage 1A cervical cancer were 10.3% (95% CI:4.4 to 18.7%), 15.2% (12.0 to 18.5%) and 5.3% (  3.7 to 15.2%),respectively. With respect to all cervical cancer cases, the rise inAAPC decreased with age from 30 to 39 years and the rateschanged little over time in those aged 40 years and above. Whenanalyses were performed excluding cases from 2009 (data notshown), eliminating the effect of media coverage (Jade Goody effect) and any resulting increase in screening, we obtained similarresults except that between 2000 and 2008 there was virtually noincrease in cancer rates in those aged 30–39 years. Average annualpercentage change analysis of HG-CIN incidence suggests agradual reduction in HG-CIN cases in 20–24 years and a rise in25–29 years age group.A birth cohort analysis of women aged 20–24 years, comparingthose invited from the age of 20 yrs (born before 1985) withthose not invited until age of 25 years (born after 1984), revealed6 cases (2.6 per 100000 women) against 11 cases (4.4 per 100000women), respectively ( P  ¼ 0.399). Analyses limited to stage 1Band higher cases showed that there were three cases (1.3 per100000) in those invited from the age of 20 years comparedwith five (2.0 per 100000) in those not invited until age of 25 years( P  ¼ 0.794).Supplementary Table S2 shows an analysis of screening historiesof young women (20–29) in the NE diagnosed with cervical cancer.More women aged 20–24 years presented with symptoms in2005–2009 compared with 2000–2004 (* P  ¼ 0.048). The cumulativeincidence per 100000 women of FIGO stage 1B and higher cases inthis age group was 1.2 and 3.1 during 2000–2004 and 2005–2009,respectively. We did not find any significant differences in screencategories between the two calendar periods for either the 20–24years or the 25–29 years age groups. In addition, there was nosignificant difference in presentation for the 25–29 years age groupbetween the two calendar periods. However, significantly lesswomen aged 25–29 years in the 2005–2009 had two previousnegative smears (* P  ¼ 0.042).Supplementary Figure S3 shows cervical screening coveragerates for women aged 20–24 and 25–29 years in the NE and Wales.As coverage is defined as having been screened in the previous 5years, it is inevitable that coverage of 25 year olds will decrease if women aged 20–24 years are no longer invited for screening.Screening coverage in Wales appears to follow similar trendsexcept that the screening coverage for women aged 20–24 years didnot show a dramatic decrease since 2004 as Wales continue toscreen this age group. Coverage rates were comparatively higher inthe NE than in Wales for women aged 20–24 years until 2004 and25–29 years until 2008.Figure 1 shows trends in various population risk factors in theNE and Wales that may have had potential effects on cervical Table 1  Age group-specific incidence of cervical cancer and HG-CIN, and Poisson regression of interaction between calendar period and age groups in the north-east of England and Wales North-East of England (NE) WalesIncidence a Poisson regression b Poisson regression c Incidence a Poisson regression b Poisson regression c Age groups 2000–4 2005–9 IRR (95% CI)  P  -value IRR (95% CI)  P  -value 2000–4 2005–9 IRR (95% CI)  P  -value IRR (95% CI)  P  -value (a) Age groups 20–24, 25–29 and 30 þ  years: Cancer and HG-CIN cases All stages30 þ  11.4 11.1 1.00 Ref. 15.7 15.2 1.00 Ref.25–29 12.0 21.0 1.45 (1.17–1.79) 0.001 1.83 (1.22–2.75) 0.004 11.5 19.8 1.46 (1.19–1.78) 0.001 1.77 (1.22–2.57) 0.00220–24 3.4 7.0 2.07 (1.03–4.13) 0.040 2.3 5.9 2.64 (1.28–5.46) 0.009FIGO 1B þ 30 þ  9.1 8.4 1.00 Ref.25–29 6.0 10.5 1.55 (1.14–2.10) 0.005 1.95 (1.11–3.42) 0.02120–24 1.2 3.1 2.89 (0.92–9.05) 0.068FIGO 1A30 þ  2.3 2.6 1.00 Ref.25–29 5.9 10.4 1.26 (0.92–1.72) 0.144 1.52 (0.82–2.81) 0.18020–24 2.3 3.9 1.45 (0.59–3.58) 0.418HG-CIN d 30 þ  64.9 61.5 1.00 Ref. 52.1 60.9 1.00 Ref.25–29 472.0 603.0 1.10 (1.06–1.14) 0.001 1.34 (1.24–1.45) 0.001 298.7 431.0 1.10 (1.06–1.15) 0.001 1.23 (1.13–1.35) 0.00120–24 432.2 230.7 0.56 (0.51–0.61) 0.001 219.0 310.9 1.21 (1.10–1.33) 0.001 (b) Age groups 20–24, 25–29, 30–34 and 35 þ : cancer cases All stages35 þ  10.6 9.8 1.00 Ref. 15.6 14.8 1.00 Ref.30–34 18.4 25.5 1.21 (1.08–1.34) 0.001 1.51 (1.08–2.13) 0.017 16.0 20.1 1.17 (1.06–1.30) 0.002 1.33 (0.96–1.84) 0.08625–29 12.0 21.0 1.93 (1.28–2.92) 0.002 11.5 19.8 1.82 (1.26–2.65) 0.00220–24 3.4 7.0 2.18 (1.09–4.37) 0.028 2.3 5.9 2.72 (1.31–5.62) 0.007 Abbreviations: CI  ¼  confidence interval; FIGO  ¼  International Federation of Gynecology and Obstetrics; HG-CIN  ¼  high-grade intra-epithelial neoplasia; IRR   ¼  incidence rateratio; Ref.  ¼  reference age group.  a Incidence rate per 100000 women calculated using age group-specific incidence for each year of the study period.  b IRR and Poissonregression to determine whether the relative risk of age groups has differed between two time periods.  c IRR and Poisson regression to determine whether the relative risk of younger age groups differed between two time periods compared with the 30 þ  or 35 þ  years age group (Table 1a and 1b, respectively).  d HG-CIN incidence data for NEavailable up to 2008. Cervical cancer incidence in young women A Patel  et al 1755 &  2012 Cancer Research UK British Journal of Cancer (2012)  106 (11), 1753–1759      C     l     i    n     i    c    a     l     S     t    u     d     i    e    s  cancer incidence rates during the 10-year study period. Incidenceof the more common sexually transmitted infections increasedsubstantially in the NE and Wales (Figures 1A–D): Numbers of episodes of Chlamydia and Herpes nearly doubled in both the20–24 and the 25–34 years age groups in the NE between 2000 and2009, with a significant rise in Wales as well. The number of new episodes of genital warts in the NE also increased by almost 25% inthe 25–34 years age group during the last 10 years. There were nomajor changes observed in the other population risk factors duringthe study period.Poisson regression, AAPC analyses and trends in the incidenceof cervical cancer and HG-CIN incidence in Wales, wherescreening continued from the age of 20 years, are detailed inTables 1 and 2 and Supplementary Figure S4. Poisson regressionand AAPC analyses revealed that the change in incidence of cervical cancer in young women of Wales since 2004 is significant,steady and similar to the NE. While registration of HG-CIN in20–24 years has dramatically and expectedly decreased in the NE,a significant increase is observed in Wales. A rise in HG-CINregistrations in the 25–29 years age group is also substantial andsimilar to the NE. DISCUSSION We identified a significant increase in the incidence of cervicalcancer in young women in the NE since the withdrawal of screening from the 20–24 years age group in 2004. Although this ispredominantly in women aged 25–29 years, there is also evidenceof an increase in women aged 20–24 years. It has been argued thatthe inclusion of stage 1A cervical cancer cases in the incidenceanalyses is likely to overestimate the potential harm of withdrawalof screening (Sasieni  et al  , 2010). We therefore analysed stageIB and higher cancers separately in the NE and still observed asignificant increase in incidence in women aged 25–29 yearsand a trend towards significance in women aged 20–24 years since2004.This does not appear to be a spurious rise in incidence due toincreased screening activity (media coverage/’Jade Goody’ effect),higher registration rates or improved detection after the introduc-tion of liquid-based cytology (LBC). The significant test resultsafter excluding cases from 2009 rules out the effects of mediacoverage. Unregistered cases at the regional cancer registry werecomparatively high during 2005–2007, precluding the possibility that the increased incidence may be related to improvedregistrations. While a meta-analysis of LBC showed up to 12%better sensitivity (NICE, 2003), transition from conventionalcervical cytology to LBC processing across the United Kingdomwas completed in 2008 (NHSCSP, 2008) and most laboratories inthe NE completed the transition by 2006. However, this could notexplain the rise in incidence as this would otherwise have affectedwomen of all ages. Also, if related to LBC, after an initial rise therewould be an expectant decline in rate of detection and theincidence rate would decrease to baseline levels. Table 2  Average annual percentage change (AAPC) in 3-year moving average incidence per 100000 women of cervical cancer and HG-CIN in thenorth-east of England and Wales North-east of England WalesIncidence a Incidence a Cancer andHG-CIN casesAge groups(years) 2000-02 2007-09AAPC(95% CI) 2000-02 2007-09AAPC(95% CI) All stages 20–24 3.4 7.4 12.8 (6.0 to 20.1) 3.5 5.3 11.4 (0.4 to 23.5)25–29 9.5 21.0 11.3 (4.4 to 18.7) 10.3 20.9 12.4 (9.8 to 15.0)20-29 6.5 13.7 10.3 (6.7 to 14.0) 6.9 12.5 11.8 (8.1 to 15.6)30-39 17.1 22.2 3.5 (0.8 to 6.2) 18.8 22.0 1.5 (  2.9 to 6.2)40–49 9.6 9.0 2.7 (  2.9 to 8.6) 17.5 18.0 0.3 (  2.4 to 3.2)50–64 8.8 6.4   4.3 (  5.9 to   2.6) 12.5 12.3   0.5 (  2.8 to 1.9)65 þ  10.4 8.3 1.2 (  0.3 to 2.8) 16.1 15.3   1.3 (  2.7 to 0.1)FIGO 1B þ  20–24 1.4 3.7 20.8 (6.8 to 36.5)25–29 3.8 12.6 13.6 (7.0 to 20.6)20–29 2.6 7.9 15.2 (12.0 to 18.5)30–39 9.9 12.2 1.3 (  1.6 to 4.2)40–49 6.2 7.9 5.4 (2.1–8.9)50–64 7.6 5.7   3.5 (  6.0 to   1.0)65 þ  10.3 8.3   2.8 (  5.5 to 0.0)FIGO 1A 20–24 1.9 3.7 6.8 (  0.5 to 14.6)25–29 5.7 8.4 5.2 (  4.1 to 15.4)20–29 3.8 5.9 5.3 (  3.7 to 15.2)30–39 7.1 10.0 6.5 (1.0 to 12.3)40–49 3.4 1.1   4.5 (  16.5 to 9.3)50–64 1.2 0.7   8.9 (  19.9 to 3.6)65 þ  0.1 0.0   18.6 (  36.9 to 5.1)2000–02 2006–08 b AAPC (95% CI) 2000–02 2007–09 AAPC (95% CI)HG-CIN 20–24 453.7 203.1   12.2 (  14.0 to   10.3) 205.9 363.8 8.4 (6.3 to 10.6)25–29 483.8 611.9 4.3 (3.1 to 5.5) 293.9 511.7 8.8 (6.6 to 10.9)30–39 288.1 298.7 0.9 (  0.2 to 2.0) 175.4 253.4 5.3 (3.5 to 7.1)40–49 91.0 83.7   0.8 (  2.6 to 1.0) 52.7 48.9 6.7 (0.1 to 13.8)50–64 16.4 10.5   7.2 (  9.3 to   5.1) 17.8 23.9 3.9 (  1.1 to 9.2) Abbreviation: CI ¼ confidence interval.  a Three-year average incidence rate per 100000 women.  b Incidence data available up to 2008. Cervical cancer incidence in young women A Patel  et al 1756 British Journal of Cancer (2012)  106 (11), 1753–1759  &  2012 Cancer Research UK   Cl   i   ni    c al    S  t   u d i    e s 
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