Breast cancer is the leading cancer affecting women in Hong Kong, followed by colorectal and lung malignancy.1 The number of new breast cancer cases in Hong Kong has tripled since the 1990s and the lifetime breast cancer risk in women is currently one in 17.1 Among the 12 345 patients studied in the cohort of the Hong Kong Breast Cancer Registry from 2008 to February 2014, 55% were diagnosed with stage II disease or above and 5% of the cohort received neoadjuvant chemotherapy.1 This cohort of patients is estimated to cover approximately 40% of patients reported by the Hong Kong Cancer Registry of the Hospital Authority.

Neoadjuvant chemotherapy has played an increasing role in the management of breast cancer over the last few decades. It was considered at least as effective as postoperative chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) in the National Surgical Adjuvant Breast and Bowel Project B-18 trial.2 Neoadjuvant chemotherapy allows disease down-staging, thus increasing the probability of successful breast-conserving therapy.3 4 In addition, tumour response can be monitored ‘in vivo’ and chemotherapeutic regimens modified accordingly. Studies have also suggested its role in disease prognostication, especially the presence of pathological complete response in highly proliferative tumours.3

The aims of this study were to identify possible tumour characteristics that may benefit from neoadjuvant chemotherapy and to evaluate the effectiveness of neoadjuvant chemotherapy in increasing the rates of breast-conserving surgery in early operable breast cancer.

This was a retrospective study carried out at the Hong Kong Sanatorium & Hospital and approved by the hospital research committee in September 2013; the requirement of patient informed consent was waived because of its retrospective nature. This study was done in accordance with the principles outlined in the Declaration of Helsinki. All patients with breast cancer who underwent neoadjuvant chemotherapy followed by definitive breast surgery from January 2004 to July 2013 were recruited. The choice of definitive breast surgery, either breast-conserving surgery or mastectomy, was determined by an experienced breast surgeon (CSY) and based on the oncological and cosmetic outcome of each patient. Patients who presented with distant metastases and those who underwent neoadjuvant hormonal therapy were excluded. Those who had stage IV disease were also excluded.

Patient records were retrieved from the breast cancer database at the Hong Kong Sanatorium & Hospital and out-patient clinic of one of the authors (CSY) by an independent research assistant who was blinded to the study hypothesis and outcome. All recruited patients had their surgery performed by CSY, who is one of the breast surgery specialists at the hospital. Patients were followed up perioperatively in the out-patient clinic of CSY. Patient demographics, pre-chemotherapy and post-chemotherapy disease staging, tumour characteristics, positron emission tomography–computed tomography findings, and prescribed chemotherapeutic agents were evaluated.

Effectiveness of neoadjuvant chemotherapy was assessed in two ways: presence of pathological complete response and the feasibility of breast-conserving surgery after chemotherapy. Intrinsic tumour characteristics that influenced treatment response were analysed. Tumour size, nodal status, tumour grade, hormonal receptor status, human epidermal growth factor receptor 2 (HER2) receptor status, Ki67 level, and chemotherapeutic agents used were the independent variables in this study. Statistical analysis was performed with SPSS (Windows version 20.0; IBM Corp, Armonk [NY], United States) and a P value of <0.05 was considered statistically significant. Univariate analysis was performed with Student’s t test and Chi squared test where appropriate. Definitions of various terms used in this study are listed in the Appendix.

From January 2004 to July 2013, 2156 patients underwent breast cancer surgery at Hong Kong Sanatorium & Hospital by an experienced breast surgeon (CSY). Stage II or III disease was diagnosed in 48% and 105 (5%) of all patients underwent neoadjuvant chemotherapy. Three patients were excluded due to significant missing data. A total of 102 were ultimately recruited.

Characteristics of patients are summarised in Table 1. Almost all recruited patients had stage II or III disease before commencement of neoadjuvant chemotherapy. Invasive ductal carcinoma constituted more than 90% of all diagnosed breast cancers. One quarter of the recruited patients had triple-negative disease and one third had HER2-positive disease. In our study, 48 patients received sequential anthracycline-taxane-based chemotherapy and 52 received taxane-based chemotherapy only. One patient received four cycles of anthracycline-based chemotherapy only and another patient received gemcitabine and vinorelbine. There were 35 patients prescribed herceptin as part of their neoadjuvant chemotherapy.

After commencement of neoadjuvant chemotherapy, the mean tumour size reduced by more than half, from 4 cm to <2 cm. The HER2-positive group showed a relatively greater tumour size reduction to almost 75% (Fig). On the contrary, the mean tumour size in luminal A breast cancers remained relatively static despite neoadjuvant chemotherapy.

More than 80% of the studied population presented with N1 disease or above. After neoadjuvant chemotherapy, the proportion of patients with N0 disease increased from 15% to 43%. Just over half (51%) of the studied group achieved a reduction in nodal staging following neoadjuvant chemotherapy (Table 2). Similarly, patients with HER2-positive disease or triple-negative disease showed a more significant nodal down-staging after chemotherapy (P=0.007).

Effectiveness of neoadjuvant chemotherapy was determined by the presence of pathological complete response. Pathological complete response was achieved by 23% (n=23) of patients and 60% had a partial tumour response. Among these 23 patients, 18 (78%) had triple-negative disease or HER2-positive disease; oestrogen receptor (ER) status was negative in 14 patients and progesterone receptor (PR) status was negative in 17 patients. Four patients with triple-negative disease or HER2-positive disease had nodal down-staging from N2 or N3. Breast cancers with negative ER status (P=0.039) or negative PR status (P=0.029) had a higher chance of pathological complete response in univariate analysis (Table 3). Other factors including the Ki67 value, tumour grade, and the prescribed chemotherapeutic regimen did not appear to influence the rate of pathological complete response.

Pathological complete response was achieved by 23 patients, of whom 15 (65%) underwent breast-conserving surgery; whereas only 39% of those with partial or no response had breast conservation. Univariate analysis revealed that patients who had pathological complete response following neoadjuvant chemotherapy had a higher chance of successful breast-conserving surgery (P=0.028). Mastectomy was required in eight patients despite a pathological complete response due to pre-chemotherapy large tumour size, extensive carcinoma in situ, or central location of the tumour.

Among those with pathological complete response, 11 (79%) of 14 stage II patients and four (50%) of eight stage III patients eventually had breast-conserving surgery. Patients with stage II disease showed a trend for more breast-conserving surgery after neoadjuvant therapy although this was not statistically significant (P=0.15).

The change of treatment plan after neoadjuvant chemotherapy is shown in Table 4. Before the commencement of neoadjuvant chemotherapy, one quarter of patients (n=26) were scheduled for breast-conserving surgery and three quarters for mastectomy (n=72). After chemotherapy, one third of those scheduled for mastectomy (24 patients) changed to breast-conserving surgery. The number of breast-conserving surgeries increased from 26 to 45, with an increase of 19% of all patients.

After neoadjuvant chemotherapy, 24 patients with planned mastectomy underwent breast-conserving surgery and 48 continued with mastectomy. On the other hand, five patients with planned breast-conserving surgery underwent mastectomy after neoadjuvant chemotherapy as a result of disease progression or patient’s preference (Table 4). Among the 24 patients with successful conversion from mastectomy to breast-conserving surgery, 21 had tumour size of <5 cm and 18 had stage II disease. Pre-chemotherapy disease staging (P=0.001) and tumour size (P=0.005) were important factors that determined successful conversion to breast-conserving treatment in univariate analysis (Table 5). The breast-conserving surgery to mastectomy ratio in patients with stage II disease was 32:14 patients, ie 2.3 to 1. On the contrary, 13 patients with stage III disease underwent breast-conserving surgery and 38 underwent mastectomy, ie a ratio of 1:3 for stage III disease. Among those who underwent breast-conserving surgery, 93% had tumour size of <5 cm. The corresponding proportion in those who underwent mastectomy was 60%. Tumours with size of <5 cm were more likely to be amenable to successful breast-conserving surgery. Other factors including the Ki67 index, tumour grade, and the prescribed chemotherapeutic regimen did not appear to influence the rate of breast-conserving surgery.

Neoadjuvant chemotherapy was introduced in the 1980s as standard treatment for locally advanced breast cancers, defined as stage III disease (and a subset of stage IIB disease).5 6 In the last decade, the use of neoadjuvant chemotherapy has been extended to patients with early operable primary breast cancers with promising results. The aim of this study was to evaluate the response of early operable breast cancers to neoadjuvant chemotherapy and the predictors of good responders.

Efficacy of neoadjuvant chemotherapy and adjuvant chemotherapy has been carefully evaluated in a number of publications. A prospective randomised trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07) recruited 423 breast cancer patients with stage II to III disease and randomised them to neoadjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) or adjuvant CMF.7 The adjuvant CMF group showed superior results in recurrence-free survival, although the OS was similar. Nonetheless, this ‘old’ chemotherapeutic regimen has now mostly been replaced by anthracycline-taxane-based chemotherapy.

With the emergence of newer chemotherapeutic agents, the National Surgical Adjuvant Breast and Bowel Project B-18 published the largest prospective study with the use of AC (doxorubicin and cyclophosphamide).2 Neoadjuvant chemotherapy was at least as effective as adjuvant chemotherapy after a 9-year follow-up. A similar study by the European Organization for Research and Treatment of Cancer published an update after 10 years of follow-up.8 There was no difference in OS or relapses between patients with preoperative and postoperative chemotherapy. Those with neoadjuvant chemotherapy had more breast-conserving treatment. Further subgroup analysis showed a comparable loco-regional recurrence rate between patients initially allocated to receive breast-conserving treatment and those who did after tumour downsizing.8

Meta-analysis of 14 randomised controlled trials that included patients with mostly stage II or III disease showed similar results.9 The loco-regional recurrence rate was also comparable between the two groups. There was a statistically significant decrease in mastectomy rate that favoured neoadjuvant chemotherapy.

In our study, patients with stage II to III disease were further stratified in the subgroup analysis. Stage II disease was considered early operable breast cancer while patients with stage III disease represented those with locally advanced disease. This stratification was in line with the MD Anderson Cancer Centre Classification of locally advanced disease.5 Patients with early operable breast cancer showed comparatively greater benefits following neoadjuvant chemotherapy in terms of the rate of pathological complete response and breast-conserving surgery.

Pathological complete response has been one of the commonly used study endpoints in publications. It has been suggested to correlate with a better long-term outcome. Meta-analysis by Mieog et al9 found improved OS in patients with pathological complete response. The definition of pathological complete response varies from institution to institution, however. In our study, we adopted the definition recognised by the MD Anderson Cancer Centre and in the ABCSG study,10 in which there should be no invasive residual disease in breast or nodes although non-invasive breast residuals are allowed. Studies have shown no difference in DFS or OS between patients with ypT0ypN0 and ypTisypN0 tumours.3 11

Of note, the rate of pathological complete response appears to be different among various intrinsic types of breast cancer.12 In 2005, Rouzier et al13 stratified breast cancer patients into four molecular classes using the genetic profile from a fine-needle aspiration specimen. Patients with basal-like and c-erbB2+ breast cancers had the highest rate of pathological complete response. Age younger than 50 years and ER-negative status were independent variables with a higher likelihood of pathological complete response. In our study, core biopsies with immunohistochemical staining and proliferation index were used to classify patients into luminal A, luminal B, triple-negative, or HER2-positive subgroups and also showed consistent findings.

Carey et al14 described the phenomenon of triple-negative paradox in 2007. Basal-like and HER2+/ER- subtypes were more chemosensitive than their luminal counterparts. They were more likely to have pathological complete response but those with residual disease also had a higher likelihood of relapse and worse outcome. The study by the German Breast Group in 2012 highlighted the impact of pathological complete response on prognosis in different intrinsic subtypes of breast cancer.10 Patients with ypT0N0 tumours had the best DFS (P<0.001) and a trend of better OS. More importantly, pathological complete response was predictive of DFS and OS in highly aggressive tumours only such as those with negative ER or PR status. Patients with HER2-positive or triple-negative tumours did better if they achieved pathological complete response after neoadjuvant chemotherapy. Residual disease in breast and nodes, on the contrary, was associated with worse distant DFS.15

Last but not the least, recent publications have described possible changes in receptor status before and after neoadjuvant chemotherapy although the significance remains controversial.16 In our study, change in ER status was evident in 10% of the study group and that of HER2 in 50%.

The current study has several limitations. First, this was a retrospective study and the database in the earlier period was incomplete with missing information. There were three patients with significant missing information who were excluded from this small study. Second, there may be selection bias as patients chosen for neoadjuvant chemotherapy were subject to surgeon assessment and patient preference. This study represents the experience of neoadjuvant chemotherapy by one experienced breast surgery specialist in one private hospital in Hong Kong. As such, the findings may not apply to other breast cancer patients in public hospitals or in other countries. Third, long-term survival data are not included in the present study, and significance of pathological complete response is not known. Lastly, the number of cases in this study was small, therefore further subgroup analysis in patients with pathological complete response or successful conversion to breast-conserving surgery was not possible. It does not allow further multivariate analysis for controlling potential confounding factors. Future study in this area with a larger sample size may be useful to guide patient selection for systemic treatment of breast cancer in a neoadjuvant setting.

Neoadjuvant chemotherapy has expanded indications from treatment of locally advanced breast cancers to render it operable, to downsizing early operable breast cancers enabling breast-conserving surgery. The current study has shown an increased rate of breast-conserving surgery with neoadjuvant chemotherapy, especially in the early operable group. Negative hormonal status was an independent variable that determined pathological complete response.

All authors have disclosed no conflicts of interest.

1. Hong Kong Breast Cancer Registry Report No. 8. Hong Kong Breast Cancer Foundation. Available from: http://www.hkbcf.org. Accessed Feb 2016.

2. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15:2483-93. Crossref

3. Gampenrieder S, Rinnerthaler G, Greil R. Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future. J Oncol 2013;2013:732047. Crossref

4. Thompson AM, Moulder-Thompson SL. Neoadjuvant treatment of breast cancer. Ann Oncol 2012;23 Suppl 10:x231-6. Crossref

5. Giordano SH. Update on locally advanced breast cancer. Oncologist 2003;8:521-30. Crossref

6. Alassas M, Chu Q, Burton G, Ampil F, Mizell J, Li BD. Neoadjuvant chemotherapy in stage III breast cancer. Am Surg 2005;71:487-92.

7. Taucher S, Steger GG, Jakesz R, et al. The potential risk of neoadjuvant chemotherapy in breast cancer patients—results from a prospective randomized trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07). Breast Cancer Res Treat 2008;112:309-16. Crossref

8. van Nes JG, Putter H, Julien JP, et al. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat 2009;115:101-13. Crossref

9. Mieog JS, van der Hage JA, van de Velde CJ. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg 2007;94:1189-200. Crossref

10. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796-804. Crossref

11. Mazouni C, Peintinger F, Wan-Kau S, et al. Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol 2007;25:2650-5. Crossref

12. Bhargava R, Beriwai S, Dabbs DJ, et al. Immunohistochemical surrogate markers of breast cancer molecular classes predicts response to neoadjuvant chemotherapy: a single institutional experience with 359 cases. Cancer 2010;116:1431-9. Crossref

13. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005;11:5678-85. Crossref

14. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13:2329-34. Crossref

15. Corben AD, Abi-Raad R, Popa I, et al. Pathologic response and long-term follow-up in breast cancer patients treated with neoadjuvant chemotherapy: a comparison between classifications and their practical application. Arch Pathol Lab Med 2013;137:1074-82. Crossref

16. Pedrini JL, Francalacci Savaris R, Casales Schorr M, Cambruzi E, Grudzinski M, Zettler CG. The effect of neoadjuvant chemotherapy on hormone receptor status, HER2/neu and prolactin in breast cancer. Tumori 2011;97:704-10.

Catheter-associated urinary tract infection (CA-UTI) is a major cause of hospital-acquired infection, with local data showing 4.9 infections per 1000 catheter-days.1 Internationally, an estimated 900 000 nosocomial UTIs occur every year, prolonging the mean duration of hospital stay by 1 to 3.8 days. It has been estimated that approximately 80% of UTIs are related to the presence of an indwelling urinary catheter. In severe cases, these infections may lead to bacteraemia, urosepsis, and even mortality.2 3 A case-control study also suggested that patients with CA-UTI had excess costs of US$3803 compared with patients without infection.4 Therefore, by prevention of CA-UTI, a significant reduction in morbidity and mortality, as well as the health care economic burden, can be anticipated.

Bactiguard-coated Foley catheters (Bactiguard, Sweden) were approved by the US Food and Drug Administration in 1994. These catheters have a stable noble metal alloy and hydrogel coating (also referred to as silver alloy and hydrogel–coated, SAH) on the outer- and inner-luminal surfaces of the catheter, providing repellent and anti-infective properties by preventing the formation of microbial biofilm. The coating consists of gold, silver and palladium, and also preserves the urethral mucosal integrity and helps to avoid the onset of inflammation. Previous studies of CA-UTI prevention had asymptomatic bacteriuria (ASB) alone or in combination with symptomatic UTI as the endpoint so their clinical relevance was called into question. We conducted a prospective, interventional study to provide additional data on the effectiveness of the noble metal alloy urinary catheter in the prevention of CA-UTI, using the updated surveillance definition of National Healthcare Safety Network (NHSN) managed by the Centers for Disease Control and Prevention (CDC). This surveillance definition was adopted in 2009 and modified the criteria for symptomatic infection, as well as adding a category and definition for asymptomatic bacteraemic UTI together with the removal of ASB completely.5 To study the effect on ASB, we adopted the criteria used in the Infectious Diseases Society of America practice guideline developed in 2009.6

This single-centre 1-year prospective study was completed in 2012 in a regional rehabilitation hospital in Hong Kong. The study population was in-patients in two medical rehabilitation wards. All patients over 18 years of age on either of the wards during the study period with an indwelling catheter for longer than 24 hours were recruited after giving informed consent. Patients who underwent suprapubic catheterisation, single in-and-out catheterisation for collection of a urine specimen, intermittent catheterisation for urine drainage, catheterisation for less than 24 hours, or who were catheterised with a silicone Foley catheter, and those who had been treated with antibiotics for a UTI were excluded from the study. Both of the study wards rotated through the two different interventions in two 6-month periods in order to act as a self-control to minimise the potential problem of variability in medical and nursing practice that might affect the outcomes. Conventional latex Foley catheters without hydrogel (sized Fr 12, 14, and 16) were used for catheterisation on both wards during the first half of the study period; SAH catheters (sized Fr 12, 14, and 16) were used during the second half of the study period. If a catheter was changed due to the presence of infection, the appropriate catheter according to the month of the study was used. Thus it was possible for patients who required a catheter for a long time and underwent catheter exchange to be exposed to both types of urinary catheter (Fig 1).

The definition of CA-UTI was adopted and modified from the CDC/NHSN definition of symptomatic UTI (Appendix5 6). Routine, regular screening and clinical urine samples were collected from all subjects according to the hospital protocol. Routine urine samples were taken from all subjects at four fixed time-points: on admission, on catheterisation, before removal of the catheter, and before hospital discharge. Screening samples were taken weekly. Clinical samples were taken whenever a patient demonstrated symptoms and signs of UTI, or as part of a sepsis workup. The incidence of CA-UTI in the two groups was analysed in terms of the absolute number of CA-UTI episodes and the number of CA-UTI episodes per 1000 catheter-days. Values were expressed as mean ± standard deviation. Comparison between the two groups was performed by Pearson’s Chi squared test, Student’s t test, and one-way analysis of variance test when appropriate with a two-sided significance level of 0.05. The rate ratio of CA-ASB and CA-UTI between the two groups was compared by exact Poisson test for rate ratio. The occurrence of CA-UTI between the two groups was also analysed with Kaplan-Meier analysis. Results were analysed using the Statistical Package for the Social Sciences (Windows version 21.0; SPSS Inc, Armonk [NY], US) and R version 3.1.2.

This study was done in accordance with the principles outlined in the Declaration of Helsinki.

During the 1-year study period, 306 patients were recruited. The male-to-female ratio was 1:1.13 and the mean age was 81.1 ± 10.5 years (Table 1). Overall, 187 patients used a conventional catheter only, 36 patients used a SAH catheter only, and 83 patients used both a conventional and a SAH catheter (Fig 1).

The total numbers of catheter-days were 4352 and 7474 in the SAH and conventional groups, respectively. The numbers of CA-UTI episodes were 28 and 70, respectively. Thus the incidences of CA-UTI per 1000 catheter-days in the SAH and conventional groups were 6.4 and 9.4, respectively (P=0.095) with a rate ratio of 0.69 (95% confidence interval [CI], 0.42-1.08). There was a 31% reduction in CA-UTI incidence in the SAH group. Using Kaplan-Meier analysis and log-rank test, SAH catheter was associated with a significantly lower rate of CA-UTI (P=0.045; Fig 2). Regarding CA-ASB, the incidences per 1000 catheter-days in the SAH and conventional groups were 70.8 and 67.2, respectively (P=0.467) with a rate ratio of 1.05 (95% CI, 0.91-1.22). Results are summarised in Table 2. Blood cultures were taken from patients who developed CA-UTI. In both groups, none of the patients with CA-UTI developed bacteraemia. Escherichia coli was the most commonly involved urinary pathogen and accounted for 36.7% of all cases, followed by Candida albicans (17.3%) and Proteus mirabilis (14.3%) [Table 3]. The same pathogens were observed in both groups.

This study was not a randomised controlled trial. Thus to eliminate patient selection bias, a subgroup analysis was performed among those patients who used both types of catheter (n=83). These patients had more catheters used and more catheter-days than those patients who used only one type of catheter (Table 4a). This was due to study design where longer-term users had a higher chance of exposure to both types of urinary catheter. Among them, the total numbers of catheter-days were 3210 and 3457 in the SAH and conventional groups, respectively. The numbers of CA-UTI episodes were 17 and 35, respectively. This resulted in the incidences of CA-UTI per 1000 catheter-days in the SAH and conventional groups being 5.3 and 10.1, respectively (P=0.027) with a rate ratio of 0.52 (95% CI, 0.27-0.96). There was a statistically significant reduction of 48% in CA-UTI incidence in the SAH group (Table 4b). Because the catheters were exchanged when an infection occurred, the CA-UTI reducing effect resulted in less need to exchange a SAH catheter—the mean catheterisation time per person was 17.0 days for a SAH catheter compared with 10.8 days for a conventional catheter and 13.6 days for patients using both catheters (Table 4a).

To examine the presence of outcome difference in relation to gender in the entire study population, we also performed a subgroup analysis based on gender differences (Table 4c). In male patients (n=144), the number of CA-UTI episodes was 15 in the SAH group (total catheter-days, 1966) and 33 in the conventional group (total catheter-days, 3529). The incidences of CA-UTI per 1000 catheter-days in the SAH and conventional groups were 7.6 and 9.4, respectively (P=0.551) with a rate ratio of 0.82 (95% CI, 0.41-1.54). For female patients (n=162), the number of CA-UTI episodes was 13 in the SAH group (total catheter-days, 2386) and 37 in the conventional group (total catheter-days, 3945). The incidences of CA-UTI per 1000 catheter-days in the SAH and conventional groups were 5.4 and 9.4, respectively (P=0.108), with a rate ratio of 0.58 (95% CI, 0.28-1.12).

Urinary tract infection is one of the most commonly encountered infections in daily clinical practice and the majority of cases are catheter-related. Although a number of clinical practices such as aseptic technique for catheter insertion, closed drainage systems, and shorter duration of catheterisation have been introduced in an attempt to reduce the onset of CA-UTI, the incidence remains high.3 7 Therefore, research for strategies or new technologies to prevent CA-UTI is still needed. Since the early 1990s, research has focused on different anti-infective catheter-coating materials but results have been generally inconclusive. Bactiguard-coated Foley catheters, an essential noble metal (gold, silver, and palladium) alloy and hydrogel–coated catheter, have been introduced to slow bacterial colonisation.

In the early 2000s, a randomised cross-over study by Karchmer et al8 demonstrated that the risk of UTI could be decreased by 21% on wards and by 32% among patients when a noble metal alloy catheter was used instead of a conventional catheter. Since then, more studies to compare anti-infective urinary catheters with conventional urinary catheters have been carried out. The noble metal alloy indwelling catheter has been shown in multiple large clinical trials and smaller case studies to reduce the incidence of CA-UTI, when compared with conventional catheters.9 10 11 12 13 14 15 These studies have examined endpoints such as bacteriuria and symptomatic CA-UTI, or surveillance-defined UTI.8 16 17 In a study by Pickard et al,17 noble metal alloy catheters were found to be ineffective in reducing the incidence of symptomatic surveillance-defined UTI when used in short-term (mean, 2 days) surgical patients and they did not support the routine use of these catheters in this patient group. Lack of effect is not surprising due to the short catheterisation time and low-risk patient group. In a more recent multicentre cohort study in 2014, Lederer et al4 examined the impact of noble metal alloy catheters on symptomatic CA-UTI and antibiotic use based on the NHSN surveillance and concluded that a 58% relative reduction (P<0.0001) in NHSN-defined CA-UTI rate was observed and 60% fewer antibiotics were used when compared with conventional catheters.

In the present study, we were able to demonstrate a 31% reduction in the incidence of CA-UTI episodes per 1000 catheter-days in the SAH group although it did not reach statistical significance, likely due to too small study groups. We believe that the incidence rate per catheter-days is a more appropriate comparison to reflect the risk of infection associated with different types of catheter as it also takes into account the duration of catheterisation, which is known to be an important factor associated with the incidence of CA-UTI. This is also reflected by the fact that the noble metal alloy catheter can be left in situ for the longest period of time. Although the cost of each SAH catheter (approximately HK$100) is higher than that of a conventional catheter (approximately HK$15), we believe the benefit of longer duration and potential reduction in CA-UTI justify its use.

With subgroup analysis, the effect of a noble metal alloy catheter on reduction of CA-UTI was more prominent in long-term users and female patients. In patients who used both catheters and who served as their own control, a significant reduction (48%, P=0.027) was observed in the SAH group. The same reduction was not observed in those who used only one type of urinary catheter whose number of catheters used and catheter-days were significantly fewer (Table 4a and 4b). We cannot give an exact explanation for this observation but we believe the protective effect of Bactiguard catheters is best seen in patients who require long-term urinary catheterisation. Nonetheless, it must be emphasised that the effect due to mixed use of catheters is unknown. The reduction in CA-UTI was also slightly more prominent in female patients (rate ratio of CA-UTI episodes per 1000 catheter-days, 0.58; Table 4c). Whether these are genuine and significant findings will warrant future randomised controlled studies to confirm.

This study has several limitations. First, this was a non-randomised study with a lack of blinding of outcome observers. Second, some patients might have used both catheters and the effects of each catheter type might have confounded the results. Third, as patients were recruited from a regional rehabilitation hospital, their underlying different medical conditions and risk factors might have affected the outcomes. As patients admitted during the two 6-month periods were incomparable, confounding by underlying risk factors for CA-UTI could not be excluded.

Our findings suggest that SAH-coated catheters may be effective in reducing CA-UTI based on CDC’s NHSN surveillance definition. The effect seems to be more pronounced in high-risk patients such as long-term users and female patients. Future randomised controlled studies on this subject should be carried out based on these pilot data.

All authors have disclosed no conflicts of interest.

1. Kong MY. Systematic review of the effective approach for limiting urinary catheter use and duration to reduce nosocomial catheter-associated urinary tract infections in hospitalized patients. Hong Kong: Faculty of Health and Social Sciences, the Hong Kong Polytechnic University; 2010.

2. Centers for Disease Control. Public health focus: surveillance, prevention, and control of nosocomial infections. MMWR Morb Mortal Wkly Rep 1992;41:783-7.

3. Maki DG, Tambyah PA. Engineering out the risk for infection with urinary catheters. Emerg Infect Dis 2001;7:342-7. Crossref

4. Lederer JW, Jarvis WR, Thomas L, Ritter J. Multicenter cohort study to assess the impact of a silver-alloy and hydrogel-coated urinary catheter on symptomatic catheter-associated urinary tract infections. J Wound Ostomy Continence Nurs 2014;41:473-80. Crossref

5. Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention. The National Healthcare Safety Network manual. Atlanta, GA: Centers for Disease Control and Prevention; 2009.

6. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010;50:625-63. Crossref

7. Salgado CD, Karchmer TB, Farr BM. Prevention of catheter-associated urinary tract infection. In: Wenzel RP, editor. Prevention and control of nosocomial infections. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003: 297-311.

8. Karchmer TB, Giannetta ET, Muto CA, Strain BA, Farr BM. A randomized crossover study of silver-coated urinary catheters in hospitalized patients. Arch Intern Med 2000;160:3294-8. Crossref

9. Gentry H, Cope S. Using silver to reduce catheter-associated urinary tract infections. Nurs Stand 2005;19:51-4. Crossref

10. Newton T, Still JM, Law E. A comparison of the effect of early insertion of standard latex and silver-impregnated latex foley catheters on urinary tract infections in burn patients. Infect Control Hosp Epidemiol 2002;23:217-8. Crossref

11. Gould CV, Umscheid CA, Agarwal RK, Kuntz G, Pegues DA; Healthcare Infection Control Practices Advisory Committee. Guideline for prevention of catheter-associated urinary tract infections 2009. Infect Control Hosp Epidemiol 2010;31:319-26. Crossref

12. Schumm K, Lam TB. Types of urethral catheters for management of short-term voiding problems in hospitalized adults: a short version Cochrane review. Neurourol Urodyn 2008;27:738-46. Crossref

13. Seymour C. Audit of catheter-associated UTI using silver alloy-coated Foley catheters. Br J Nurs 2006;15:598-603. Crossref

14. Rupp ME, Fitzgerald T, Marion N, et al. Effect of silver-coated urinary catheters: efficacy, cost-effectiveness, and antimicrobial resistance. Am J Infect Control 2004;32:445-50. Crossref

15. Verleyen P, De Ridder D, Van Poppel H, Baert L. Clinical application of the Bardex IC Foley catheter. Eur Urol 1999;36:240-6. Crossref

16. Johnson JR, Kuskowski MA, Wilt TJ. Systematic review: antimicrobial urinary catheters to prevent catheter-associated urinary tract infection in hospitalized patients. Ann Intern Med 2006;144:116-26. Crossref

17. Pickard R, Lam T, MacLennan G, et al. Antimicrobial catheters for reduction of symptomatic urinary tract infection in adults requiring short-term catheterisation in hospital: a multicentre randomised controlled trial. Lancet 2012;380:1927-35. Crossref

Lewy body dementia (LBD) includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).1 Pathological hallmarks of LBD include α-synuclein neuronal inclusions (Lewy bodies and Lewy neurites) with subsequent neuronal loss.1 The difference between DLB and PDD lies in the sequence of onset of dementia and parkinsonism, although syndromes and pathological changes become similar with progression.1 2 Thus, they are regarded as a continuum instead of two separate entities. In western studies, approximately 10% to 15% of patients with dementia had DLB.1 In contrast, only 3% of 1532 patients with dementia followed up at the memory clinic of Queen Mary Hospital in Hong Kong had LBD (unpublished data). It is likely that LBD remains under-recognised among the Chinese population.

Compared with autopsy, sensitivity and specificity for clinical diagnosis of DLB have been reported to be 32% and 95%, respectively.1 In our memory clinic, 50% of DLB patients were initially misdiagnosed (mostly as Alzheimer’s disease [AD] in 75% of cases).3 There has been only one case series of 35 Chinese DLB patients and diagnosis was based mainly on clinical criteria.4 The presence of occipital hypometabolism on [¹⁸F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (¹⁸FDG-PET) has a sensitivity of 90% and specificity of 71% to 80% in differentiating AD and DLB patients.5

Pathologies of AD are common in DLB patients; 35% of patients with Parkinson’s disease fulfil the pathological diagnostic criteria of AD, while deposition of amyloid plaques is present in approximately 85% of DLB patients.6 A meta-analysis revealed a positive amyloid scan in 57% and 35% of patients with DLB and PDD, respectively.5 A higher cortical amyloid burden has been associated with greater cortical and medial temporal lobe atrophy in LBD patients.6 Significant cortical amyloid burden may accelerate the cognitive decline in LBD patients, suggesting the possibility of a synergistic contribution of AD pathologies to LBD dementia.6 On ¹⁸FDG-PET, apart from bilateral occipital hypometabolism, some LBD patients also demonstrate an AD pattern of hypometabolism, ie temporoparietal, posterior cingulate gyrus or precuneus hypometabolism (Fig).7 In a recent study comparing 12 patients with DLB and an AD pattern of hypometabolism on ¹⁸FDG-PET with 11 patients with DLB and no AD pattern of hypometabolism, the former had a higher prevalence of visual hallucinations and extracampine hallucination.7 As far as we are aware, an AD pattern of functional imaging has not been studied in Chinese patients with DLB.

In contrast with AD, the clinical features of patients with DLB are unfamiliar to the general public. In a recent study that involved 125 carers of LBD patients, 82% to 96% expressed a wish to have information and support about visual hallucinations, changes in the brain and the body, and ways to cope with behavioural changes.8 Unfortunately clinical studies of LBD among the Chinese population are limited and none has examined the long-term outcomes of LBD, including falls, dysphagia, aspiration pneumonia, pressure sores, mortality, and behavioural and psychological symptoms of dementia (BPSD).

Based on a review of the clinical records of all LBD patients followed up in our memory clinic, the current study aimed to review the presenting clinical features and identify risk factors for long-term outcomes including falls, dysphagia, aspiration pneumonia, pressure sores, and mortality in Chinese patients with LBD. It was hoped that this would provide useful clinical information for carers of such patients. We also wished to identify any difference in clinical features of LBD patients with and without an AD pattern of functional imaging. We hypothesised that LBD patients with an AD pattern of functional imaging would have a young age at presentation or diagnosis due to concomitant AD pathologies.

This was a retrospective case series of Chinese LBD patients. The case records of Chinese patients with LBD who attended a memory clinic at Queen Mary Hospital between 1 January 2007 and 31 December 2015 were reviewed. This study was done in accordance with the principles outlined in the Declaration of Helsinki. Probable DLB was diagnosed according to McKeith criteria2 (Table 11 2). Probable PDD was diagnosed according to the following: the patient should meet the diagnostic criteria of Queen Square Brain Bank criteria with dementia developing in the context of established Parkinson’s disease with cognitive impairment in more than one domain and severe enough to impair daily life (Table 11 2). The differentiation between DLB and PDD was based on temporal sequence of symptoms—for DLB, dementia developed before or within 1 year of parkinsonism (ie the clinical syndrome characterised by tremor, bradykinesia, rigidity, and postural instability); for PDD, dementia developed more than 1 year after the established diagnosis of Parkinson’s disease.1 All patients underwent functional imaging in the form of ¹⁸FDG-PET or technetium-99m hexamethylpropylene amine oxime single-photon emission computed tomography (SPECT) that would show either hypometabolism or hypoperfusion of the occipital lobes, respectively. Data on baseline demographics, baseline and first-year Mini-Mental State Examination (MMSE) score,9 Clinical Dementia Rating (CDR) score,10 age-adjusted Charlson Comorbidity Index,11 baseline Neuropsychiatric Inventory (NPI) score,12 baseline Barthel index–20,13 presenting cognitive symptoms, and BPSD were derived from clinical records. ‘Time to diagnosis’ was defined as the difference between the date of first presentation to the memory clinic and the date of first diagnosis of LBD. Patients with DLB were further classified as having an ‘AD imaging pattern’ if the functional imaging demonstrated bilateral temporoparietal hypometabolism or hypoperfusion with or without precuneus and posterior cingulate gyrus hypometabolism or hypoperfusion (Fig).7 14

Clinical outcomes including falls, dysphagia, aspiration pneumonia, development of pressure sores, and mortality were traced. For patients with a history of falls, geriatric day hospital (GDH) training was traced including the pre-/post-training Elderly Mobility Scale15 and Berg Balance Scale.16 Parkinsonism medication was often titrated at the GDH. Dysphagia was further subclassified as oral or pharyngeal according to the clinical assessment by a speech therapist (ST) or, if available, a video fluoroscopic swallowing study (VFSS).17 Penetration was defined as barium material entering the airway but not passing below the vocal cords; aspiration was defined as barium material passing below the level of the vocal cords.18 The locations of pressure sores and staging, according to National Pressure Ulcer Advisory Panel,19 were recorded. ‘Time to event’ was defined as the difference between the date of diagnosis and first appearance of these events.

Parametric variables were expressed as mean ± standard deviation and non-parametric variables were expressed by median (interquartile range [IQR]). Descriptive statistics were used to express the frequency of defining features of LBD. Chi squared test or Fisher’s exact test was used to compare categorical variables. Independent-samples t test or Mann-Whitney U test were used to compare continuous variables when appropriate. Statistical significance was inferred by a two-tailed P value of <0.05. All statistical analyses were carried out using the Statistical Package for the Social Sciences (Windows version 18.0; SPSS Inc, Chicago [IL], United States).

There were 23 patients with LBD (16 with DLB and 7 with PDD). The mean age at presentation was 76 ± 7 years and the mean MMSE score at presentation was 19 ± 7 with a total duration of follow-up of 72 patient-years (mean follow-up, 1138 ± 698 days). The baseline demographics of the patients are summarised in Table 2. There was no statistically significant difference in baseline demographics between DLB and PDD patients. The time to diagnosis appeared to be longer but not statistically significant for PDD patients, possibly due to very small numbers in the two groups. The overall accuracy of diagnosis was 52%. Six (38%) of the 16 DLB patients were initially misdiagnosed as AD. The frequency of defining clinical characteristics of LBD among DLB and PDD patients is summarised in Table 3. There were no statistically significant differences (results not shown). Of note, 69% of DLB patients presented with parkinsonism and 74% of LBD patients had vivid visual hallucinations. Information about the content of visual hallucinations was available for 14 of 17 patients: 50% (n=7) involved persons, 7% (n=1) involved objects, 21% (n=3) a combination of persons and animals, 7% (n=1) a combination of insects and animal, 7% (n=1) a combination of insects and objects, and 7% (n=1) a combination of animal and objects. An NPI score was available for 78% (18/23) at baseline, of whom 83% (15/18) had a score of ≥1, and 78% (14/18) had at least one NPI subcategory rated as severe, ie ≥4. The three most common BPSD as indicated by a NPI score of ≥1 were visual hallucination (56%), anxiety (50%), and apathy (50%). There was no significant difference in BPSD in terms of NPI score for DLB and PDD patients (results not shown).

Of the patients, 16 (70%) had a total of 23 falls (all non-syncopal) with four complicated by bone fractures and two associated with intracerebral haemorrhage. The event rate was 0.32 per person-years. Ten patients underwent GDH training after their fall(s). The median time to first GDH training (from the time of diagnosis) was 56 (IQR, 56-663) days with a mean time of 93 ± 44 days. Paired-samples t test did not identify any significant pre-/post-training difference in Elderly Mobility Scale15 or Berg Balance Scale16 scores (10 ± 4 vs 11 ± 5, P=0.81 and 25 ± 13 vs 25 ± 14, P=1.0, respectively). Comparison of LBD patients with and without a fall history revealed no significant difference in clinical features (including visual hallucination, parkinsonism, and fluctuation of consciousness) or medication (including benzodiazepine or antipsychotics) [results not shown]. Parkinsonism was numerically more prevalent among fallers (88% vs 57%; P=0.14).

Of the patients, six (26%) had a total of 13 episodes of pneumonia, and 12 (52%) had dysphagia. The mean time to first episode of aspiration pneumonia was 866 ± 689 days (median, 634; IQR, 315-1456 days; n=6) and to first diagnosis of dysphagia 951 ± 734 days (median, 862; IQR, 311-1624 days; n=12). Five patients underwent VFSS (time to VFSS: 831 ± 728; median, 723; IQR, 154-1562 days). Three of four patients with penetration developed aspiration pneumonia; both patients with aspiration on VFSS developed aspiration pneumonia. The event rates were 0.17 and 0.18 per person-years for dysphagia and aspiration pneumonia, respectively. Patients with LBD with a history of aspiration pneumonia compared with those without were more likely to have been identified by the ST to have dysphagia (100% vs 35%; P=0.01), oral dysphagia (83% vs 29%; P=0.04), pharyngeal dysphagia (83% vs 29%; P=0.04), or dysphagia that required Ryle’s tube insertion (67% vs 12%; P=0.02) [Table 4].

Six (26%) patients developed pressure sores with four over the sacrum and two over the heel (two in stage 1, two in stage 3, and two in stage 4). The mean time to development of pressure sore was 978 ± 599 days (median, 994; IQR, 379-1528 days). The event rate was 0.08 per person-years. A comparison between LBD patients with or without pressure sores did not identify any significant difference in clinical features (results not shown).

Seven (30%) patients died of various diseases: three (43%) of pneumonia, two (29%) of unexplained cardiac arrest (UCA), and one (14%) each of pressure sore sepsis and choking. The mean time to death was 894 ± 617 days (median, 798; IQR, 312-1597 days). The event rate was 0.10 per person-years. Deceased patients with LBD, compared with alive patients, scored a higher presenting CDR (median [IQR]: 1 [1-2] vs 0.5 [0.5-1.0]; P=0.01), lower mean baseline Barthel index (13 ± 7 vs 18 ± 4; P=0.04), and were more likely to have been prescribed levodopa (86% vs 31%; P=0.03).

Of the patients, 19 underwent ¹⁸FDG-PET and four underwent perfusion SPECT imaging. Twelve patients (9 DLB and 3 PDD) had an AD pattern of functional imaging: all 12 had bilateral temporoparietal lobe hypometabolism/hypoperfusion; three patients concomitantly had hypoperfusion/hypometabolism over the posterior cingulate gyrus and one patient had additional hypometabolism over the precuneus. Patients with LBD with an AD pattern of functional imaging compared with those without were younger at presentation (73 ± 6 vs 80 ± 6 years; P=0.02) and had a lower MMSE score at 1 year (15 ± 8 vs 22 ± 6; P=0.05). There was no difference in the presentation of visual hallucination between the two groups of patients (Table 5).

An accurate diagnosis of LBD is important. It allows prescription of acetylcholinesterase inhibitors or avoidance of antipsychotics in view of the risk of neuroleptic sensitivity. An overall accuracy of clinical diagnosis of 52% in our study is similar to findings in western studies, eg 62% by a neurologist.20 Our results reveal that no single diagnostic criteria or test is infallible and the diagnosis needs follow-up review and support from functional imaging when appropriate. In our series, 38% of DLB patients were initially misdiagnosed as AD. This is thought to have been related to the presence of amnesia in all patients at initial presentation: only 69% of DLB patients presented with parkinsonism. There was no difference in the clinical features of DLB and PDD patients. Braak et al21 have proposed a pathological staging of Parkinson’s disease with Lewy body pathology starting in the dorsal IX/X motor nucleus or adjoining intermediate reticular zone, and spreading rostrally in the brainstem then to the limbic system and subsequently to the neocortex with the underlying mechanism being the spread of α-synuclein from cell to cell. This might explain why DLB and PDD can progress and later overlap clinically.

Compared with the previous literature review of Chinese LBD case reports (1980-2012) by Han et al4 including 31 DLB and four PDD patients with a younger mean age of onset (67 ± 10 years), more patients in our series presented with cognitive decline (100% vs 60%), parkinsonism (78% vs 9%), visual hallucinations (74% vs 9%), and rapid eye movement sleep behaviour disorder (48% vs 11%). These differences may be related to the heightened awareness of the core features of LBD among Chinese doctors in recent years or because patients in our series presented at a more advanced stage of dementia (Han et al4 did not state the severity of dementia). Nonetheless, both case series reported similar rates of postural hypotension (9% vs 3%) and BPSD (83% vs 86%).4 The rate of postural hypotension in both case series is much lower than that reported in other literature on DLB patients, ie 50%.22 The lower rates of postural hypotension may be related to under-recognition. Similar to our findings, in a study of 22 Chinese DLB patients (mean age, 74 ± 8 years; mean MMSE score, 16 ± 7; mean NPI score, 24 ± 16), three most commonly observed BPSDs were visual hallucinations (86%), delusions (64%), and anxiety (59%); total NPI score was an independent predictor of caregiver burden (odds ratio=1.537; P=0.048).22 Clinicians should pay particular attention to BPSD, particularly visual hallucinations and anxiety symptoms, when managing Chinese LBD patients.

In addition, falls, dysphagia, and pressure sores can contribute to carer stress but they were not included in previous studies of LBD patients.23 24 Nearly 70% of our LBD patients experienced falls. This rate is greater than the previously reported rates of 11% to 44%.25 26 Although visuospatial impairment, cognitive fluctuation, parkinsonism, or visual hallucinations were proposed as possible mechanisms that contributed to falls, only parkinsonism was identified in one study of 51 AD and 27 DLB patients as an independent risk factor.25 26 Because of the limited sample size, no significant risk factors could be identified in our series. With regard to the finding of limited improvement in mobility after GDH training, it is likely that many factors affect the mobility of LBD patients. These factors include dementia, postural hypotension, and poor balance from disease. Clinicians should alert carers of the risk of falls and offer advice about general measures for falls prevention, including addressing environmental risk factors and use of safety alarms. Compared with Londos et al’s finding17 that 29% of 82 LBD patients (median age, 77 years; median MMSE score, 20) had dysphagia on VFSS, we reported a higher rate of 52%. When identified by STs, LBD patients and their carers should be given advice about diet modification (eg use of thickeners) and postural changes (eg chin tuck). In addition, clinicians should titrate the levodopa dose as far as possible.27

Given that LBD is an irreversible neurodegenerative disease, advance care planning (ACP) forms a major part of care.28 Our data for dysphagia, aspiration pneumonia, pressure sores, and mortality can offer useful information during ACP for Chinese LBD patients. Since those patients who have died had a higher presenting CDR score, lower Barthel Index, and greater usage of levodopa (which probably reflects more severe parkinsonism), ACP should be initiated earlier in LBD patients with these features. It has been reported that LBD patients can have UCA and in our series two (28.6%) patients died of UCA. Unexplained cardiac arrest is proposed to be related to pathological involvement of the intermediolateral columns of the spinal cord, autonomic ganglia, and sympathetic neurons, affecting either respiration or heart rhythm.29 Such risk of UCA should be explained during ACP. Presence of hypometabolism/hypoperfusion over the temporoparietal lobes/precuneus/posterior cingulate gyrus was used as surrogate markers of concomitant AD pathologies in our LBD patients. As far as we are aware, this is the first study to show that concomitant AD pathologies among Chinese LBD patients can result in an early age of presentation or diagnosis and lower MMSE score at 1 year. Our findings provide further evidence of the synergistic contribution of AD pathologies to LBD dementia.6

This study has several limitations. It was a single-centre retrospective case series, therefore, we considered clinical features only as present or absent when clearly stated as such. This might have affected our results. Pathological diagnosis was not obtained including pathological proof of concomitant AD pathologies. Since all subjects were recruited from the memory clinic, LBD patients who present to a psychiatric clinic may be different, eg with more BPSD or visual hallucinations. The severity of parkinsonism was not graded so the influence of parkinsonism on long-term outcomes such as falls or aspiration pneumonia was not fully analysed. Although our case series comprised the largest number of Chinese patients with LBD supported by functional imaging, the number remained limited. Our findings should be confirmed by a larger study with Pittsburgh compound B imaging to delineate the concomitant presence of amyloid plaques.

Falls, dysphagia, aspiration pneumonia, and pressure sores were common among LBD patients. Lewy body dementia patients with an AD pattern of neuroimaging had an earlier age of diagnosis or presentation and lower 1-year MMSE scores. Such information is useful in the formulation of a management plan for Chinese LBD patients.

All authors have disclosed no conflicts of interest.

1. Walker Z, Possin KL, Boeve BF, Aarsland D. Lewy body dementias. Lancet 2015;386:1683-97. Crossref

2. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology 2005;65:1863-72. Crossref

3. Shea YF, Ha J, Lee SC, Chu LW. Impact of ¹⁸FDG PET and ¹¹C-PIB PET brain imaging on the diagnosis of Alzheimer’s disease and other dementias in a regional memory clinic in Hong Kong. Hong Kong Med J 2016;22:327-33.

4. Han D, Wang Q, Gao Z, Chen T, Wang Z. Clinical features of dementia with lewy bodies in 35 Chinese patients. Transl Neurodegener 2014;3:1. Crossref

5. Valkanova V, Ebmeier KP. Neuroimaging in dementia. Maturitas 2014;79:202-8. Crossref

6. Gomperts SN. Imaging the role of amyloid in PD dementia and dementia with Lewy bodies. Curr Neurol Neurosci Rep 2014;14:472. Crossref

7. Chiba Y, Fujishiro H, Ota K, et al. Clinical profiles of dementia with Lewy bodies with and without Alzheimer’s disease-like hypometabolism. Int J Geriatr Psychiatry 2015;30:316-23. Crossref

8. Killen A, Flynn D, De Brún A, et al. Support and information needs following a diagnosis of dementia with Lewy bodies. Int Psychogeriatr 2016;28:495-501. Crossref

9. Chiu FK, Lee HC, Chung WS, Kwong PK. Reliability and validity of the Cantonese version of Mini-Mental State Examination: a preliminary study. J Hong Kong Coll Psychiatr 1994;4(2 Suppl):S25-8.

10. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;43:2412-4. Crossref

11. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-83. Crossref

12. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308-14. Crossref

13. Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: a reliability study. Int Disabil Stud 1988;10:61-3. Crossref

14. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:263-9. Crossref

15. Smith R. Validation and reliability of the Elderly Mobility Scale. Physiotherapy 1994;80:744-7. Crossref

16. Berg KO, Wood-Dauphinee SL, Williams JI, Maki B. Measuring balance in the elderly: validation of an instrument. Can J Public Health 1992;83 Suppl 2:S7-11.

17. Londos E, Hanxsson O, Alm Hirsch I, Janneskog A, Bülow M, Palmqvist S. Dysphagia in Lewy body dementia—a clinical observational study of swallowing function by videofluoroscopic examination. BMC Neurol 2013;13:140. Crossref

18. Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. Dysphagia 1996;11:93-8. Crossref

19. National Pressure Ulcer Advisory Panel. NPUAP pressure injury stages. Available from: http://www.npuap.org/resources/educational-and-clinical-resources/npuap-pressure-injury-stages/. Accessed 7 May 2016.

20. Galvin JE. Improving the clinical detection of Lewy body dementia with the Lewy body composite risk score. Alzheimers Dement (Amst) 2015;1:316-24. Crossref

21. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24:197-211. Crossref

22. Takemoto M, Sato K, Hatanaka N, et al. Different clinical and neuroimaging characteristics in early stage Parkinson’s disease with dementia and dementia with Lewy bodies. J Alzheimers Dis 2016;52:205-11. Crossref

23. Liu S, Jin Y, Shi Z, et al. The effects of behavioral and psychological symptoms on caregiver burden in frontotemporal dementia, Lewy body dementia, and Alzheimer’s disease: clinical experience in China. Aging Ment Health 2016 Feb 16:1-7. Epub ahead of print. Crossref

24. Leggett AN, Zarit S, Taylor A, Galvin JE. Stress and burden among caregivers of patients with Lewy body dementia. Gerontologist 2011;51:76-85. Crossref

25. Imamura T, Hirono N, Hashimoto M, et al. Fall-related injuries in dementia with Lewy bodies (DLB) and Alzheimer’s disease. Eur J Neurol 2000;7:77-9. Crossref

26. Kudo Y, Imamura T, Sato A, Endo N. Risk factors for falls in community-dwelling patients with Alzheimer’s disease and dementia with Lewy bodies: walking with visuocognitive impairment may cause a fall. Dement Geriatr Cogn Disord 2009;27:139-46. Crossref

27. Alagiakrishnan K, Bhanji RA, Kurian M. Evaluation and management of oropharyngeal dysphagia in different types of dementia: a systematic review. Arch Gerontol Geriatr 2013;56:1-9. Crossref

28. Jethwa KD, Onalaja O. Advance care planning and palliative medicine in advanced dementia: a literature review. BJPsych Bull 2015;39:74-8. Crossref

29. Molenaar JP, Wilbers J, Aerts MB, et al. Sudden death: an uncommon occurrence in dementia with Lewy bodies. J Parkinsons Dis 2016;6:53-5. Crossref

The combined oral contraceptive (COC) pill is an effective contraception. It has a very low-risk profile documented over several decades and its protective effect on endometrial and ovarian carcinoma has been well established.1 It is also an effective treatment for menstrual problems and polycystic ovarian syndrome,2 3 which are common in adolescents.4 5 6 7 The prevalences of menorrhagia, dysmenorrhoea, and menstrual symptoms in adolescent girls have been reported to be 17.9%, 68.7%, and 37.7%, respectively.4 The prevalence of polycystic ovarian syndrome in adolescent girls has been reported to be 16% in those who attended a local paediatric and adolescent gynaecology clinic.5 Nonetheless, the use of COC pills in Chinese women has remained low; only 1% of women of reproductive age (20-49 years) in China used the pills in 2010.8 There are some obstacles to access although family planning is a relatively well-funded area of health care in China and has been implemented for decades. In Hong Kong, the situation is slightly less unusual. From an online survey conducted in Hong Kong, 12.6% of women had used an oral contraceptive in the year prior to the survey, but many of them had stopped using it.9 According to the annual report of the Family Planning Association of Hong Kong in 2014-2015, 22% of the 48 363 clients who practised birth control, including women who were both married and unmarried, used an oral contraceptive.10 Only 6% of teenage girls who attended the youth health care centres used COC pills for contraception.11

Although sex education has been integrated into the primary and secondary educational curriculum for many years, efforts to provide quality sex education have been limited.12 According to a survey conducted by the Hong Kong SAR Government, sex education at the junior secondary school level is limited to an average of 3 to 4 school hours only.13 Sometimes concepts emphasised included protection of self and avoidance of sex, especially prior to marriage.14 The median age of marriage in Hong Kong is now close to 30 years. It is notable that Hong Kong has a high rate of therapeutic abortion that is underestimated by official statistics because an indeterminate proportion is performed in mainland China due to cost considerations. In women attending for their antenatal visit, a high proportion of 36.5% reported a previous therapeutic abortion (unpublished data from our institute). This suggests that women of reproductive age may not have been educated about contraception. There is little published information on the use of COC pills for the management of menstrual problems in Hong Kong but it is likely to be low. Misconceptions and myths about COC pills are likely to be the main obstacles to use. Although extensive high-quality information about use of COC is currently available from various sources, many women remain unaware of the non-contraceptive benefits of COC. They also have little awareness of the risks of COC.15 For female adolescents, their decision about whether to use COC is likely to be influenced by their parents, especially their mothers, who may be giving advice to their daughters based on little or erroneous knowledge. This may lead mothers to make decisions that are not in their daughter’s best interests.

Focused education about COC may lead to a more balanced view, both in adolescents and their mothers. In a study of Korean and Japanese university students, significant correlation between knowledge of and positive attitude towards COC pills was reported.16 Mothers in Asia are also often involved in their teenage daughters’ decision to begin sexual relationships, the use of contraceptives, and even vaccination.17 18 Since the mothers’ attitude may affect use of COC by their daughters, we explored Chinese mothers’ knowledge of and attitudes towards such use. Mothers’ knowledge about the COC pills and factors affecting their attitude were also evaluated.

The study was conducted from October 2012 to March 2013 in the gynaecology clinic of a tertiary teaching hospital in Hong Kong. Women who attended the clinic or accompanied a daughter to the clinic, and who had one or more daughters aged 10 to 18 years were recruited. Women who did not speak or read Chinese were excluded. The participants completed a 41-item questionnaire to assess their knowledge of and attitude towards use of COC pills by their daughters. Firstly, they were asked to self-assess their own knowledge of the COC pill. The knowledge domain consisted of 19 items testing their knowledge of the non-contraceptive health benefits and side-effects of COC pills, and three items on contra-indications to use of COC pills. For each item, participants were asked to respond “yes”, “no”, or “don’t know”. They were then asked about their attitudes to the use of COC pills by their daughters aged 10 to 18 years for the management of dysmenorrhoea, menorrhagia, acne, or as a contraceptive. They were asked to respond from “strongly agree”, “agree”, “disagree”, to “strongly disagree”. Reasons for agreeing or disagreeing with the use of COC pills and the appropriate age or life-events for using COC pills by their daughters were also asked. Finally, demographic data and their personal experience in using COC pills were collected. Knowledge score and uncertainty score were calculated for the participants based on their response15 16—knowledge score was defined as the score of correct answers with 1 score given for each correct answer (ie range from 0-22); a “don’t know” reply would create the uncertainty score. The participants provided written informed consent, and approval was obtained from the local ethics committee (CRE-2012.186).

Descriptive statistics were used to summarise participants’ demographic information. Association between participant characteristics and overall attitude was explored using Chi squared and independent-samples t test. A P value of <0.05 was considered statistically significant. All statistical analyses were conducted using the SPSS (Windows version 18.0; SPSS Inc, Chicago [IL], United States). Assuming that 50% of the women accepted the use of COC pills by their daughters with an accepted error of 0.05%, 278 women were required. An additional 10% was recruited to prepare for an incomplete questionnaire.

Apart from 150 women who were excluded because they did not have a daughter aged 10 to 18 years, a total of 317 women were invited to participate; 302 agreed and 300 (94.6%) completed the questionnaire. Demographic characteristics of the participants are shown in Table 1. Their mean age was 45.2 years (range, 28-58 years). The median number of daughters was one and most participants (88.3%) were married. Most (>70%) had high school education. In all, 125 (41.7%) were ever-users of COC pills, including both current and ex-users. Overall, 175 (58.3%) reported that they had knowledge about the COC pills, while 125 (41.7%) reported no knowledge.

The rates of giving correct answers about the COC pill and the comparison between ever- and never-users of COC pills are shown in Table 2. Of a total possible score of 22, the mean (± standard deviation) knowledge score of all the participants was 5.0 ± 4.7. Of all the participants, only approximately 20% of the mothers correctly answered that COC pills would not cause carcinoma of ovary and corpus; 26.0%, 29.7%, and 30.3% respectively correctly answered that COC pills did not have proven teratogenicity, cause pelvic inflammatory disease and infertility; 10.3% knew that COC pills would not cause weight gain and 25.7% answered that COC pills would not lead to a depressive mood. In all, 43.3%, 33.0%, and 25.3% knew that COC pills had the benefits of regulating the menstrual cycle, decreasing menstrual flow, and helping to relieve dysmenorrhoea, respectively. Moreover only 20% knew that the COC pills are not contra-indicated in people with a family history of breast cancer but is contra-indicated in thromboembolism. The knowledge score of the 175 women who responded to have knowledge of the COC pills was significantly higher than those who reported lack of knowledge (8.0 ± 4.4 vs 3.0 ± 3.7; P<0.001). Among those who declared they had knowledge about the use of COC pills, their sources of knowledge were from medical professional (63.3%), media (30.3%), friends (24.6%), family members (6.9%), school (2.9%), and others (1%).

The rate of responding “uncertain” to the health benefit, side-effects, or contra-indications of COC use ranged from 43.7% to 71.0% for each item. The mean uncertainty score among all participants was 13.0 ± 7.6. The uncertainty score was significantly higher in participants who reported to have lack of knowledge when compared with those reported to have knowledge about COC pills (15.6 ± 7.1 vs 9.1 ± 6.7; P<0.001).

Among the ever-users, 43 (34%), five (4%), and 96 (77%) women reported that COC pills had been used to manage their own menstrual problems, acne problems, and as contraception, respectively. Table 3 lists the participants’ acceptance rate of COC use by their daughters in different gynaecological conditions and the comparison between ever- and never-users of COC pills. More ever-users than never-users accepted the use of COC for their daughter’s gynaecological indications. Participants who accepted their daughter’s use of COC also had a higher knowledge score and lower uncertainty score (Table 4). Table 5 shows the participants’ reasons for accepting use of COC pills by their daughters. Recommendation by medical professionals was the major reason, followed by the knowledge that COC pills provided effective contraception.

Age, education level, and whether they had previous experience of side-effects of COC pills were not associated with participants’ acceptance of COC use by their daughters. Among the 125 ever-users of COC pills, 65 (52.0%) reported they had experienced side-effects, including weight gain (n=45), fluid retention (n=25), headache (n=12), increase in appetite (n=8), mode disturbance (n=8), and acne (n=4). Table 6 lists the reasons for disagreement with the use of COC pills by their daughters for menstrual problems. Finally, only 71 (23.6%) participants thought that the use of COC pills was appropriate in girls aged 12 to 18 years.

Our study highlights a notable lack of knowledge about the use of COC pills in many Hong Kong Chinese mothers. Many were uncertain or had erroneous beliefs about the use of COC pills. They believed that such usage would lead to cancers, fetal deformity, and cause infertility and pelvic inflammatory disease. These misconceptions and uncertainties may further reinforce their non-acceptance of the COC pills as an appropriate medication for their daughters. This inevitably often leads to suboptimal treatment for their daughters.

Fear of increased risk of cancer is an important reason for low acceptance of COC pills and only 22% of our participants thought it did not increase the risk for carcinoma of ovary or uterus. More than 60% of the participants were uncertain about the risk of cancer with the use of COC pills (results not shown). Research has shown that contraceptives have a significantly protective effect on carcinoma of ovary and corpus uteri.19 20 In fact, a collaborative re-analysis of individual data from 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies revealed that while women were taking COC pills and in the 10 years after stopping, there was a small increase in the relative risk of breast cancer.21 There was, however, no significant excess risk of having breast cancer diagnosed ≥10 years after stopping use of COC pills. The breast cancer incidence rises steeply with age. The estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use. The estimated excess number of breast cancers diagnosed up to 10 years after stopping use from the age of 16 to 19 years among 10 000 women has been reported to be 0.5 (95% confidence interval, 0.3-0.7) only.21 The Nurses’ Health Study with 121 701 participants followed up for 36 years revealed that longer duration of COC use was strongly associated with premature mortality due to breast cancer.22 Another highlight was that only 20.7% of our participants knew that a family history of breast cancer was not a contra-indication to use of COC pills.

Another common misconception is that the use of COC pills can lead to future subfertility. The COC pill preserves fertility by diminishing the risk of ectopic pregnancy.23 According to a review, 1-year pregnancy rates after discontinuation of COC ranged from 79% to 96%, similar to those reported following discontinuation of barrier methods or no contraception.24 Moreover, the progestogen effect of COC pills results in production of thick, tenacious cervical mucus that resists penetration by bacteria and spermatozoa and reduces the risk of upper genital tract infection. Use of COC pills was also quoted to be protective against symptomatic pelvic inflammatory disease, with a 50% reduction in rate of hospitalisation for the disease, with itself being a risk factor for subfertility.25 The COC pill does not protect against sexually transmitted infections. On the other hand, there is no evidence to support the notion that the use of COC pills is associated with high-risk sexual behaviour in adolescents, which is a very common fear among Hong Kong mothers.

Primary dysmenorrhoea is prevalent during adolescence. Approximately 6.4% of adolescents or 29% of those reporting severe dysmenorrhoea seek help from a physician.4 A review and meta-analysis of five trials of the use of COC pills concluded that it was more effective than placebo in managing dysmenorrhoea.2 One of the most common problems reported by adolescents is irregular and/or profuse menstruation. The COC pill is also effective in treating and preventing heavy menstrual bleeding. In our study, only 25% to 43% of the participants knew that it is an appropriate treatment for menstrual problems and 50% were uncertain.

The fear of side-effects often leads to reluctance to using new treatments.18 In many cases, such fears are often unfounded. In our study, participants believed that weight gain and depressive mood were side-effects of COC pills, although pooled analysis of a placebo-controlled trial showed no difference in weight gain.26 Furthermore, depressive symptoms are common in adolescence.27 In a randomised controlled study, there was no difference in mood changes throughout the menstrual cycle between COC users and non-users.28 In a prospective study of 43 adolescents, subjects anticipated more side-effects than they actually experienced after 6 months of taking COC pills.29

It is important to provide correct information to women and their teenage daughters if they are contemplating the use of COC pills. In our study, 40% of participants indicated that recommendation from a medical professional was a critical factor in their acceptance of the use of COC pills by their daughters.

Only 19% of participants were aware that thromboembolism is a contra-indication to COC use. Venous thromboembolism in Asians has been reported to be low.30 A recent case-control study confirmed that current exposure to any COC poses a 3-times higher risk of venous thromboembolism compared with no exposure in the previous year.31 The risk is higher with COC pills containing desogestrel (odds ratio, 4.3), gestodene (3.6), drospirenone (4.1), and cyproterone (4.3) than the second-generation COC pills with levonorgestrel (2.4) and norgestimate (2.5).31 The risk of venous thromboembolism is also increased for COC users with a family history of venous thromboembolism.32 Clinicians should assess the woman’s personal and family history of thromboembolism, and provide information about the warning symptoms of venous thromboembolism before prescribing a new generation pill. As recommended by the World Health Organization, the COC pill is not contra-indicated in smokers <35 years old33; approximately 30% of our participants answered this correctly.

This study has several limitations. First, there may be selection bias as subjects were women who presented to the gynaecology clinic or accompanied their daughter to a gynaecology clinic for a gynaecological problem. The results may not be generalised to the whole population of Hong Kong. Second, the questionnaire was not validated and the questions did not include all aspects of the use of COC pills. Third, we relied on women’s self-reported use of COC pills and could not verify the information. Despite these, the questionnaire included the most widely studied aspects of non-contraceptive benefits and risks of the COC pill and knowledge score or uncertainty score have been used in previous literature.15 16 Although this study was conducted in only one centre and in Chinese women only, it helps clinicians to understand the low levels of acceptance of and compliance with prescribed COC pills.

The degree of misconception among Hong Kong mothers about COC use is of concern. Hong Kong has a well-developed education system with many highly regarded universities. The reported limited sex education in schools may be responsible for this knowledge gap of Hong Kong mothers.13 This may in turn have an impact on the advice they give their daughters, who are usually compliant with their mother’s wishes. Specific training in communication and counselling skills should be provided to health care professionals when promoting sexual health to women and adolescents.34

Our study found that the Hong Kong Chinese women who attended a gynaecology clinic of a tertiary centre had a low acceptance rate of the use of COC pills by their daughters. This low acceptance was associated with a lack of knowledge and misconception of the risks and benefits of the COC pills. Such ignorance will exert an adverse influence on the choice of treatment for many gynaecological problems in teenage daughters.

All authors have disclosed no conflicts of interest.

1. Vessey M, Painter R. Oral contraceptive use and cancer. Findings in a large cohort study, 1968-2004. Br J Cancer 2006;95:385-9. Crossref

2. Proctor ML, Roberts H, Farquhar CM. Combined oral contraceptive pill (OCP) as treatment for primary dysmenorrhoea. Cochrane Database Syst Rev 2001;(4):CD002120.

3. Nader S, Diamanti-Kandarakis E. Polycystic ovary syndrome, oral contraceptives and metabolic issues: new perspectives and a unifying hypothesis. Hum Reprod 2007;22:317-22. Crossref

4. Chan SS, Yiu KW, Yuen PM, Sahota DS, Chung TK. Menstrual problems and health-seeking behaviour in Hong Kong Chinese girls. Hong Kong Med J 2009;15:18-23.

5. Chung PW, Chan SS, Yiu KW, Lao TT, Chung TK. Menstrual disorders in a Paediatric and Adolescent Gynaecology Clinic: patient presentations and longitudinal outcomes. Hong Kong Med J 2011;17:391-7.

6. Esmaelizadeh S, Delavar MA, Amiri M, Khafri S, Pasha NG. Polycystic ovary syndrome in Iranian adolescents. Int J Adolesc Med Health 2014;26:559-65. Crossref

7. Christensen SB, Black MH, Smith N, et al. Prevalence of polycystic ovary syndrome in adolescents. Fertil Steril 2013;100:470-7. Crossref

8. Wang C. Trends in contraceptive use and determinants of choice in China: 1980-2010. Contraception 2012;85:570-9. Crossref

9. Lo SS, Fan SY. Acceptability of the combined oral contraceptive pill among Hong Kong women. Hong Kong Med J 2016;22:231-6.

10. The Family Planning Association of Hong Kong. 2014-2015 Annual report. Available from: http://www.famplan.org.hk/fpahk/en/template1.asp?style=template1.asp&content=about/annualreport.asp. Accessed 28 Apr 2016.

11. The Family Planning Association of Hong Kong. Youth sexuality in Hong Kong secondary school survey. Available from: http://www.famplan.org.hk/fpahk/en/template1.asp?content=info/research.asp. Accessed 28 Apr 2016.

12. Che FS. A study of the implementation of sex education in Hong Kong secondary schools. Sex Educ 2005;5:281-94. Crossref

13. Survey of life skills-based education on HIV/AIDS at junior level of secondary schools in Hong Kong. Red Ribbon Centre, Department of Health, Hong Kong SAR Government; 2014.

14. Wong WC, Lee A, Tsang KK, Lynn H. The impact of AIDS/sex education by schools or family doctors on Hong Kong Chinese adolescents. Psychol Health Med 2006;11:108-16. Crossref

15. Voqt C, Schaefer M. Disparities in knowledge and interest about benefits and risks of combined oral contraceptives. Eur J Contracept Reprod Health Care 2011;16:183-93. Crossref

16. Lim HJ, Lee MS, Cho YH, Kazumi U. A comparative study of knowledge about and attitudes toward the combined oral contraceptives among Korean and Japanese university students. Pharmacoepidemiol Drug Saf 2004;13:741-7. Crossref

17. Bachar R, Yogev Y, Fisher M, Geva A, Blumberg G, Kaplan B. Attitudes of mothers toward their daughters’ use of contraceptives in Israel. Contraception 2002;66:117-20. Crossref

18. Chan SS, Cheung TH, Lo WK, Chung TK. Women’s attitudes on human papillomavirus vaccination to their daughters. J Adolesc Health 2007;41:204-7. Crossref

19. Cibula D, Gompel A, Mueck AO, et al. Hormonal contraception and risk of cancer. Hum Reprod Update 2010;16:631-50. Crossref

20. Bitzer J. Oral contraceptives in adolescent women. Best Pract Res Clin Endocrinol Metab 2013;27:77-89. Crossref

21. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713-27. Crossref

22. Charlton BM, Rich-Edwards JW, Colditz GA, et al. Oral contraceptive use and mortality after 36 years of follow-up in the Nurses’ Health Study: prospective cohort study. BMJ 2014;349:g6356. Crossref

23. Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 2004;190 (4 Suppl):S5-22. Crossref

24. Mansour D, Gemzell-Dianielsson K, Inki P, Jensen JT. Fertility after discontinuation of contraception: a comprehensive review of the literature. Contraception 2011;84:465-77. Crossref

25. Guillebaud J, MacGregor A. Contraception: your questions answered. 6th ed. London: Churchill Livingstone; 2013.

26. Gallo MF, Lopez LM, Grimes DA, Carayon F, Schulz KF, Helmerhorst FM. Combination contraceptives: effects on weight. Cochrane Database Syst Rev 2014;(1):CD003987. Crossref

27. Saluja G, Iachan R, Scheidt PC, Overpeck MD, Sun W, Giedd JN. Prevalence of and risk factors for depressive symptoms among young adolescents. Arch Pediatr Adolesc Med 2004;158:760-5. Crossref

28. Walker A, Bancroft J. Relationship between premenstrual symptoms and oral contraceptive use: a controlled study. Psychosom Med 1990;52:86-96. Crossref

29. Rosenthal SL, Cotton S, Ready JN, Potter LS, Succop PA. Adolescents’ attitudes and experiences regarding levonorgestrel 100 mcg/ethinyl estradiol 20 mcg. J Pediatr Adolesc Gynecol 2002;15:301-5. Crossref

30. Lee WS, Kim KI, Lee HJ, Kyung HS, Seo SS. The incidence of pulmonary embolism and deep vein thrombosis after knee arthroplasty in Asians remains low: a meta-analysis. Clin Orthop Relat Res 2013;471:1523-32. Crossref

31. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015;350:h2135. Crossref

32. Zöller B, Ohlsson H, Sundquist J, Sundquist K. Family history of venous thromboembolism is a risk factor for venous thromboembolism in combined oral contraceptive users: a nationwide case-control study. Thromb J 2015;13:34. Crossref

33. Medical eligibility criteria for contraceptive use. 5th ed. Geneva: World Health Organization; 2015.

34. Yip BH, Sheng XT, Chan VW, Wong LH, Lee SW, Abraham AA. ‘Let’s talk about sex’—a knowledge, attitudes and practice study among paediatric nurses about teen sexual health in Hong Kong. J Clin Nurs 2015;24:2591-600. Crossref

Glioblastoma multiforme (GBM) is a malignant primary brain tumour with an incidence of 1 to 2 per 100 000 population in Hong Kong.1 The survival of patients with GBM remains dismal, mainly due to its inevitable progression and recurrence. Little progress was made until the last decade. The establishment of concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ) and the discovery of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation in association with significantly better outcome were the two major and inspiring breakthroughs.2 3 Before these developments, the treatment for GBM was homogeneous but desperate, and comprised surgery and irradiation only.

In 2001, TMZ was first used in the treatment of recurrent high-grade glioma in Hong Kong. Its favourable anti-tumour activity and acceptable safety profile were proven in a local study.4 In 2005, TMZ was the first chemotherapy to show objective survival benefit as a primary treatment when used together with radiotherapy as part of CCRT in GBM.2 Since then, CCRT for GBM has become the norm in Hong Kong.

In the last decade, opinion has changed about the goal of surgical resection in treating glioma. Ample evidence has shown that maximum safe resection in GBM improves survival. Neurosurgeons have therefore revised their objective of surgery from a diagnostic biopsy or limited debulking to a maximum safe resection. Knowing the infiltrative nature of the tumour, surgeons have a demanding job of balancing maximum resection and safe surgery. Awake craniotomy and mapping technique are two essential surgical techniques that enable safe resection.5 The goal of maximum resection can be achieved with a fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA).6

Given these changes to the management of GBM, we therefore analysed the changes in overall survival of GBM over the past 10 years in Hong Kong.

Data were retrieved from the Chinese University of Hong Kong Otto Wong Brain Tumour Centre brain tumour registry. The registry has been collecting data from all histology-proven glioma patients in the institute since January 2003. Patients aged 18 years or above with histologically proven glioma diagnosed in the institute were included in the registry. Patients with histologically confirmed World Health Organization grade IV GBM during January 2003 to December 2005 and January 2010 to December 2012 were recruited and grouped. Patients treated between 2006 and 2009 were excluded because the surgical policy was evolving and the availability of chemotherapy was variable during the period. Therefore this would be a heterogeneous group of patients with various treatments due to availability or affordability. Patients with an unstable neurological condition or who were considered a poor medical risk after surgery resulting in Karnofsky Performance Scale score of below 70 were excluded, as were those who received initial chemotherapeutics other than TMZ, ie procarbazine, lomustine, vincristine, or bevacizumab. Data on type of surgery, extent of resection, tumour histology, irradiation and chemotherapy parameters were collected as well as information about patient’s age and gender. The registry defined the death date according to the electronic patient record in the Hospital Authority Clinical Management System. For patients who defaulted from clinical follow-up, telephone follow-up ascertained death date. The study end date was 30 June 2015.

During 2003 to 2005, all patients were treated with surgical resection and adjuvant radiotherapy; TMZ was only used in patients with recurrent disease. Ability to pay for chemotherapy was the key determinant of its application and utility. In our hospital, TMZ was prescribed at a dose of 200 mg/m² once per day for 5 days in a 28-day cycle.

With regard to the contouring methodology of irradiation, either European Organisation for Research and Treatment of Cancer or Radiation Therapy Oncology Group protocol was chosen according to the serial assessment of both pre- and post-operative magnetic resonance imaging (MRI) scans. A total dose of 60 Gy irradiation was delivered to the tumour bed and its adjacent tissue in 30 fractions, with 2 Gy each.

Since 2009, neuroradiologists have been responsible for assessing the extent of resection by MRI on postoperative day 1. Total resection was defined as no remaining contrast enhancement on MRI T1-weighted and subtraction scans of T1 plain with T1 plus contrast. For patients in whom the enhancing lesion was still noticeable, the resection was categorised as debulking.

In the 2010-2012 cohorts, TMZ was recommended to all patients. The dosage was 75 mg/m²/day concomitant with radiotherapy, then 150-200 mg/m²/day on the first 5 days every 4 weeks for 6 cycles, in accordance with the regimen described by Stupp et al.2 Methylation status of the MGMT was detected using methylation-specific polymerase chain reaction at our institution. The method has been explained in detail in one of our earlier studies.7 Survival was calculated from the date of surgery for brain tumour to death. Kaplan-Meier survival curves were used to compare different groups of biopsy versus surgical resection and chemoradiotherapy versus radiotherapy alone.

This audit review was done in accordance with the principles outlined in the Declaration of Helsinki.

Demographics, management, and survival of patients are shown in the Table.

During the period 1 January 2003 to 31 December 2005, 26 patients with a mean age of 52.2 years were eligible for study. Two patients below the age of 18 years were excluded from the registry. The median overall survival for this cohort was 7.4 months (Fig 1). Eight (30.7%) patients underwent biopsy only, with a non-inferior median overall survival compared with the remaining 18 patients who underwent resection (7.2 months vs 7.4 months, P=0.988, log-rank test; Fig 2). Total removal could be achieved in only two patients, with overall survival of 14.7 and 28.8 months, respectively. For the remaining 16 patients who underwent debulking surgery, the median overall survival was 7.2 months.

During the period 1 January 2010 to 31 December 2012, 42 patients with a mean age of 55.1 years were identified. One patient was excluded because he declined CCRT after surgery and opted for alternative medicine. The median overall survival was markedly prolonged to 12.7 months (P<0.001, log-rank test; Fig 1). The proportion of patients who had biopsy (9/42, 21.4%) during 2010 to 2012 remained similar to 10 years ago (8/26, 30.8%). Patients with resection performed was not significantly different between the two periods (P=0.404, Chi squared test). Overall survival of the surgical resection group was distinctly longer than that for the biopsy group (15.2 months and 4.5 months, respectively; P=0.026, log-rank test; Fig 3). A higher proportion of patients achieved total surgical removal in 2010-2012 than in 2003-2005, being 35.7% (15/42) and 7.7% (2/26), respectively (P=0.015, Chi squared test). The difference between debulking and total resection remained undefined in the 2010-2012 arm (13.0 months vs 16.0 months; P=0.966, log-rank test) by the time of analysis.

Of the 42 patients with GBM during 2010-2012, CCRT was initiated in 23, accompanied by a meaningful longer median survival of 17.9 months compared with only 4.5 months for those given radiotherapy only (P=0.001, log-rank test; Fig 4). Data for MGMT were available in 33 patients. The overall survival of 19 patients with methylated MGMT promoter was longer than that of 14 patients with unmethylated MGMT promoter, being 28.4 months and 6.3 months, respectively (P<0.001, log-rank test).

Improvement in 2-year survival was also evident, from 11.5% in the earlier cohort, to 21.4% in the later one.

Glioma has attracted international research interest over the last 20 years in both clinical and laboratory setting. The determination to fight the disease yielded with proven survival benefit of TMZ in recurrent high-grade glioma in 2000.8 A 6-month event-free survival of 21% in TMZ compared favourably with 9% for procarbazine.8 The full effect of TMZ was reported in a randomised trial as primary treatment for GBM in 2005.2 The regimen included two phases of TMZ, starting with a concomitant phase of daily low-dose TMZ during the course of radiotherapy, followed by the adjuvant phase of a high-dose TMZ for 5 days during each 28-day cycle for 6 cycles.2 The results of the study benchmarked a standard for chemotherapy in the treatment of GBM. The median survival of 14.6 months in the CCRT arm compared favourably with the 12.1 months of the control radiotherapy-alone arm.2

In Hong Kong, TMZ was first introduced in 2001. Its safety and effect had been tested and reported in a small series of recurrent high-grade glioma.4 The use of CCRT in Hong Kong was also reported with favourable results.9 The overall survival was much improved in these 10 years from 7.4 months in 2003-2005 to 12.7 months in 2010-2012. Among the cohorts in 2010-2012, however, only 54.8% (23/42) received CCRT. This can be attributed to the fact that in 2010, TMZ, whilst already incorporated into the Hospital Authority Drug Formulary, was listed as a self-financed item only. The financial burden on patients was the major cause of low usage during the time.

In 2011, TMZ was granted conditional funding through the Samaritan Fund scheme. Approval of funding was based on the financial situation of the patient and the tumour’s MGMT methylation status, with approval only granted to patients with tumours with MGMT methylation. This may have been a cost-effectiveness consideration because the largest survival benefit would be in MGMT-methylated GBM. Local data showed that only 43% of local GBM were methylated in MGMT status,9 thus essentially limiting the possibility of funding for less than half of the patients with GBM. Thus, within the 2010-2012 cohort, only patients diagnosed from 2011 onwards with tumours of methylated MGMT status (accounting for roughly a further half of the patient population) would have benefited from the scheme. This may account for the relatively low number of patients treated with CCRT. Then the policy of restricting funding based on MGMT status was re-addressed and such criterion was removed in 2013. Currently, support of Samaritan Fund for TMZ is available for eligible patients with GBM based on their financial situation, and regardless of their tumour MGMT status.

The treatment of CCRT had made an impact not only on clinical outcomes, but also on the working dynamics between different professional disciplines involved in the management of patients with GBM. The need for timely arrangement and administration of radiotherapy and chemotherapy within a short postoperative window has encouraged a multidisciplinary team approach. This continues to be the current treatment delivery model for patients with GBM in many hospitals in Hong Kong. Better clinical outcomes encouraged professional enthusiasm. In this atmosphere, a local group of clinicians got together and founded the Hong Kong Neuro-Oncology Society in 2011.

The reasons for longer survival of GBM in recent years are likely to be multifactorial. The extent of surgical resection has been intensely studied over the last two decades. Nonetheless, since a prospective randomised surgical study would be unethical, evidence to support maximum safe resection must be gleaned retrospectively. Despite this, neurosurgical professionals were convinced that surgical resection was the first and major treatment for GBM. Surgical conservatism was abandoned and the demand for maximum safe resection was set out by neurosurgeons. This change was reflected in the decrease in surgical biopsy rate from 30.8% in 2003-2005 to 21.4% in 2010-2012. The ability of total surgical removal of the contrast-enhancing tumour was also increased from 7.7% in 2003-2005 to 35.7% in 2010-2012. Local neurosurgeons have been equipped with two surgical techniques to achieve maximum safe resection in the last 10 years—the technique of cortical mapping and awake surgery was brought to all local neurosurgeons in two workshops of commissioned training organised by the Hospital Authority in 2003 and 2010. This technique allows safer resection of the tumour at or near the eloquent area of the brain. A tumour fluorescent technique (5-ALA) was introduced in 2009 that facilitated detection of residual tumour for maximum resection. In 2003-2005, the survival of the surgical resection group and biopsy group was similar but in 2010-2012, those in the surgical resection group survived longer. The difference was probably due to both aggressive surgical resection and CCRT in the latter group.

The major limitation of this study was the presence of potential confounding factors during the 10-year study period. Such factors included incomplete data of MGMT methylation status and extent of resection in the 2003-2005 group. There was no MGMT methylation testing or day-1 MRI scan after resection in 2003-2005. The interval between surgery and commencement of radiotherapy has been controlled to within 4 weeks since 2009 but this was not the case in 2003-2005. All these confounding factors made valid comparison of the effect of surgical resection or chemotherapy during these two time periods difficult. Moreover, the registry included only surgical patients who had undergone biopsy or resection, and excluded a small group of patients, who were usually elderly (age >70 years) or with poor co-morbidities, who may have received radiotherapy or chemotherapy alone.

Hong Kong has made substantial improvements in the management of GBM with improved survival over the last decade. The combination of aggressive surgical strategy and CCRT are probably the driving force for the improvement.

None of the authors has disclosed any conflicts of interest.

1. Pu JK, Ng GK, Leung GK, Wong CK. One-year review of the incidence of brain tumours in Hong Kong Chinese patients as part of the Hong Kong Brain and Spinal Tumours Registry. Surg Pract 2012;16:133-6. Crossref

2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. Crossref

3. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997-1003. Crossref

4. Chan DT, Poon WS, Chan YL, Ng HK. Temozolomide in the treatment of recurrent malignant glioma in Chinese patients. Hong Kong Med J 2005;11:452-6.

5. Chan DT, Kan PK, Lam JM, et al. Cerebral motor cortical mapping: awake procedure is preferable to general anaesthesia. Surg Pract 2010;14:12-8. Crossref

6. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006;7:392-401. Crossref

7. Dong SM, Pang JC, Poon WS, et al. Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors. J Neuropathol Exp Neurol 2001;60:808-16. Crossref

8. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000;83:588-93. Crossref

9. Chan DT, Kam MK, Ma BB, et al. Association of molecular marker O⁶Methylguanine DNA methyltransferase and concomitant chemoradiotherapy with survival in Southern Chinese glioblastoma patients. Hong Kong Med J 2011;17:184-8.