In Hong Kong, career opportunities in obstetrics and gynaecology (O&G) for medical graduates have undergone a roller-coaster ride over the last two decades. For O&G, the number of new trainees per year in the territory dropped from 11 in 2000 to a trough of five in 2004, followed by a steep rise to 22 in 2006.1 This trend was driven by multiple factors, notably the local birth rate and the influx of non-eligible person deliveries during this period.

According to the discussion paper ‘Manpower requirement and strategies for doctors’ published by the Hospital Authority in 2010, the annual intake requirement of O&G doctors was projected to be 20 for the period 2010 to 2016.2 Recruitment of O&G resident trainees in the latest Annual Recruitment Exercise in 2015 was unexpectedly difficult, however. Among the 24 O&G resident trainee posts available in the Annual Recruitment Exercise for Resident Trainees 2015/16,3 less than 50% were filled by May 2015 and 11 posts remained vacant in July 2015,4 thus creating a manpower crisis in O&G.

The trend of declining interest of medical graduates in pursuing O&G as a career has likewise been observed in overseas studies5 6 with various factors explored, such as perception of O&G clerkship,5 6 7 lifestyle,5 7 gender,5 7 8 and medicolegal issues.5 7 Local data on this topic are lacking. A literature search revealed one local study on specialty choice of medical graduates was conducted 20 years ago9 and another focused on the specialty of family medicine.10 In view of the recent manpower crisis, there was an urgent need to perform a study on this topic as it might guide manpower planning and formulation of solutions.

The objectives of this study were to evaluate the career interest of the most recent medical graduates in Hong Kong, especially their level of career interest in O&G, and to identify key influential factors for career choice and career interest in O&G.

This was a cross-sectional questionnaire survey. All medical graduates of the University of Hong Kong (HKU) and the Chinese University of Hong Kong (CUHK), who graduated in 2015 and attended the pre-internship lectures held in their medical school on 5 and 8 June 2015 respectively, were invited to participate. This study was approved by the Institutional Review Board of the University of Hong Kong / Hospital Authority Hong Kong West Cluster and the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee.

All medical graduates who attended the lectures were given an information sheet and consent form. Those who consented were invited to complete a self-administered anonymous questionnaire in English that was collected on the same day by the investigator.

The questionnaire comprised 14 questions in three sections: (1) demographic data, (2) current view on career choice, and (3) view on O&G as a career. The second section explored the first three choices of specialty as a career and the extent of influence of 28 items on career choice. The third section evaluated the current level of career interest in O&G, the extent of influence of 28 items on career interest in O&G, and the impact on the level of career interest in O&G of five possible changes. The 28 items were potential influential factors that were identified from overseas studies5 6 7 8 in the following categories: (1) ability, interest, and personality, (2) clerkship experience, (3) influence of family, peers, and seniors, (4) medicolegal issues, (5) nature of the specialty, (6) other experience related to the specialty, (7) career prospects, (8) religion, and (9) training and working conditions.

All statistical analyses were performed using PASW Statistics 18, Release Version 18.0.0 (SPSS Inc., 2009, Chicago [IL], US). Categorical data were presented as counts and percentages. Continuous data were expressed as median (interquartile range) as they were highly skewed. Chi squared test and Fisher’s exact test were used to compare categorical data. For continuous data, as they were highly skewed, a non-parametric test (Mann-Whitney U test or Kruskal-Wallis H test) was used. Results with a P value of <0.05 were considered statistically significant.

In order to investigate the structure of the potential factors influencing career choice and career interest in O&G, an exploratory factor analysis by the extraction method of principal component analysis with varimax rotation was performed. An exploratory factor analysis was performed instead of a confirmatory factor analysis because the factor structure was uncertain. The number of factors to be extracted was based on the result from the scree-plots and the Kaiser’s eigenvalue criterion (eigenvalue >1). Missing values were excluded listwise. The quality of the factor analysis models was assessed by Bartlett’s test of sphericity and the Kaiser-Meyer-Olkin (KMO) measure of sampling adequacy.

In June 2015, there were 323 new medical graduates in Hong Kong, of whom 163 were from HKU and 160 were from CUHK. Among them, 283 attended the pre-internship lectures (157 HKU graduates and 126 CUHK graduates); 238 participants were recruited who constituted 73.7% of all 323 medical graduates and 84.1% of 283 medical graduates in the lectures. Five questionnaires were excluded from analysis due to significant missing data (four missing the level of career interest in O&G and one missing the extent of influence of factors for career interest in O&G). Thus, 233 questionnaires were analysed.

Table 1 shows the demographic data of participants. There were 229 (98.3%) participants who planned to undergo specialty training after internship. Table 2 shows the distribution of their first three choices of specialty. There were 13 (5.7%) participants who indicated O&G as their first choice of specialty and 37 (16.2%) participants who listed O&G among their first three choices of specialty, of whom 29 (78.4%) were female and eight (21.6%) were male.

On a scale of 1 (no interest at all) to 10 (extremely interested), the median (interquartile range) score for the current level of career interest in O&G was 3 (1-6). The association between demographics and level of career interest in O&G is shown in Table 3. Gender was significantly associated with level of career interest in O&G with females more interested than males. There was also a statistically significant association between gender and listing O&G among the first three choices of specialty (P=0.001).

In the exploratory factor analysis, the values of KMO measure of sampling adequacy were >0.6. The P values of Bartlett’s test of sphericity were both <0.05. These figures indicated that the use of factor analysis was appropriate to investigate the underlying factors in this study. Eight underlying factors were extracted for career choice and seven underlying factors were extracted for career interest in O&G. All had an eigenvalue of >1, implying that these factors were meaningful. The total percentage of variance explained by the eight underlying factors for career choice and that for the seven underlying factors for career interest in O&G were both 68.0%, meaning these factors could explain 68.0% of the condition.

The three factors with the highest percentage of variance explained were identified as the key influential factors. The key influential factors for career choice and career interest in O&G are shown in Table 4.

Comparison of gender with the median of key influential factors for career choice and career interest in O&G revealed no difference except for clerkship experience. This was the strongest key influential factor for career interest in O&G. The median rating by female participants was 21 (18-24) and that for male participants was 19 (16-22) [P=0.021].

Impact on career interest in O&G of five potential changes was evaluated (Fig). Decreasing the frequency of on-call duty and better remuneration had the highest positive impact. The option of part-time training with a longer training period had the lowest positive impact but highest negative impact.

To our knowledge, this is the first study in Hong Kong to investigate the career interest of medical graduates in O&G and the influential factors. It was satisfactory to have a participation rate of 73.7% of the 323 medical graduates in Hong Kong this year.

Medicine and surgery were the most popular specialty choices. This is consistent with previous local studies.9 10 On the other hand, O&G ranked eighth when combined with the first three choices and sixth as the first choice. This is a reduction from previous local studies in which its popularity was ranked as third9 and fourth10, respectively.

The level of career interest in O&G was low with a median score of 3 (out of 10). Female participants had a higher career interest in O&G than their male counterparts, which is consistent with overseas studies.8

The key influential factors for career choice and career interest in O&G were consistent, namely clerkship experience, working style, and career prospects.

Working style was the strongest key influential factor for career choice, with the highest percentage of variance explained (26.4%). The items included in this factor had a similar coefficient of around 0.8, reflecting that each item made a similar contribution to this factor. This factor was important to both female and male medical graduates with no statistically significant gender difference. The focus on a work-life balance has attracted increasing attention, not just locally but globally, and is not unique to the medical profession. There were 149 (63.9%) participants who considered a decreased on-call frequency would have a positive impact on their level of interest in O&G. This had the highest positive impact among the five possible changes explored. Efforts should be made to avoid the vicious cycle of lack of manpower and increased on-call frequency in order to maintain the attractiveness of O&G to future generations of the profession. In addition, providing better remuneration, such as a special honorarium for extra on-call duties, might be explored, especially when manpower is insufficient. This was thought to increase career interest in O&G by 141 (60.5%) participants.

Clerkship experience was the strongest key influential factor for career interest in O&G with the highest percentage of variance explained (28.9%). Included in this factor, five items had a higher contribution with coefficients of above 0.6, namely (1) overall learning experience in O&G clerkship, (2) interaction with O&G interns and trainees, (3) interaction with O&G specialists, consultants, and professors, (4) hands-on experience in O&G clerkship, and (5) interaction with midwives and O&G nurses. This result is consistent with overseas findings of the important influence of perception of clerkship, including interaction with O&G staff, on career interest in O&G.5 6 It emerges that O&G nurses, midwives, interns, trainees, and specialists play a vital role in ensuring a positive O&G clerkship experience.

Noticeably, this was the only key influential factor with a significant gender difference (P=0.021): the clerkship experience of female participants had a more positive impact on their career interest in O&G compared with males. The reason behind this phenomenon was beyond the scope of this study. Interestingly, Chang et al6 suggested that male medical students were more likely to increase their level of career interest in O&G during the clerkship. Assuming this finding is applicable to our local students, further study of gender difference in clerkship experience may help improve the imbalanced gender ratio of O&G trainees. In our study, 126 (54.1%) participants agreed that a more balanced gender ratio of staff would have a positive impact on career interest in O&G.

It might be surprising to note that some items that might have been expected to be influential—such as interest in the specialty,10 compatibility with personality, and availability of training posts—were not among the key influential factors in this study.

There are several limitations of this study. First, recruitment of participants was affected by the attendance of medical graduates at the pre-internship lectures: 87.6% of all medical graduates. In addition, participation in this study was voluntary: 45 (15.9%) of 283 medical graduates who attended the lectures did not participate. The reason for non-participation was not documented. There may be potential response bias as those with a low career interest in O&G may have been less keen to participate. Other possible reasons for non-participation were unwillingness to disclose career interest or uncertain career interest. A similar study may be conducted with interns towards the end of the internship when career interest is usually clearer. There may be possible changes in career interest and influential factors at another stage of career development. Some external factors, such as the availability of training posts at the time of application, may become more influential at this juncture. Second, the findings have weak generalisability as there are many external factors that change with time and may be different in different parts of the world. It may be useful to conduct similar study periodically to obtain an updated trend to facilitate manpower planning. Third, the items of possible influential factors included in the questionnaire were not exhaustive and were selected with reference to previous studies.

The study confirmed the observation of a low level of career interest in O&G among medical graduates and the decreasing popularity of O&G as a career choice. Key influential factors for career interest in O&G and career choice included working style, clerkship experience, and career prospects. Encouragingly, there are modifiable elements among these factors, where improvement can be made by faculties, college, frontline staff, and hospital administrators.

We would like to thank Prof TP Lam and Dr Gilberto KK Leung, Institute of Medical and Health Sciences Education, Li Ka Shing Faculty of Medicine, The University of Hong Kong and Prof Tony KH Chung, Faculty of Medicine, The Chinese University of Hong Kong for their support and endorsement for this study to be conducted in the Faculties. We are grateful to Dr WC Leung, Chairman of Education Committee, The Hone Kong College of Obstetricians and Gynaecologists and the Chief of Service of our respective departments: Dr Anita Yeung, Prof Ernest HY Ng, and Dr TH Cheung, for their support. We would also like to acknowledge Dr Carmen KM Choi and Dr Daniel Wong for their helpful comments on the questionnaire.

1. Au Yeung SK. Impact of non-eligible person deliveries in obstetric service in Hong Kong. Hong Kong J Gynaecol Obstet Midwifery 2006;6:41-4.

2. Manpower requirement and strategies for doctors, Hospital Authority Administrative and Operational Meeting Paper No 693. Available from: http://www.ha.org. hk/haho/ho/cad_bnc/AOM-P693.pdf. Accessed 5 May 2015.

3. Posts available, Annual Recruitment Exercise for resident trainees 2015/16, Hospital Authority. Available from: http://www.ha.org.hk/ho/resident.htm. Accessed 5 May 2015.

4. Unfilled resident trainee post for Annual Recruitment Exercise 2015/16, Hospital Authority. Available from: http://www.ha.org.hk/ho/resident.htm. Accessed 3 Jul 2015.

5. Gariti DL, Zollinger TW, Look KY. Factors detracting students from applying for an obstetrics and gynecology residency. Am J Obstet Gynecol 2005;193:289-93. Crossref

6. Chang JC, Odrobina MR, McIntyre-Seltman K. Residents as role models: the effect of the obstetrics and gynecology clerkship on medical students’ career interest. J Grad Med Educ 2010;2:341-5. Crossref

7. Fogarty CA, Bonebrake RG, Fleming AD, Haynatzki G. Obstetrics and gynecology—to be or not to be? Factors influencing one’s decision. Am J Obstet Gynecol 2003;189:652-4. Crossref

8. Schnuth RL, Vasilenko P, Mavis B, Marshall J. What influences medical students to pursue careers in obstetrics and gynecology? Am J Obstet Gynecol 2003;189:639-43. Crossref

9. Lam TP. Specialty choice of medical graduates. Hong Kong Pract 1996;18:504-12.

10. Wu SM, Chu TK, Chan ML, Liang J, Chen JY, Wong SY. A study on what influence medical undergraduates in Hong Kong to choose family medicine as a career. Hong Kong Pract 2014;36:123-31.

Mushroom poisoning is a global phenomenon and can be a source of major mortality and morbidity. Although Hong Kong people consume a large volume of mushrooms, there are few clinical studies and reviews related to local mushroom poisoning.1 2 The diagnosis of mushroom poisoning should be based on clinical features, laboratory investigations, and mushroom identification. Due to the lack of leftover mushroom samples in most cases, emergency physicians and clinical toxicologists usually have to diagnose mushroom poisoning based on clinical syndromes alone without mushroom identification by mycologists. Diaz3 has reviewed and established the classification of mushroom poisoning based on the time of presentation and target organ systemic toxicity. With respect to the time of presentation, mushroom poisoning is categorised as early onset (<6 hours), late onset (6-24 hours), or delayed onset (>1 day). Early-onset toxicities include several neurotoxic, gastrointestinal, and allergic syndromes. Late-onset toxicities include hepatotoxic, accelerated nephrotoxic, and erythromelalgia syndromes. Delayed-onset toxicities include delayed nephrotoxic, delayed neurotoxic and rhabdomyolytic syndromes. Syndromic approaches guide earlier diagnosis and facilitate empirical treatment.3

In Hong Kong, scattered cases of mushroom poisoning are reported every year. In a report published by the Centre for Health Protection (CHP), there were 13 reported cases of wild mushroom poisoning between January 2002 and May 2005.1 Symptoms occurred 0.5 to 5 hours post-ingestion and included vomiting (100%), abdominal pain (100%), diarrhoea (69%), nausea (56%), dizziness (50%), sweating (37%), numbness (31%), palpitation (19%), malaise (13%), fever (13%), and headache (6%).2 Of these patients, seven required hospitalisation and all of them completely recovered. Individual cases of mushroom poisoning have been announced in CHP press releases from time to time. In another report, seven patients presented with mainly gastrointestinal symptoms after wild mushroom consumption between May 2007 and August 2010.2 There have been no reports of life-threatening wild mushroom poisoning in Hong Kong before this case series.

Since its establishment in 2005, the Hong Kong Poison Information Centre (HKPIC) has provided a 24-hour telephone consultation service to health care professionals in Hong Kong for poison information and clinical management advice. We are actively involved in the diagnosis and management of mushroom poisoning cases in local hospitals. Supported by Prof SW Chiu from the School of Life Sciences of The Chinese University of Hong Kong, mycological identification can be provided whenever mushroom samples are available in a poisoning case. The objectives of this study were to review the clinical features and mycological identifications in mushroom poisoning cases recorded by the HKPIC.

Mushroom poisoning cases recorded by HKPIC from 1 July 2005 to 30 June 2015 were retrospectively reviewed. Information on patient demographic details, clinical presentation, sources of mushroom, investigation results, mycological identification results, and clinical outcome were obtained. Descriptive statistics were used for data analysis.

During the 10-year study period, there were 67 cases of mushroom poisoning. All cases were reported from hospitals of the Hospital Authority. All patients were Chinese; 29 (43%) were male and 38 (57%) were female. The median age was 47 (range, 2-86) years. Of the 67 cases, 52 (78%) occurred between April and September when the climate in Hong Kong is optimal for mushroom growth. In 66 cases, the mushrooms were intentionally consumed as delicacies. There was one case of accidental ingestion, in which a 2-year-old boy ingested a wild mushroom in a park. Ingestion with recreational, suicidal, or malicious intent was not recorded in this case series.

The most common clinical presentation was gastrointestinal symptoms (Table 1). Symptoms mimicking gastroenteritis were the presenting feature in 60 (90%) patients. The diagnosis of these 60 patients included gastroenteritic mushroom poisoning in 38, cholinergic mushroom poisoning in five, food poisoning in eight, food allergy in two, and seven cases of amatoxin poisoning.

Neurological symptoms were also commonly reported: 20 (30%) patients presented with one or more symptoms including dizziness, numbness, hallucination, headache, or confusion (Table 1). Most of them (15 of 20 patients) presented with both neurological and gastrointestinal symptoms. Four patients presented with neurological symptoms including visual hallucinations, dizziness, generalised weakness, and malaise without gastrointestinal symptoms. They were subsequently diagnosed with hallucinogenic mushroom poisoning. One patient presented with malaise, muscle fasciculation, and profuse sweating that was diagnosed as cholinergic mushroom poisoning.

The symptom onset time was documented in 62 patients (Table 2). Among them, 53 patients developed symptoms within 6 hours of mushroom consumption (early-onset group). The median time of symptom onset was 2 hours post-ingestion (interquartile range [IQR], 2). Most patients (50 out of 53) presented with early-onset gastrointestinal symptoms. No severe clinical outcomes were observed in this group of patients and all recovered with symptomatic treatment and short duration of hospital care.

Symptoms developed 6 hours or more after mushroom consumption in nine patients (late-onset group). The median time of symptom onset was 11 hours post-ingestion (IQR, 2). This group of patients represented potentially life-threatening mushroom poisoning. All seven cases of amatoxin poisoning in this case series were found in this group. The remaining two cases included one case of hallucinogenic mushroom poisoning caused by Tylopilus nigerrimus, and one case of food poisoning.

The source of poisonous mushrooms was documented in 64 cases (Table 3). In 34 (51%) cases, the mushrooms were self-picked from a park, hillside, or roadside. The locations were usually close to the patient’s home. On the other hand, 14 (21%) cases purchased the mushrooms in Hong Kong and 16 (24%) purchased them in mainland China. All patients with amatoxin poisoning collected the mushroom from the wild. The source of mushrooms was not documented in three (4%) cases.

Mycological identification was achieved in 28 cases (Table 4). The diagnosis of amatoxin poisoning was confirmed by the presence of amatoxin and/or phallacidin in the urine of five patients.

The aim of this study was to describe the pattern of mushroom poisoning in Hong Kong. Four mushroom poisoning syndromes, together with food poisoning and food allergy, were identified to be the cause of all mushroom poisoning cases in this study. The typical clinical features and the management of the four local mushroom poisoning syndromes are summarised in Table 5.4

As an extensive urban city, commercially sold cultivated mushrooms are easily available and these are the mushrooms consumed by most Hong Kong citizens every day. Nonetheless the Chinese generally believes that wild-harvested products, including mushrooms, have higher nutritional and medicinal values. The risky behaviour of collecting and consuming wild mushrooms was considered to be rare in Hong Kong. This can be illustrated by the relatively few reported cases of poisoning during the study period. There are over 388 known species of mushroom in Hong Kong,5 of which fewer than 10% are edible, and a majority have unknown edibility. Although mushrooms are macroscopic organisms with visible morphological features, many mushroom species share a similar appearance and misidentification is common. There is no correlation between a particular morphological feature and poisonous nature of a mushroom species. Even with genus Amanita, there are edible and inedible species. There is no simple way to differentiate edible and poisonous mushroom species. Even in expert hands, mushroom identification frequently depends on the microscopic features that can usually be seen in a laboratory setting. Different edible and inedible or poisonous mushroom species can share a similar habitat and grow in close proximity in the wild. Collection of mixed species often happens. Cooking or other means of food processing cannot detoxify a poisonous mushroom. With the report of life-threatening amatoxin poisoning from ingestion of local wild mushrooms, Hong Kong citizens would be well advised to stop the risky behaviour of consuming self-picked mushrooms from the wild.

Consumption of poisonous mushrooms can cause various signs and symptoms, such as gastroenteritis, disturbances in central nervous system, and liver failure.3 As mushroom identification is usually not available early on in patient care, doctors should treat their patients according to the clinical syndrome (Table 54). An important predicting factor to consider is the latency from ingestion to onset of symptoms. The finding of our case series is compatible with overseas reports.3 6 Patients with early-onset symptoms, typically within 6 hours post-ingestion, all had a benign course of disease (Table 2). The mainstay of treatment is supportive, with intravenous fluids, antiemetic, antispasmodics, or analgesic for those patients who present with gastrointestinal symptoms.

Seven cases of amatoxin poisoning reported in this case series confirms the existence of deadly amatoxin-containing mushroom in our locality. Poisonous Amanita species have long been found in Hong Kong. Although local cases of amatoxin poisoning have not been reported in Hong Kong before 2013, it has been well-reported in mainland China.7 8 9 According to a report published by Guangzhou Municipal Centre for Disease Control and Prevention, there were 92 cases of mushroom poisoning with 13 deaths in the years 2002 to 2005.9 The reported species of mushroom involved in 70% of cases were the amatoxin-containing mushroom Amanita exitialis and the gastroenteritic mushroom Chlorophyllum molybdites.9 For amatoxin poisoning, the latency between ingestion and onset of symptoms was typically 6 to 24 hours.3 For our seven cases of amatoxin poisoning, this latency ranged from 8 to 12 (median, 11) hours. There were four male and three female patients, with a median age of 44 (range, 29-74) years. All cases presented with persistent vomiting and diarrhoea, deranged liver function tests, and were able to give a history of wild mushroom ingestion. Three were imported cases. Two of them ate wild mushrooms in South Africa and one patient ate wild mushrooms in China. In four patients, wild mushrooms were picked locally in the country park of the New Territories. One imported case presented to hospital in Hong Kong 5 days after wild mushroom consumption and died of multi-organ failure soon after hospital admission. The remaining six cases were managed according to overseas experience in the treatment of amatoxin poisoning.10 11 12 Treatment included intravenous silibinin, oral silymarin, intravenous N-acetylcysteine, oral multiple-dose activated charcoal, high-dose intravenous penicillin, and early charcoal haemoperfusion. Two local cases progressed to liver failure and required liver transplantation. The remaining four cases recovered with medical treatment. The diagnosis of amatoxin poisoning was confirmed by the presence of amatoxin and/or phallacidin in the urine in five patients. Mycological examination identified Amanita farinosa as the causative mushroom in a local incident with two patients (Table 4). This is the first report of this Amanita species in Hong Kong.

Hallucinogenic mushroom poisoning has not been previously reported locally. The clinical presentation of our four cases included dizziness, headache, generalised weakness and numbness. Three out of four patients presented with visual hallucination. Although one patient did not report any hallucinations, the patient was included as a suspected case of hallucinogenic mushroom poisoning based on compatible neurological symptoms following consumption of porcini. The symptom onset time was documented in two cases and was 2 hours and 10 hours post-ingestion. The source of mushroom was recorded in three cases as mainland China. In only one case was mycological identification performed (Table 4).

There were 13 cases of bolete poisoning in this case series. All cases were related to consumption of porcini. Porcini is considered to be a delicacy by many mushroom lovers. It includes a number of edible Boletus species, with Boletus edulis being the best known. Not all Boletus are edible, however, and mixing edible and inedible species is possible in wild mushroom harvesting. There are reports of bolete poisoning in English and Chinese literature.6 Bolete consumption has been associated with outbreaks of neuropsychiatric symptoms in Southwest China (eg Yunnan province) in recent years.13 14 15 According to these reports, consumption of inedible boletes typically presented with gastrointestinal and neurological symptoms including visual and auditory hallucination. In our case series, two out of 13 cases of bolete poisoning presented with neuropsychiatric symptoms without gastrointestinal symptoms. The two unrelated cases purchased mushrooms from Yunnan province. The first patient presented with numbness and weakness in all four limbs, dizziness, and malaise after mushroom consumption. The time of symptom onset was not documented and symptoms resolved on the same day as mushroom consumption. No mushroom sample was obtained for identification. The second patient developed dizziness, malaise, and visual hallucination 10 hours after mushroom consumption. Her symptoms resolved 48 hours post-ingestion. The causative mushroom was identified as T nigerrimus, an inedible bolete. Hallucinogenic mushroom poisoning caused by T nigerrimus has not been reported in the English literature.

In the cases of bolete poisoning, 11 out of 13 presented with gastrointestinal symptoms after mushroom consumption. Four patients purchased the mushrooms locally, and seven purchased the mushrooms in China. In most cases, the mushrooms were commercially packed as a product containing wild-harvested boletes in dried slices. Mycological identification was performed in 10 cases. These 10 cases represented six poisoning incidents. In five incidents involving eight patients, the wild-harvested porcini showed mixing up of edible porcini and inedible boletes. In the remaining one incident, the mushrooms were identified as an edible species, although microscopic examination revealed them to be rotten with dried worm and mold (Table 4). The diagnosis was food poisoning with possibly bacterial contamination of spoiled mushroom in this incident.

Most cases of mushroom poisoning in Hong Kong follow a benign course. Life-threatening cases of amatoxin poisoning are occasionally seen. Doctors should consider this diagnosis in patients who present with gastrointestinal symptoms whose onset is 6 hours or more after mushroom consumption. In this review, all patients with amatoxin poisoning picked the poisonous mushroom from the wild. Wild mushroom picking and consumption should be strongly discouraged.

1. Centre for Health Protection. Food poisoning associated with wild mushroom. Communicable Disease Watch 2005;2:41-2.

2. Chan TY, Chiu SW. Wild mushroom poisonings in Hong Kong. Southeast Asian J Trop Med Public Health 2011;42:468-9.

3. Diaz JH. Syndromic diagnosis and management of confirmed mushroom poisonings. Crit Care Med 2005;33:427-36. Crossref

4. Hoffman RS, Howland MA, Lewin NA, et al. Goldfrank’s toxicologic emergencies. 10th edition. New York: McGraw-Hill Education; 2015.

5. Chang ST, Mao XL. Hong Kong mushrooms. Hong Kong: The Chinese University Press; 1995.

6. Schenk-Jaeger KM, Rauber-Lüthy C, Bodmer M, Kupferschmidt H, Kullak-Ublick GA, Ceschi A. Mushroom poisoning: a study on circumstances of exposure and patterns of toxicity. Eur J Intern Med 2012;23:e85-91. Crossref

7. Jin LM, Li Q. 金連梅, 李群. [Analysis of food poisoning incidents during 2004 to 2007 in China] 2004-2007年全國食物中毒事件分析 [in Chinese]. [Disease Surveillance] 疾病監測 2009;24:459-61.

8. Guo SH, Liu FQ, Liu XY, Chen Y. 郭綬衡，劉富强，劉秀英，陳焱. [Analysis of food-borne disease incidents in Jiangsu, Zhejiang, Hunan, Hubei and Hebei Province during 2000 to 2002] 2000-2002年江蘇、浙江、湖南、湖北、河北五省食物源性疾病發病情况分析 [in Chinese]. [Practical Preventive Medicine] 實用預防醫學 2004;11:867-71.

9. Mao XW, Li YY, He JY, Jing QL. 毛新武，李迎月，何潔儀，景飲隆. [Investigation of mushroom poisoning in Guangzhou City from 2000 to 2005] 廣州市 2000-2005年蘑菇中毒調查 [in Chinese]. [China Tropical Medicine] 中國熱帶醫學 2007;7:166-7.

10. Ward J, Kapadia K, Brush E, Salhanick SD. Amatoxin poisoning: case reports and review of current therapies. J Emerg Med 2013;44:116-21. Crossref

11. Enjalbert F, Rapior S, Nouguier-Soulé J, Guillon S, Amouroux N, Cabot C. Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 2002;40:715-57. Crossref

12. Giannini L, Vannacci A, Missanelli A, et al. Amatoxin poisoning: a 15-year retrospective analysis and follow-up evaluation of 105 patients. Clin Toxicol (Phila) 2007;45:539-42. Crossref

13. Ji X, Ma Z, Zhu H, Pan YZ. 及曉，馬征，朱輝，潘軼竹. [Report of two cases of mental disorder due to ingestion of Boletus speciosus] 小美牛肝菌所致精神障礙2例 [in Chinese]. [Clinical Journal of Psychiatry] 臨床精神醫學雜誌 2014;24:240.

14. Liu MW, Zhou H, Hao L, Zhang MQ. 劉明偉，周惠，郝麗，張明謙. [Analysis of 61 cases of boletus poisoning] 牛肝菌中毒61例分析 [in Chinese]. [Chinese Journal of Misdiagnosis] 中國誤診學雜誌 2008;8:111.

15. Zhou YJ, Wei GL, Chen GH. 周亞娟，魏桂蘭，陳桂華. [Investigation of Rhubarb boletus food poisoning] 一起黄粉牛肝菌食物中毒事件調查 [in Chinese]. [Occupational Health and Damage] 職業衛生與病傷2008;23:115-6.

Prostate cancer is the most common cancer diagnosed in men in developed countries. In the United States, there were 240 890 estimated new cases in 2011, accounting for 29% of all new cancers in men and over 33 000 deaths.1 According to the Hong Kong Cancer Registry in 2012, prostate cancer was the third most common cancer in men.2

The overall incidence of advanced-stage prostate cancer has declined in recent years, probably due to early detection and treatment following application of prostate-specific antigen (PSA) for prostate cancer screening.3 Nonetheless it has been shown that approximately 4% of patients present with metastatic disease at the time of diagnosis1 and 5% present with localised or regional disease that eventually metastasises.4

Bone is the major metastatic site of prostate cancer, and has been observed in 90% of patients during autopsy.4 Common sites of metastases include the vertebrae, pelvis, long bones, ribs, and skull. Bone metastases cause major morbidity in patients with prostate cancer. They weaken the structural integrity of bone, leading to an increased risk for skeletal-related events (SREs) such as pathological fracture, spinal cord compression, and severe bone pain requiring palliative radiotherapy or surgery to bone.5 6

The prognosis of localised and regional prostate cancer is excellent while that of metastatic prostate cancer is poor. The 5-year survival rate in patients with metastatic disease has been reported to be as low as 30%1 with a mean survival of 24 to 48 months.7 8

Evidence of the importance of SREs for survival in metastatic prostate cancer is limited. Oefelein et al9 evaluated men with prostate cancer who were prescribed androgen deprivation therapy (ADT) regardless of staging. The relative risk of skeletal fracture for mortality was 7.4. In another retrospective study, patients with bone metastasis from different primary tumours were analysed.10 In the subgroup analysis, pathological fracture increased risk of death by 20% in patients with prostate cancer although the authors failed to demonstrate statistical significance.10 A population-based cohort study demonstrated that mortality in men with metastatic prostate cancer and SREs were approximately twice that of patients with no SREs.11 Treatments for prostate cancer were, however, not recorded or analysed in the study.11

The aim of this study was to investigate the impact of SREs on survival, specifically in patients with carcinoma of the prostate with bone metastasis prescribed long-term ADT. Prognostic factors of survival in patients with SREs were also investigated.

The study period was between 1 January 2006 and 31 December 2011. Patients who were diagnosed with prostate cancer and bone metastasis and who underwent either bilateral orchiectomy or were prescribed a first dose of luteinising hormone releasing hormone analogue (LHRHa) injection during the study period at either Queen Mary Hospital or Tung Wah Hospital in Hong Kong were included. Patients were followed up until death or the last follow-up taken on 31 March 2014.

Diagnosis of carcinoma of the prostate was made following transrectal ultrasound-guided prostate biopsy, incidental histological findings of transurethral resection of a prostate specimen, biochemical diagnosis of PSA of >100 ng/mL, or other histological evidence such as bone biopsy in patients who presented with pathological fracture. Presence of bone metastasis was confirmed either by bone scan or by cross-sectional imaging such as computed tomography (CT) or magnetic resonance imaging (MRI). Patients who had evidence of bone metastases at four or more sites or visceral metastasis were regarded as having high-volume disease. Patients with medical castration were prescribed regular LHRHa injection every 3 months. Patients with underlying metabolic bone disease were excluded from study. In this study, SRE was defined in patients who developed pathological fractures, cord compression related to bone metastasis, and/or those who received irradiation or prophylactic surgery to bone metastasis.6 7 Castration-resistant prostate cancer (CRPC) was diagnosed when there were at least two consecutive rises in PSA, at least 1 week apart, with PSA of >2 ng/mL.

Data were collected from the electronic clinical management system database in the government health care system. Patients who underwent bilateral orchiectomy or received the first dose of LHRHa within the study period were shortlisted, reviewed, and then recruited as eligible patients according to the inclusion criteria. Data were collected from in-patient and out-patient records and included age at diagnosis; performance status; any bone pain at diagnosis; imaging such as bone scan, CT, and MRI; volume of metastasis; details of ADT and SREs; history of metabolic bone disease; CRPC status; treatment received for prostate cancer; and date and causes of death. Two authors (KW Wong and CF Tsang) abstracted the data and were not blinded to the outcomes.

Data were analysed using the Statistical Package for the Social Sciences (Windows version 21.0; SPSS Inc, Chicago [IL], US). The primary outcome was survival time, calculated from the date of start of ADT until death or the last follow-up. Survival was described with Kaplan-Meier curves. Univariate and multivariate analyses were performed with Cox regression model to predict prognostic factors for survival. The dependent variables were time to death (overall and cancer-specific), defined as the time from the start of ADT to death. Prognostic variables significant in the univariate analyses were entered into the multivariate Cox regression models.

A total of 119 eligible patients were identified within the study period. The mean age at prostate cancer diagnosis was 75 (range, 49-94) years. Initial ADT was by bilateral orchiectomy or LHRHa injection in 58 and 61 patients, respectively, with seven patients subsequently switched from injection to bilateral orchiectomy. The median time of follow-up was 28 (range, 1-97) months. No patient was lost to follow-up during the study.

The baseline characteristics of patients are summarised in Table 1. When stratified according to the presence of SREs, the two groups did not differ significantly in total Gleason score of prostate cancer, PSA level at the time of diagnosis, PSA nadir, Eastern Cooperative Oncology Group (ECOG) performance status, volume of metastasis, presence of bone pain at the start of ADT, or mode of ADT. Patients with SREs were slightly younger at the time of diagnosis (73.1 vs 76.3 years; P=0.04) and had a shorter mean follow-up time (28.5 vs 39.1 months; P=0.02). More patients with SREs developed CRPC when compared with those who did not have SREs (84.6% vs 65.7%; P=0.02).

The treatment received by patients with and without SREs were compared (Table 1). Only treatments received prior to development of SREs were included in Table 1 to analyse whether the baseline characteristics of treatment differed before the development of SREs. The proportion of patients prescribed chemotherapy, bicalutamide, flutamide, ketoconazole, cyproterone acetate, and calcium supplement was statistically similar for the two groups. Only two patients in each group received abiraterone and denosumab therapy. No patient received sipuleucel-T, cabazitaxel, enzalutamide, radium-223, or other novel treatment for prostate cancer throughout the study period.

Of 119 patients, 52 (43.7%) developed SREs. A total of 69 SREs were recorded—36 (69.2%) patients had one SRE, 15 (28.8%) patients had two SREs, and one patient had three SREs. Irradiation to bone for pain control accounted for 47 (68.1%) events; 14 (20.3%) events were cord compression and there were eight (11.6%) events of pathological fractures without cord compression. No patient underwent prophylactic surgery for bone metastasis. With regard to timing of SRE development, 13 (10.9%) patients had SRE as the initial presentation of metastatic prostate cancer. The overall cumulative incidence of SREs at 1 year and 5 years of diagnosis was 23.5% and 42.9%, respectively (Fig 1).

The median time required to develop CRPC status from the start of ADT was 9 months (Fig 2a). When stratified according to the presence of SREs, the median time to CRPC status from ADT initiation was significantly shorter in patients with SREs than in those without (6 vs 12 months, log-rank test, P=0.001; Fig 2b).

The actuarial overall survival (OS) and cancer-specific survival (CSS) curves are shown in Figure 3. The 5-year actuarial OS and CSS was 32% and 43%, respectively. Among men without SREs, 38 (56.7%) patients died, compared with 44 (84.6%) patients in the SRE group. When stratified according to presence of SREs (Fig 4), the median OS and CSS for patients with SREs were significantly shorter than that for patients without SREs (log-rank test: 23 vs 48 months, P=0.003 and 26 vs 97 months, P<0.001, respectively).

Various possible factors that could affect survival were analysed (Table 2a). All treatments for prostate cancer received both before and after SRE were included. Univariate analysis revealed that in terms of OS, presence of SREs (P=0.003), PSA nadir of >4 ng/mL (P<0.001), ECOG grade 2 or above (P=0.01), and calcium supplement (P=0.03) were significant risk factors. On multivariate analysis, only the presence of SREs and PSA nadir of >4 ng/mL remained statistically significant, with hazard ratio (HR) of 2.73 (95% confidence interval [CI], 1.46-5.10; P=0.002) and 3.01 (95% CI, 1.54-5.90; P=0.001), respectively. In terms of CSS, presence of SREs (P<0.001), PSA nadir of >4 ng/mL (P=0.004), and ketoconazole therapy (P=0.05) remained significant risk factors on both univariate and multivariate analyses. The HR for the presence of SREs, PSA nadir of >4 ng/mL, and ketoconazole therapy was 3.92 (95% CI, 1.87-8.23; P<0.001), 2.98 (95% CI, 1.43-6.23; P=0.004), and 2.10 (95% CI, 1.01-4.38; P=0.05), respectively.

The median survival period after occurrence of SRE was 11.5 months. A post-hoc analysis for OS and CSS after SRE revealed PSA nadir of >4 ng/mL as the only independent predictor for survival after SRE in both univariate and multivariate analyses, with HR of 10.42 (95% CI, 2.10-51.66; P=0.004) and 10.54 (95% CI, 1.94-57.28; P=0.006), respectively (Table 2b).

The importance of SREs in survival of patients with prostate cancer with different disease stage and treatments was studied10 11 12 but not specifically in patients with metastatic prostate cancer prescribed ADT. This group of patients was selected because patients with metastatic prostate cancer are at risk of developing SREs.11 In addition, ADT is the standard first-line treatment for metastatic prostate cancer.12 It has been proven to provide a clear benefit in terms of preventing SREs.13 Focusing on patients who are prescribed ADT can ensure that the effect of ADT in preventing SREs is balanced out during analysis. A study by Oefelein et al9 showed that skeletal fractures negatively correlate with OS in men with prostate cancer prescribed ADT, but it included patients with localised disease and all kinds of fracture including osteoporotic fractures. Berruti et al4 reported the incidence of skeletal complications in patients with CRPC and bone metastasis, but failed to demonstrate any difference in survival between patients with and without skeletal complications. Multivariate analysis was not performed on survival either. Daniell et al14 15 reported eight fractures in 49 patients with prostate cancer at various times following orchiectomy but did not take into account the preventive effect of ADT in SREs.13 In our study, patients with SREs had much worse OS and CSS when compared with those without SREs (23 vs 48 months and 26 vs 97 months, respectively), and remained significantly so after multivariate Cox regression analysis. To our knowledge, this is the first reported study to investigate the impact of SREs on survival in this homogeneous group of patients.

The baseline characteristics were similar between patients with or without SREs except that those with SREs were slightly younger at diagnosis (73.1 vs 76.3 years; P=0.04). This, however, does not affect data interpretation since age at diagnosis was not a significant factor in subsequent analyses for both OS and CSS. In our targeted group of patients with metastatic prostate cancer prescribed ADT, the presence of SREs was first shown to be an independent predictive factor for OS and CSS with a notable HR of 2.73 and 3.92 respectively, taking into account baseline cancer characteristics, ECOG performance status, development of CRPC status, and different treatments received. In addition, PSA nadir was found to be another predictive factor for OS and CSS. This finding has been reported in previous studies16 although most included patients who were heterogeneous in terms of clinical stage of prostate cancer. Kitagawa et al16 showed that PSA nadir of >4 ng/mL was associated with HR of 5.22 (95% CI, 2.757-9.89; P<0.001) in OS in patients with prostate cancer. The cohort, however, included patients with either locally advanced non-metastatic disease or metastatic disease. Park et al17 reported that a higher PSA nadir level correlated with shorter CSS. Similar to the previous study,16 patients with lymph node metastasis were also included. In another retrospective study,18 a high PSA nadir level was shown to be associated with shorter OS in a homogeneous group of patients with metastatic prostate cancer prescribed ADT. Nonetheless only 87 patients were included in the study. In our study, in patients who developed SREs, PSA nadir was the only predictive factor for both OS and CSS with HR of 10.42 and 10.54, respectively. This is previously unreported.

Various treatments have been proven to improve OS in patients with metastatic prostate cancer, including docetaxel,19 cabazitaxel,20 abiraterone,21 22 23 sipuleucel-T,24 and enzalutamide.25 26 Various bone-modulating agents have also been studied for patients with bone metastasis. Bisphosphonate therapy has been shown to improve bone mineral density and quality of life,27 28 and reduce the incidence of SREs in patients with metastatic CRPC in a randomised controlled trial (RCT), although there was no proven survival benefit.6 The receptor activator for nuclear factor κB ligand (RANKL) inhibitor denosumab is another bone-modulating agent proven to reduce the incidence of SREs in metastatic CRPC patients but also without survival benefit.29 30 Radium-223, a bone-seeking calcium-mimicking alpha emitter, was shown in a RCT31 to not only delay first symptomatic SRE, but also improve OS. Therefore, when investigating the incidence of SRE and survival in these groups of patients, the aforementioned treatments have to be taken into account. In our study, treatments received by patients without SREs and in patients prior to development of SREs were statistically similar (Table 1). The number of patients prescribed chemotherapy or novel hormonal agents was relatively small in our series. Sipuleucel-T, enzalutamide, and radium-223 were not available in this locality during the study period. Denosumab and abiraterone therapies were used by only two patients in each group as these medications were not subsidised by the local government and were not affordable for many patients. Docetaxel has been shown to improve bone pain and OS in a phase III RCT.19 After development of SREs, six more patients received chemotherapy in our series. All but one patient received docetaxel. The remaining patient received estramustine and etoposide before development of SREs. The fact that all patients prescribed docetaxel were in the SRE group suggests that its potential benefit in improving OS has been offset by SREs and so this is not a confounding factor in our study.

The overall prevalence of bisphosphonate therapy was low (17%). Nine patients received bisphosphonate therapy only after development of SREs. In fact, in patients receiving bisphosphonate therapy, two out of seven patients without SREs and six out of 13 patients with SREs only received one dose of bisphosphonate due to various reasons, including side-effects of the medication, affordability, and early mortality after medication. With the heterogeneous timing of start and duration of therapy, we cannot accurately comment on the benefit of bisphosphonate in our series. No further patient received RANKL inhibitor or abiraterone after development of SREs.

Since the pre-chemotherapy era, the concept of complete androgen blockade with classic hormonal manipulation by both steroidal anti-androgen, such as cyproterone acetate,32 and non-steroidal anti-androgen (such as bicalutamide,33 flutamide,34 and nilutamide35) has been widely adopted when patients develop CRPC status. This practice remains in use in this locality despite the fact that no associated survival benefit has ever been reported12 due to the side-effects and availabilities of aforementioned novel treatments for CRPC. Ketoconazole, a broad-spectrum imidazole antifungal agent, was previously the hormonal treatment of choice after anti-androgen withdrawal for complete androgen blockade.35 It works by preventing adrenal steroidogenesis with inhibition of the enzyme cytochrome P450 14 alpha-demethylase.36 Bicalutamide, flutamide, cyproterone acetate, and ketoconazole were used in our centre for hormonal manipulation. Interestingly, ketoconazole use appeared to have a deleterious effect on CSS even with multivariate Cox regression in our study. This result contradicts that of a phase III RCT35 which showed positive PSA and objective response but no survival benefit or harm. As our study was retrospective in nature, the implication of ketoconazole use is doubtful based on the results of this study and requires further evaluation.

With a median follow-up of 28 months, the incidence of SREs in men with metastatic prostate cancer was high (43.7%) and is comparable with 43.6% reported from the Danish group population-based cohort study with similar follow-up period.11 The median time to CRPC status from first ADT was 9 months, which is 5.7 months shorter than the control arm of the CHAARTED trial.37 This may be explained by the fact that the CHAARTED trial included patients prescribed ADT for less than 24 months but those with disease progression within 12 months were excluded.

We obtained local data of the natural history of metastatic prostate cancer with or without SREs and the impact of SREs on survival. A PSA nadir of >4 ng/mL was an independent poor prognostic factor for OS and CSS after development of SREs. Its clinical use in terms of predicting prognosis and patient counselling is highly feasible. Based on our results, prevention of SREs in patients with metastatic prostate cancer may translate to longer survival. Nonetheless most bone-targeting therapies, including bisphosphonate therapy and RANKL inhibitors, have failed to demonstrate survival benefit even though they prevent SREs.6 30 34 38 Radium-223 appears to hold promise as it delays symptomatic SREs by 5.8 months and improves OS by 3.8 months in metastatic prostate cancer patients.31 Further studies are needed in this field.

There are several limitations in this study. This was a retrospective study with small sample size so statistical power is limited. There are even fewer patients in post-hoc analysis. The data collected may not accurately reflect the condition of patients because the follow-up protocol was not standardised. Furthermore, the data abstraction process was not blinded. For better presentation of data, several factors such as PSA nadir, initial PSA, and age at diagnosis were analysed as categorical data. This could lead to information bias. The definition of CRPC was less stringent than that suggested from international guidelines12 because testosterone level and follow-up imaging such as bone scans were not routinely performed due to limited resources. Potential confounding factors for survival such as smoking and co-morbidity were also not included in the study and may have affected the validity of the results. The small number of patients prescribed novel treatments or bone-modulating agents did not allow a comprehensive understanding of their influence on SRE occurrence. Further prospective trials with a large cohort size are necessary.

Skeletal-related events were common in men with metastatic prostate cancer and were first shown by this study to be an independent prognostic factor of OS and CSS in patients with metastatic prostate cancer prescribed ADT. A PSA nadir of >4 ng/mL is an independent poor prognostic factor for OS and CSS following development of SREs.

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6. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879-82. Crossref

7. Galasko CS. Skeletal metastases. Clin Orthop Relat Res 1986;210:18-30. Crossref

8. Logothetis CJ, Navone NM, Lin SH. Understanding the biology of bone metastases: key to the effective treatment of prostate cancer. Clin Cancer Res 2008;14:1599-602. Crossref

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10. Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 2007;110:1860-7. Crossref

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12. Mottet N, Bastian PJ, Bellmunt J, et al. European Association of Urology Guidelines on Prostate Cancer 2014. Available from: http://uroweb.org/wp-content/uploads/1607-Prostate-Cancer_LRV3.pdf. Accessed 6 Oct 2015.

13. Nair B, Wilt T, MacDonald R, Rutks I. Early versus deferred androgen suppression in the treatment of advanced prostatic cancer. Cochrane Database Syst Rev 2002;(1):CD003506.

14. Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997;157:439-44. Crossref

15. Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000;163:181-6. Crossref

16. Kitagawa Y, Ueno S, Izumi K, et al. Nadir prostate-specific antigen (PSA) level and time to PSA nadir following primary androgen deprivation therapy as independent prognostic factors in a Japanese large-scale prospective cohort study (J-CaP). J Cancer Res Clin Oncol 2014;140:673-9. Crossref

17. Park YH, Hwang IS, Jeong CW, Kim HH, Lee SE, Kwak C. Prostate specific antigen half-time and prostate specific antigen doubling time as predictors of response to androgen deprivation therapy for metastatic prostate cancer. J Urol 2009;181:2520-4; discussion 2525. Crossref

18. Sasaki T, Onishi T, Hoshina A. Nadir PSA level and time to PSA nadir following primary androgen deprivation therapy are the early survival predictors for prostate cancer patients with bone metastasis. Prostate Cancer Prostatic Dis 2011;14:248-52. Crossref

19. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12. Crossref

20. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147-54. Crossref

21. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138-48. Crossref

22. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005. Crossref

23. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012;10:983-92. Crossref

24. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-22. Crossref

25. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424-33. Crossref

26. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-97. Crossref

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30. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813-22. Crossref

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33. Scher HI, Liebertz C, Kelly WK, et al. Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 1997;15:2928-38.

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Click here to watch a video clip showing hysteroscopic intrauterine morcellation of submucosal fibroids

Submucosal fibroids are a common cause of heavy menstrual bleeding.1 Traditionally, conventional hysteroscopic monopolar loop resection of such fibroids represents the surgical treatment of choice (Fig 1a). Hysteroscopic management of such fibroids using the intrauterine morcellation (IUM) technique (eg MyoSure, Hologic, Bedford, US; Truclear, Smith & Nephew Inc, Andover, US; Fig 1b), however, is increasingly being used worldwide but no literature concerning its safety and efficacy is available within our local population.

Our hospital is one of the first to introduce the use of the hysteroscopic IUM device in Hong Kong. This preliminary review looks at the safety, satisfaction, and efficiency of such technique when performed within our hospital and within a Chinese population. Comparisons were made between the conventional hysteroscopic monopolar loop resection technique and IUM technique with the aim of identifying the potential benefits that have been described by previous studies worldwide.

All cases of hysteroscopic resection of submucosal fibroids performed at Queen Elizabeth Hospital, Hong Kong, between 1 January 2011 and 31 December 2014, either by IUM (MyoSure) or conventional hysteroscopic monopolar loop resection, were selected and the case notes were reviewed. Choice of method was dependant on the operator but all cases using the IUM method were performed between the years 2013 and 2014 after its introduction in our department. Patients were identified from the Clinical Data Analysis and Reporting System through specialised coding. Detailed technical aspects of both operations were collected using a self-designed proforma with information collected via the Clinical Management System computerised record system. Analysis and comparison of technical details such as fibroid size, operating time, fluid deficit, operative complications, and patient satisfaction were made between the IUM and the conventional groups. Fibroid size was measured via preoperative abdominal and/or vaginal fluid–infused sonography, and confirmed during diagnostic hysteroscopy prior to resection. Those cases with prolonged operating time due to multiple operations for other indications or complications were excluded from final analysis. In our hospital, monopolar energy was used during conventional loop resection, hence glycine was used as the distending medium. With the IUM technique, since no energy source was required during morcellation, normal saline was used as the distending medium. Operating time was measured from the time the patient was anaesthetised to completion of the operation. Hence operating time included the time required to position the patient, cleaning, draping, and the time for setting up equipment. In the IUM system, fluid deficit calculations were accurately measured by the Aquilex Fluid Control System (Hologic, Bedford, US). With the conventional method, deficit calculations were based on the amount of fluid entered minus the amount of fluid suctioned and retrieved intra-operatively. Postoperatively, a satisfactory outcome was considered when the patient subjectively reported reduced menstrual bleeding and considered the operation to have improved menstrual symptoms at 3 months’ follow-up. Pre- and post-operative haemoglobin levels within 3 months of follow-up and differences between them were also investigated. All results were statistically analysed using the Statistical Package for the Social Sciences (Windows version 22.0; SPSS Inc, Chicago [IL], US). Statistical significance was represented by P values that were calculated using the Chi squared test for patient satisfaction and Mann-Whitney test for the remaining tests. P values of <0.05 were considered statistically significant for all of the data.

The research protocol was approved by the Ethics Committee of the study hospital. The patients were not required to undergo additional tests or visits, and therefore consent from the patients was not required.

During the study period, 29 patients with submucosal fibroids were treated with hysteroscopic surgery at Queen Elizabeth Hospital, Hong Kong. Conventional hysteroscopic monopolar loop resection was performed in 14 patients and IUM with the MyoSure device in 15.

Among those who underwent surgery using the conventional technique, one patient experienced a uterine perforation that required surgical repair and was excluded from data analysis. No complications occurred in any patient in the IUM group. Two patients from the IUM group and one from the conventional group were excluded due to the need for multiple procedures including endometrial ablation or laparoscopic ovarian cystectomy during the same operation. The remaining patients were all well and discharged the day after their operation regardless of the hysteroscopic technique used.

The mean size of fibroids resected was 3.3 cm (range, 2-5 cm; median, 3 cm) for the conventional technique and 3.5 (range, 1.5-6 cm; median, 3 cm) for the IUM group, although they were not significantly different (P=0.470). The operating time was significantly shorter using the IUM technique (mean, 36.6 mins; range, 17-72 mins) compared with the conventional technique (mean, 53.6 mins; range, 39-102 mins) [P=0.005]. Total fluid deficit, however, was significantly greater when using the IUM technique (1005 mL; range, 40-2600 mL) compared with the conventional technique (225 mL; range, 0-1000 mL) [P=0.003; Table 1]. No patient in either group developed any complication associated with excessive fluid absorption.

At 3 months’ follow-up, there was no significant difference in the overall outcome between the two groups: 84.6% of patients who underwent the conventional method versus 93.3% of those who underwent IUM were pleased with their overall outcome (P=0.841). Within the conventional group, the mean preoperative haemoglobin level was 95.4 g/L (range, 81-121 g/L). The mean postoperative haemoglobin level of nine patients who returned with blood results was 119 g/L (range, 91-137 g/L). The difference between pre- and post-haemoglobin level in the conventional resection group was +21.5 g/L (range, +1 to +44 g/L). In the IUM group, two patients were excluded from this part of the analysis as the indication for surgery was post-menopausal bleeding, not menorrhagia. For the remaining 11 patients, the mean preoperative haemoglobin level was 99.1 g/L (range, 62-120 g/L). The mean postoperative haemoglobin level among the nine patients in the IUM group who returned with results was 108.8 g/L (range, 90-124 g/L). The mean improvement in haemoglobin level was +17.0 g/L (range, -4 to +40 g/L). There was no significant difference between the change in haemoglobin level pre- and post-operatively between the IUM and conventional groups (P=0.235, Mann-Whitney test; Fig 2).

For both techniques, each group had two patients in whom fibroid protrusion was <60% within the uterine cavity, with the remaining patients all having >60% protrusion. Of those with <60% protrusion, each group had one (50%) of two patients who was satisfied with the procedure. In those with >60%, 100% of patients were satisfied (n=10 for conventional group and n=11 for IUM group; Table 1).

The data were further divided into groups of small and large fibroids with the cut-off of 3.0 cm to differentiate the two groups. With regard to small fibroids of ≤3.0 cm, the mean duration of procedure was significantly reduced among those using the IUM system (mean, 27.6 mins vs 53.4 mins; P=0.019), but fluid deficit was significantly greater (mean, 634.4 mL using IUM vs 80 mL using conventional technique; P=0.019; Table 2). There was no statistical difference in overall satisfaction for the two methods. When the procedure involved larger fibroids (>3.0 cm), there was no difference in operating time (P=0.527) or patient satisfaction (P=0.788) between the two methods but considerably more fluid deficit was again generated using the IUM system (mean, 328.6 mL using conventional technique vs 1839 mL using IUM; P=0.024; Table 2).

When we reviewed the data for all patients who underwent submucosal fibroid resection using the IUM technique, the procedural time was significantly reduced, while fluid deficit had a lowering trend with smaller fibroids compared with larger fibroids. Regardless of fibroid size, however, there was no significant difference in overall patient satisfaction (P=0.710; Table 3).

Hysteroscopic surgery using hysteroscopic monopolar loop resection has always been the conventional method to resect submucosal fibroids. Recently, hysteroscopic intrauterine morcellators such as MyoSure have been increasingly used as an alternative. Reports have suggested that such techniques to remove submucosal fibroids and polyps are as effective as the conventional hysteroscopic resection while fibroid symptom–related quality of life is improved and the recurrence of endometrial polyp reduced.2 3 Reports have suggested that IUM may be associated with adverse complications such as bowel damage, hysterectomy, uterine perforation, and pelvic infection, but an adverse event complication rate of <1% for hysteroscopic morcellation technique is lower than that for conventional electrocautery.4 Other reports have suggested additional benefits such as reduction in instances of uterine perforation, cervical dilation, thermal bowel injury, and intrauterine adhesions when comparing the use of such a device with conventional methods. Operating time, fluid absorption, and the need for a second operation may also be reduced.5 6 7

Despite its increasing popularity worldwide, the IUM technique remains a relatively new concept within the Chinese population. In this retrospective review, among the 13 patients who underwent IUM for the management of submucosal fibroids, none developed intra-operative complications or postoperative complications that could lead to an extended hospital stay.

Excessive fluid deficit and subsequent fluid absorption remains a concern with hysteroscopic surgery. Electrolyte imbalance as well as cardiac collapse and death can occur in severe cases. This is more likely if hypotonic glycine is used as the uterine distention medium: normal saline reduces such risks.8 In our study, the IUM technique was associated with significantly higher fluid deficit regardless of fibroid size being morcellated. One explanation of this is the fast fluid pumping device that is used with the IUM. High fluid flow within the cavity is important to maintain a clear view during the morcellation procedure and to maintain a high intrauterine pressure to prevent bleeding during the myoma morcellation process. Normal saline was used in the IUM technique instead of glycine (which was used in conventional technique). Despite its significantly higher fluid deficit, no patients experienced any associated complications.9 In both techniques and regardless of the size of the submucosal fibroids, the total amount of fluid deficit remained within or just above the maximum limit of 2500 mL of saline or 1000 mL glycine set by AAGL (American Association of Gynecologic Laparoscopists).10 One patient who underwent IUM had 100 mL (2600 mL) above the recommended maximum fluid deficit limit. This was due to the additional time required to completely resect a large 6-cm fibroid and avoided a second operation. This patient recovered well and did not have any complications. Hence despite the excessive fluid deficit, IUM remains a safe procedure.

When the technicalities of both techniques were compared, the total time required for the operation was significantly reduced when the IUM technique was used. This was particularly significant if the fibroid size was ≤3 cm but not if the fibroid was >3 cm; 3 cm was chosen as the cut-off between small and large fibroid as previous studies have already shown morcellation of submucosal fibroids of ≤3.0 cm to be safe and effective.11 12 One of the main reasons for the reduced operating time was the constant suction mechanism at the morcellator blade of the IUM device. This suction constantly removes resected material to maintain a clear view of the uterine cavity. The material is collected directly into the Aquilex Fluid Control System that is required for the MyoSure IUM device. As a result, unlike the conventional method, the need to constantly remove fibroid chips during the procedure is avoided and hence operating time is reduced. With the larger-sized fibroids, the time needed to morcellate the large fibroid will still be considerable so there is a smaller difference compared with conventional methods. One may suggest that the reduced time difference may be due to the experience of the operator, as the IUM is a new technique within our department. Previous study has suggested that both experienced operators and training doctors favour the morcellation technique and the learning curve is minimal.12 Familiarisation with the setup of the system, the technique of hysteroscopic morcellation, management of a loose cervix that can cause fluid leakage as well as fluid control to maintain haemostasis versus a clear visual field remain a challenge. Given more experience with the IUM system, reduced operating times will become more significant. This proposed reduction in operating time will benefit both patient (eg anaesthetic exposure) and the institution (reduced waiting time for operation). Other potential benefits described by other studies such as reduced uterine perforation, cervical dilation, thermal bowel injury, and intrauterine adhesions5 6 7 cannot be determined given the small number of cases performed so far. Nonetheless, there has been one case of uterine and subsequent bowel perforation with the conventional technique and none with the IUM technique in this study.

Patient satisfaction in terms of reduced or improved menstrual symptoms showed no significant difference at 3 months’ follow-up when the IUM technique was compared with the conventional technique. Haemoglobin levels improved following hysteroscopic resection of fibroid regardless of the technique used, with no significant difference in improvement between the two groups. Patient satisfaction again showed no statistically significant difference regardless of the size of the submucosal fibroids, suggesting that the IUM technique can be applied to large fibroids. If cases were carefully selected and only submucous fibroids with less than 50% of the contents intramural were surgically resected as suggested by Di Spiezio Sardo et al,7 the satisfaction rate would remain the same between the two techniques, that is both achieved 100% satisfaction.

Although results regarding safety, effectiveness, and benefits of the IUM technique appear to be promising, this study remains a preliminary overview as the strength of the evidence is limited by the small number of cases. The limited sample may not be representative of the general population and the two groups using different techniques may not be comparable. As a result of the small numbers, this in itself and the non-parametric test used due to the lack of numbers reduce its statistical power. Limitations also arise when the skill of the surgeon varies and the total operating time incorporates the time for preparation and setting up for the procedure. The latter may cause discrepancy in the actual total operating time. Further prospective studies or randomised controlled trials with more subjects, a limited number of surgeons with similar hysteroscopic skills, and a more accurate surgical time measurement would be more beneficial. More standardised outcome measures using a combination of haemoglobin improvement, menstrual chart, and/or patient satisfaction surveys may also improve the strength of future studies.

This retrospective review suggests that hysteroscopic IUM is a safe and effective technique for management of menorrhagia secondary to submucosal fibroid. Preliminary data suggest the technique to be as safe and effective as, and less time-consuming than, conventional techniques. Maximum benefit would be achieved if submucosal fibroid cases for IUM resection were carefully selected, with particular reference to patients in whom >50% of the fibroid protrudes into the uterine cavity and where maximum diameter is ≤3 cm.

No conflicts of interest were declared by authors.

1. Puri K, Famuyide AO, Erwin PJ, Stewart EA, Laughlin-Tommaso SK. Submucosal fibroids and the relation to heavy menstrual bleeding and anemia. Am J Obstet Gynecol 2014;210:38.e1-7. Crossref

2. Rubino RJ, Lukes AS. Twelve-month outcomes for patients undergoing hysteroscopic morcellation of uterine polyps and myomas in an office or ambulatory surgical center. J Minim Invasive Gynecol 2015;22:285-90. Crossref

3. AlHilli MM, Nixon KE, Hopkins MR, Weaver AL, Laughlin-Tommaso SK, Famuyide AO. Long-term outcomes after intrauterine morcellation vs hysteroscopic resection of endometrial polyps. J Minim Invasive Gynecol 2013;20:215-21. Crossref

4. Haber K, Hawkins E, Levie M, Chudnoff S. Hysteroscopic morcellation: review of the manufacturer and user facility device experience (MAUDE) database. J Minim Invasive Gynecol 2015;22:110-4. Crossref

5. Wamsteker K, Emanuel MH, de Kruif JH. Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstet Gynecol 1993;8:736-40.

6. Stamatellos I, Apostolides A, Tantis A, Stamatopoulos P, Bontis J. Fertility rates after hysteroscopic treatment of submucous fibroids depending on their type. Gynecol Surg 2006;3:206-10. Crossref

7. Di Spiezio Sardo A, Mazzon I, Bramante S, et al. Hysteroscopic myomectomy: a comprehensive review of surgical techniques. Hum Reprod Update 2008;14:101-19. Crossref

8. Tarneja P, Tarneja VK, Duggal BS. Complications of hysteroscopy surgery. Medical Journal Armed Forces India 2002;58:331-4. Crossref

9. Isaacson KB, Olive DL. Operative hysteroscopy in physiologic distention media. J Am Assoc Gynecol Laparosc 1999;6:113-8. Crossref

10. AAGL Advancing Minimally Invasive Gynecology Worldwide, Munro MG, Storz K, Abbott JA, et al. AAGL Practice Report: Practice Guidelines for the Management of Hysteroscopic Distending Media: (Replaces Hysteroscopic Fluid Monitoring Guidelines. J Am Assoc Gynecol Laparosc. 2000;7:167-168.). J Minim Invasive Gynecol 2013;20:137-48. Crossref

11. Hamerlynck TWO, Dietz V, Schoot BC. Clinical implementation of the hysteroscopic morcellator for the removal of intrauterine myomas and polyps. A retrospective descriptive study. Gynecol Surg 2011;8:193-6. Crossref

12. Emanuel MH, Wamsteker K. The Intra Uterine Morcellator: a new hysteroscopic operating technique to remove intrauterine polyps and myomas. J Minim Invasive Gynecol 2005;12:62-6. Crossref

With the widespread use of advanced imaging such as computed tomography (CT), many renal tumours are now incidentally discovered before the patient becomes symptomatic. These tumours are often of small size. This has led to the emerging practice of partial nephrectomy (PN) rather than radical nephrectomy (RN) that has been the gold-standard treatment for localised renal tumours for over 40 years.1 Studies have shown that cancer control can be achieved by PN in patients with T1a tumours,2 3 4 5 and some studies also supported the extended use of PN for T1b tumours.6 7 8 9 In addition, patients who undergo PN have been shown to be at decreased risk of renal impairment.10

Nonetheless, many surgeons in Hong Kong continue to perform RN for all renal tumours, regardless of their size. The major concerns are the technical difficulty of PN and the associated major postoperative complications.

The aim of this study was to compare the oncological outcome, survival, and changes in renal function in patients who underwent RN or PN for T1 renal cancer in our centre. Patients were predominantly of Chinese ethnicity.

We retrospectively reviewed the data of patients who underwent RN or PN at our centre between January 2005 and December 2010. Patients with a solitary tumour of 7 cm or less in diameter and a normal contralateral kidney were included. The decision to perform PN was based on tumour characteristics (size, proximity to collecting system and major vessels) and the surgeon’s preference. Exclusion criteria were: end-stage renal failure (glomerular filtration rate [GFR] <15 mL/min/1.73 m²), history of renal transplantation, known hereditary renal cancer, known poor or non-functioning contralateral kidney, history of nephrectomy, and preoperative evidence of tumour metastases.

Preoperative parameters including age, gender, serum creatinine, and estimated GFR were studied. We used the modified Charlson-Romano index to compare patient co-morbidity.11 We also compared postoperative outcome for the RN and PN groups, including length of hospital stay, complications, and 90-day mortality. Severity of complications was graded using the Clavien-Dindo classification system.12

Our study outcome included 5-year overall survival, cancer-free survival, change in renal function in terms of estimated GFR (eGFR), and new onset of chronic kidney disease (CKD)—GFR was calculated with the four-variable Modification of Diet in Renal Disease formula: eGFR = 32 788 x serum creatinine (µmol/L)^-1.154 x age^-0.203 x [1.212 if black] x [0.742 if female]13; CKD was defined as GFR of <60 mL/min/1.73 m². Patients were followed up according to international guidelines, with slight variation in timing of imaging due to examination waiting time issues. In general, follow-up was scheduled every 3 months within the first year of operation with measurement of serum creatinine and GFR, and CT scan was performed approximately 12 months following surgery. Patients were subsequently followed up every 6 months, with renal function checked at each visit, and imaging studies (ultrasonography or CT) performed annually for the first 5 years and thereafter once every 2 years.

For preoperative characteristics and postoperative outcome, P value was determined by the Chi squared test and Mann-Whitney U test for categorical and continuous variables, respectively. Kaplan-Meier model was used for 5-year overall and cancer-free survival, and the postulated 5-year probability of freedom from CKD. Risk of new onset of CKD was calculated with Cox proportional hazards regression, adjusted for age, Charlson Comorbidity Index (CCI), preoperative GFR, gender, and tumour size; with time to CKD development as dependent variable; death, loss to follow-up, or last follow-up date before 31 December 2012 were censored in the analysis. Overall survival was analysed by Cox proportional hazards regression adjusted with Fuhrman grade of tumour, in addition to the above factors. We did not include diabetes mellitus as it was included in the CCI. We considered a 2-sided P value of <0.05 as statistically significant. All statistical analyses were performed with the Statistical Package for the Social Sciences (Windows version 20.0; SPSS Inc, Chicago [IL], US).

A total of 86 patients were reviewed, with a mean (± standard deviation) follow-up time of 43.5 ± 22.4 months. Four (5%) patients were lost to follow-up with their status unknown by the end of our study. Overall, RN was performed in 38 patients and PN in 48. Age, gender, and preoperative serum creatinine level and GFR were similar between the two groups. The mean age of RN and PN groups was 61 years and 63 years, respectively (P=0.48), with a respective mean preoperative GFR of 80.8 mL/min/1.73 m² and 75.0 mL/min/1.73 m² (P=0.38). Six (16%) patients in the RN group and 11 (23%) in the PN group had a preoperative GFR of <60 mL/min/1.73 m²; one patient in the PN group had a preoperative GFR of <30 mL/min/1.73m². Most patients in the RN and PN groups had a CCI of <2 (84% vs 85%; P=0.87). The respective mean follow-up time was 42.1 ± 24.0 and 44.5 ± 21.3 months (P=0.62) [Table 1].

Tumours were more complex in the RN group in terms of the R.E.N.A.L. score14 derived from preoperative CT (8.4 vs 6.7, P<0.001). The mean tumour size, based on final pathological examination, was also larger in the RN group (4.8 cm vs 2.5 cm, P<0.001). In the RN group, 24 (63%) patients had a T1b tumour compared with three (6%) in the PN group (P<0.001). Comparison of the first half of our study period (2005-2008) with the second half (2009-2010) revealed that tumour characteristics were similar in the PN group, in terms of both size (2.4 cm vs 2.5 cm; P=0.93) and R.E.N.A.L. score (6.2 vs 7.0; P=0.32). Most tumours in both groups were of the clear cell type. The RN group had more Fuhrman grade 3 tumours but the difference was not significant (Table 1). All resections enjoyed clear resection margins on final pathological examination.

All RNs were performed via a laparoscopic approach. An open procedure was performed for 29 (60%) of the PNs, eight (17%) were performed via a laparoscopic approach, and 11 (23%) with robotic assistance. Of the latter, conversion to an open procedure was required in two cases. Operating time was significantly longer in the PN group (250 mins vs 345 mins; P<0.001). None of the PNs were converted to RN.

All PNs were performed with vascular control achieved by hilar clamping. Overall, 28 (58%) PNs were performed with cold ischaemia using ice slush, with a mean cold ischaemia time of 70 minutes; among these, 23 (82%) were an open procedure and two were conversion of robotic-assisted laparoscopic PN to open procedure. Of the PNs, 20 (42%) were performed with warm ischaemia, and the mean warm ischaemia time was 32 minutes; all laparoscopic PNs were performed with warm ischaemia. The complexity of tumour in terms of R.E.N.A.L. score was significantly lower in the warm ischaemia group (5.7 vs 7.5; P=0.01).

Patients in the PN group had a longer postoperative hospital stay (6 vs 13 days; P<0.001); one of whom died within 90 days of surgery of cholecystitis and septic complications unrelated to the renal cancer.

Postoperative complication rates were similar between the two groups (P=0.19), although the PN group had more Clavien grade III or above complications (0% vs 10%; Table 2). Four patients had persistent urine leakage that was successfully treated with retrograde injection of surgical adhesive glue; one patient developed pseudoaneurysm of the segmental branch of the renal artery, which was treated by angiographic embolisation. No long-term morbidity or mortality occurred. Complication rate was not associated with patient age, CCI, R.E.N.A.L. score of tumour, or operative parameters (operative approach, operating time, and ischaemia time).

An overall excellent oncological outcome was achieved by both groups. Extensive metastases were evident 3 months after operation in one patient in the RN group but these were not apparent before operation. By 31 December 2012, 32 (84%) RN and 43 (90%) PN patients were alive. The overall 5-year survival for the RN and PN groups was 84.2% and 89.6% (P=0.29) respectively, and the cancer-free survival was 97% and 100% (P=0.29) respectively. Both RN and PN did not affect overall survival (hazard ratio=0.84; 95% confidence interval [CI], 0.17-4.02; P=0.82), after adjustment for age, CCI, preoperative GFR, gender, tumour size, and Fuhrman grade (Table 3).

Patients who underwent RN had a greater median reduction in GFR than PN patients (35.4% vs 12.6%; P<0.001), and the degree of reduction was most distinctive in the first year after operation (Fig 1). In the PN group, one patient with a preoperative GFR of 30 mL/min/1.73 m² developed stage 5 CKD 4 years after surgery and required renal replacement therapy. Preoperative GFR was >60 mL/min/1.73 m² in 32 patients in the RN group and in 36 patients in the PN group. At their last follow-up, CKD was developed in 18 (56%) patients who underwent RN but new-onset CKD was evident in only five (14%) of the PN group (P<0.001). The majority of the CKD cases were stage 3 (94% in RN group and 80% in PN group); none was in stage 5. Cox proportional hazards regression model showed that RN was the most significant factor contributing to the development of CKD (RN vs PN, hazard ratio=5.44; 95% CI, 1.26-23.55; P=0.02; Table 4). The postulated probability of freedom from new-onset CKD in 5 years, by Kaplan-Meier model, was 33% and 81% in the RN and PN groups, respectively (P<0.001; Fig 2).

Many surgeons have underestimated the impact of renal impairment after RN for renal cancer, on the basis that organ donors who undergo nephrectomy are not at increased risk of renal failure or death.15 16 17 Nonetheless, donors represent a different population as they are often young and fit. Patients with renal cancer are often older and have co-morbidities such as hypertension and diabetes mellitus. In our study, 21% of our patients had a GFR of <60 mL/min/1.73 m² prior to surgery and 15% had a CCI of ≥2. Therefore it is logical that this cohort of patients may benefit from a surgical technique that preserves more of their renal function.

Our study showed that PN resulted in less renal deterioration in terms of GFR, with RN having a hazard ratio of 5.44 for development of CKD, after taking into consideration the patient co-morbidities, gender, age, and tumour size. The postulated probability of freedom from new onset of CKD in 5 years in our series was 33% following RN and 81% following PN. This echoes the finding of Huang et al10 who reported the 3-year probability of freedom from new onset of CKD as 35% after RN and 80% after PN; RN remained an independent risk factor for development of new-onset CKD with a hazard ratio of 3.82.

A community-based study showed that CKD was an independent risk factor for the development of cardiovascular events, hospitalisation, and death.18 In a population-based cohort of 7769 patients, RN was associated with a 1.23-fold increase in overall mortality compared with PN (P=0.001), and a higher rate of non–cancer-related mortality.19 Huang et al10 also demonstrated that RN was associated with a 1.46-fold increased risk of overall mortality, although the risk of a cardiovascular event was not increased in the RN group. Evidence that PN decreases overall mortality remains contradictory. A randomised controlled trial showed that RN had comparable overall survival with PN after a median follow-up of 9.3 years.20 In our study we did not show a significant difference in overall survival between PN and RN groups.

Another concern of PN is its cancer control, since the prevention of local recurrence is of paramount importance. The extent of resection is affected by tumour size, proximity to the collecting system, and location and degree of exophytic growth. It is generally accepted that PN can achieve excellent oncological outcome for tumours smaller than 4 cm, with a long-term 5-year and 10-year cancer-free survival rates of 92% to 100%.2 21 22 23 Studies have demonstrated the feasibility of PN for tumours larger than 4 cm without compromising the oncological outcome, although there was a higher risk of peri-operative bleeding and other complications.23 24 In our cohort, we achieved a 100% clear surgical resection margin with PN, and no local recurrence was found after 5 years.

Increased peri-operative morbidity is traditionally a concern in PN. There were more Clavien grade III complications and a longer hospital stay for patients who underwent PN in our cohort. The most common complication in an open PN series was urine leakage, with a mean incidence of 6.5% (range, 2.1%-17%).25 26 In a multicentre review of 51 laparoscopic PNs, postoperative urine leakage was observed in three (6%) patients.27 The results of a previous series by Gill et al,28 supported by our results, suggested that both tumour location and diameter were not related to the occurrence of urine leakage. In contrast to the logical thinking that calyceal entry was not observed during renorrhaphy, it has been suggested that central coagulation necrosis with electrocautery is responsible for fistula formation.27 The use of a ureteral catheter and retrograde dye injection after haemostasis has been advocated to help identify any calyceal opening, but this was not supported in a retrospective series by Bove et al29 that involved 54 patients with and 49 patients without ureteral catheter placement. We believe that the adoption of cold cutting and elevation of the tumour from the tumour bed by the suction cannula, which also simultaneously aspirates the blood, can avoid coagulation necrosis and a clear operative field can be maintained so that any breaching of calyceal integrity can be identified. The use of a ureteral catheter can be an adjunct measure in equivocal cases when the tumour is abutting the calyceal lining on preoperative imaging.

Our study have some limitations. Since it was a retrospective study, patients were not randomised and there was a selection of smaller and less complex tumours in the PN group. There were also other confounding factors such as patient’s smoking status that were not included, hence the two groups were not totally comparable, although other patient demographics were similar. As a proportion of preoperative imaging could not be retrieved, the R.E.N.A.L. score could not be calculated for every patient included, and this contributed another confounding factor. Only three patients had T1b renal cancer in the PN group, thus the oncological outcome may be more certain in T1a renal cancer. Our stratified analysis in T1a renal cancer had a similar result with PN having an equivalent oncological outcome and superior renal function preservation, although the result is not shown here. In addition, the risk of tumour recurrence, negative effect of CKD and their effect on survival might not be truly reflected in our relatively short follow-up time. Nonetheless with experience, renal tumours of 4 cm or more in diameter may be amenable to safe PN with equivalent oncological outcome and a lower chance of progression to CKD. This may translate into improved overall survival.30

Partial nephrectomy can preserve more renal function and reduce the risk of development of CKD compared with RN. Excellent cancer control and a low local recurrence rate can still be achieved with PN for T1 tumours, in particular T1a tumours and tumours with a low R.E.N.A.L. score. Although RN continues to constitute a significant proportion of surgical procedures for T1 renal cancer in our locality, we recommend that, if technically feasible, PN should be performed for all T1a and selected T1b renal cancers.

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2. Fergany AF, Hafez KS, Novick AC. Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup. J Urol 2000;163:442-5. Crossref

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26. Kim FJ, Rha KH, Hernandez F, Jarrett TW, Pinto PA, Kavoussi LR. Laparoscopic radical versus partial nephrectomy: assessment of complications. J Urol 2003;170:408-11. Crossref

27. Jeschke K, Peschel R, Wakonig J, Schellander L, Bartsch G, Henning K. Laparoscopic nephron-sparing surgery for renal tumors. Urology 2001;58:688-92. Crossref

28. Gill IS, Desai MM, Kaouk JH, et al. Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J Urol 2002;167:469-76. Crossref

29. Bove P, Bhayani SB, Rha KH, Allaf ME, Jarrett TW, Kavoussi LR. Necessity of ureteral catheter during laparoscopic partial nephrectomy. J Urol 2004;172:458-60. Crossref

30. Weight CJ, Larson BT, Gao T, et al. Elective partial nephrectomy in patients with clinical T1b renal tumors is associated with improved overall survival. Urology 2010;76:631-7. Crossref