Prostate cancer is the second most frequently diagnosed cancer of men worldwide, with the highest incidence and prevalence rates occurring in more developed societies.1 The incidence of prostate cancer is also increasing in Asian countries.2 Many reasons have contributed to this recent rise in incidence in Asia, including the increase in the ageing population, the westernised diet, and also the increased use of serum prostate-specific antigen (PSA) for cancer detection.3 4 Although current evidence supports the use of PSA testing to decrease the incidence of metastatic disease and prostate cancer–specific mortality,5 the use of serum PSA for the early detection of prostate cancer is still controversial.6 7 One of the concerns is the risk of overdiagnosis and overtreatment of low-risk cancer that may result in more potential harm than benefit to patients.8 9 10 There are many types of prostate cancer screening approaches. Currently, there is no structured prostate cancer screening programme in Asia. Therefore, early diagnosis of prostate cancer in Asia is by an opportunistic case-finding approach, that is, offering PSA testing to an individual without obvious signs and symptoms of prostate cancer. Information on the characteristics of prostate cancer diagnosed by various approaches in Asia is lacking, however. We postulated that patients diagnosed by a case-finding approach, such as during a routine health check or a consultation for symptoms with a low suspicion of prostate cancer origin, would have a better prognosis than those who presented with symptoms related to prostate cancer, with or without metastatic disease. We investigated the relationship between the mode of presentation and the characteristics of prostate cancers diagnosed in our hospital.

This was a prospective cohort study to assess consecutive adult male patients diagnosed with prostate cancer at Prince of Wales Hospital, a regional hospital in Hong Kong, between September 2011 and February 2013. Institutional ethics approval was obtained for the study. Informed consent was obtained from all study subjects prior to enrolment in the study.

All patients aged 18 years or above at our hospital with histological confirmation of prostate cancer were identified and approached for inclusion in this study. After informed consent was obtained, information on the initial presentation of the patient’s condition, prostate cancer characteristics at diagnosis, and the initial treatment plan were collected. Patients were then followed up for a minimum of 2 years, and the clinical outcome was assessed. All cancer was graded using the Gleason grading system that is based on the histological pattern of the cancer tissue. The tissue was graded from 1 (well-differentiated) to 5 (poorly differentiated). Each biopsy was given two scores, the first indicated the most common pattern and the second, the highest grading.11 Our scoring system for prostate cancer consists of staging according to TNM staging 201012 and risk stratification according to the National Comprehensive Cancer Network (NCCN) guideline.13

Subjects were divided into four groups according to the initial clinical presentation of their prostate cancer by two investigators who were blinded to the clinical outcome during the assessment and then confirmed by a senior investigator. Any discrepancy was discussed and a final allocation made. The health check group (group 1) included patients in whom a raised PSA was detected during a routine health check. Group 2 comprised patients diagnosed with prostate cancer by the case-finding approach after they presented with symptoms with no/low clinical suspicion of prostate cancer (eg renal cysts, non-specific abdominal pain). Group 3 comprised patients with a high clinical suspicion of prostate cancer or malignant disease, for example, lower urinary tract symptoms with abnormal digital rectal examination (DRE), bone pain, or weight loss. Finally, those patients with a histological diagnosis of prostate cancer made following transurethral resection of the prostate (TURP) but with no preoperative suspicion of prostate cancer were assigned to the TURP group (group 4).

Since prostate cancer arises mostly from the peripheral zone (in contrast to benign prostate hyperplasia [BPH] that commonly arises from the transition zone), patients with early-stage prostate cancer are usually asymptomatic.14 Not until the tumour becomes locally advanced (with clinical signs of abnormal DRE) do patients have voiding symptoms attributed to prostate cancer. Therefore, in a patient who presents with lower urinary tract symptoms (LUTS) and normal DRE, the symptoms are more likely related to BPH, not secondary to prostate cancer. Testing of PSA is not routine for male patients with LUTS.15 16 According to the Guidelines from the European Association of Urology, PSA measurement should only be performed to assess the risk of progression of LUTS or if a diagnosis of prostate cancer would change disease management.16 For patients who present with LUTS but with a low clinical suspicion of prostate cancer (ie normal DRE), PSA testing is considered case-finding for prostate cancer. In this study, such patients were assigned to group 2. This also applied to other presenting symptoms with no or low suspicion of being related to prostate cancer. Nonetheless, in subjects with LUTS and clinical symptoms or signs suspected to be secondary to prostate cancer, such as abnormal DRE findings, PSA testing would be part of the diagnostic process for prostate cancer, not case-finding. As a result, these patients would be assigned to group 3.

After all data were collected, descriptive statistics were applied. A Chi squared test or Fisher’s exact test was used to determine any relationship between the categorical outcome measures. Analysis of variance or Kruskal-Wallis test was used for normal or skewed data, and then followed by post-hoc comparisons with Bonferroni adjustment. Kaplan-Meier survival analysis was applied to analyse survival among the four groups. Data management and analysis were performed using the Statistical Package for the Social Sciences (Windows version 22.0; SPSS Inc, Chicago [IL], US). A two-tailed test was used with significance set at P<0.05.

From September 2011 to February 2013, 126 consecutive patients with newly diagnosed, histologically confirmed prostate cancer were managed in our centre. One patient refused to participate in this study, and five patients were not capable of providing informed consent. Therefore 120 patients were enrolled in this study: group 1 (n=12), group 2 (n=53), group 3 (n=46), and group 4 (n=9) [Table 1]. The initial presenting symptoms of patients in groups 2 and 3 are listed in Table 2. In group 2, 43 patients presented with LUTS (including three with acute urinary retention) with low clinical suspicion of prostate cancer. Ten patients presented with other symptoms—seven with other urological symptoms and three with other general surgical problems. Among them, three patients (one with loin pain, one with erectile dysfunction, and one with hernia) were found to have abnormal DRE during consultation. In group 3, 33 patients presented with LUTS (nine patients with acute urinary retention) and abnormal DRE. Three patients presented with haematuria and DRE during initial workup was abnormal and a subsequent diagnosis was made of prostate cancer. Nine patients presented with metastatic symptoms, eg bone pain, acute spinal cord compression, and abnormal soft tissue mass. One patient presented with weight loss and was subsequently diagnosed to have non-metastatic prostate cancer (Table 2).

The overall mean age was 71.0 (range, 54-90) years (Table 1). Age and serum PSA level were statistically significantly different across groups. Multiple comparisons with Bonferroni correction revealed that patients in group 3 were significantly older than those in groups 1 and 2 (P<0.001). Patients in group 3 also had a significantly higher serum PSA level compared with those in group 1 (P=0.044) and group 2 (P=0.045) by Kruskal-Wallis test. In group 3, 41 (89.1%) patients had an abnormal DRE (P<0.001).

With regard to disease status, the numbers of patients with a Gleason sum of ≥7 were seven (58.3%) in group 1, 12 (22.6%) in group 2, 32 (69.6%) in group 3, and four (44.4%) in group 4. In accordance with the NCCN guideline, the number of patients with disease more severe than very low or low risk were eight (66.7%) in group 1, 30 (56.6%) in group 2, 43 (93.5%) in group 3, and seven (77.8%) in group 4 (Table 1). In group 3, 24 (52.2%) patients had metastatic disease at initial presentation, a much higher rate than in the other groups (P<0.001, Fisher’s exact test).

Since both groups 1 and 2 had no prostate cancer–related symptoms, we tried to combine the two groups to assess the characteristics of prostate cancer diagnosed by a case-finding approach. Group 3 patients had significantly older age, higher serum PSA level, more aggressive disease (Gleason sum ≥7), and more metastatic disease at presentation than the combined groups 1 and 2 patients (P<0.001 for all parameters; Table 3).

The types of primary treatment administered are listed in Table 4. The number of patients receiving radical local therapy (either surgery or radiotherapy) was 10 (83.3%) in group 1, 44 (83.0%) in group 2, 11 (23.9%) in group 3, and one (11.1%) in group 4. Systemic androgen deprivation therapy was prescribed to one (8.3%) patient in group 1, three (5.7%) in group 2, 26 (56.5%) in group 3, and two (22.2%) in group 4 (P<0.0005). Because group 3 had significantly more patients with locally advanced and metastatic disease, significantly fewer could be managed with curative-intent local therapy. Among those patients with very low– or low-risk disease in groups 1 and 2, one (25%) and five (21.7%) respectively elected to have conservative management, either watchful waiting or active surveillance.

The median follow-up period was 32 months (interquartile range, 28-35 months). No patients were lost to follow-up. Eleven (9.2%) patients died—10 (21.7%) in group 3 and one (11.1%) in group 4. No patient in groups 1 or 2 died during the follow-up period. The causes of death in group 3 patients were directly related to prostate cancer in seven patients, metastatic bladder cancer in one patient, and acute myocardial infarction in two patients. The cause of death of the patient in group 4 was secondary to advanced rectosigmoid carcinoma. Therefore, the overall rate of cancer-specific survival for the total cohort was 91.0%, but 100% for each of groups 1, 2, and 4 compared with only 76.8% for group 3 (P=0.006, log-rank test; Fig).

Since the introduction of PSA testing, there has been a worldwide change in the presentation of prostate cancer. More and more prostate cancers are diagnosed at a lower risk level and earlier stage for which curative treatment can be offered.17 18 As a result, the use of PSA testing for early detection of prostate cancer is believed to be one of the factors that has led to the decrease in overall prostate cancer mortality in many developed areas.2 From our cohort, we also observed that patients with prostate cancer diagnosed by case-finding approach using PSA testing (groups 1 and 2) had significantly more clinically localised disease and hence a higher chance of receiving curative-intent treatment than those patients who presented with prostate cancer–related symptoms (group 3).

We also observed that the short-term cancer-specific mortality rate of patients who presented with prostate cancer–related symptoms (group 3) was significantly higher than that in the other groups. In our cohort, more than half of the patients in group 3 already had metastasis at diagnosis. Because patients presenting with metastasis have a much poorer outcome than other patients,19 20 it was not surprising that the mortality rate for patients who presented with symptoms was also higher. This indirectly supports the case-finding approach by PSA testing in patients with symptoms but no/low clinical suspicion of prostate cancer, as it might help to decrease the incidence of metastatic disease and hence the mortality related to prostate cancer.21

Although PSA testing is widely performed in western countries to detect early prostate cancer, its use in Asian countries is still not a common practice. From a population-based telephone survey involving 1002 Chinese men aged ≥50 years in Hong Kong, only 9.5% had ever had a PSA test, and only 3.7% of the total sample had PSA test done during a routine health check.22 Even in more developed Asian countries such as Japan and South Korea, only 15% to 20% of the population had had a PSA test.23 Only 10% of the prostate cancers in our cohort were diagnosed during a self-initiated health check with PSA testing. Therefore, offering a PSA test as case-finding for prostate cancer during a patient’s consultation for non-prostate-cancer–related symptoms is an alternative approach for early detection of prostate cancer. We believe that this case-finding approach is feasible for the detection of early prostate cancer in our region, where public awareness and use of PSA testing is still low. Certainly, patients need to be well informed about the nature and implications of PSA testing before the test is performed.24 25

The main concerns surrounding the use of PSA testing for the detection of early prostate cancer are overdiagnosis and overtreatment.8 9 10 Only approximately 36% of patients in the study cohort had very low– or low-risk disease that might not require aggressive intervention.13 26 Even in those patients with prostate cancer diagnosed by PSA testing (ie groups 1 and 2), more than 50% were in the intermediate- or higher-risk groups. Testing of PSA level did help to detect patients with significantly high-risk prostate cancer that warranted further treatment. To minimise the risk of overtreatment, the Melbourne Consensus Statement advises uncoupling of the prostate cancer diagnosis from the intervention.5 Offering active surveillance to patients with low-risk disease will help to minimise the potential harm of overtreatment. In our cohort, for patients in groups 1 and 2 with very low– or low-risk disease, six (22.2%) opted for observation with no active treatment. We believe this concept should be promoted to both clinicians and patients, rather than limiting the use of PSA testing for the case finding of prostate cancer.

Currently, some newly proposed strategies, such as determination of the baseline PSA level earlier in life27 28 and the use of newer diagnostic tools,29 30 might help to reduce unnecessary prostatic biopsies and overdiagnosis of low-risk prostate cancer. Nonetheless, since most of these studies were conducted in Caucasian-based populations, further studies in Asian populations are necessary to verify their suitability in our region.

Although our data show that the short-term outcome of patients who present with prostate cancer–related symptoms seems to be worse than those diagnosed by PSA testing, this might be due to potential lead-time bias, that is, the increase in survival is actually due to the length of time between the detection of a disease by PSA testing and its usual clinical presentation and diagnosis. This will result in an increase in survival time for patients diagnosed by PSA testing. Other potential bias is length-time bias which suggests that annual PSA may only detect slow-growing tumours, that screening for prostate cancer does not detect the very tumour for which it is intended.

The aim of our study was not to assess the role of PSA testing in the detection of early prostate cancer or its effect on long-term outcome and survival of patients. Rather, we aimed only to compare cancer characteristics and short-term outcome among patients with different presentations. We also did not analyse the potential harm of PSA testing, prostatic biopsy, or morbidities related to treatment. The positive rate for prostatic biopsy depends on the level of serum PSA and DRE finding. From local experience, for patients with a normal DRE, the positive rate of prostatic biopsy for serum PSA level of 4-10 ng/mL and 10-20 ng/mL was only 6.7%-13.4% and 10.3%-21.8%, respectively.31 32 33 Therefore, information on this would be helpful during patient counselling for prostatic biopsy. Another limitation of our study was the relatively small sample size from a single centre in Hong Kong, therefore our results might not represent the general situation in Hong Kong. Further studies, especially with multicentre collaboration, may help to confirm the applicability of our results in the local population.

Patients with prostate cancer presenting with related symptoms had more metastatic disease and poorer survival than those diagnosed by a case-finding approach using PSA testing during a health check or management of symptoms with a low suspicion of prostate cancer. More than half of the patients diagnosed by this case-finding approach belonged to intermediate- or higher-risk groups for which active treatment was recommended. Apart from a self-initiated health check with PSA testing, offering PSA testing to appropriate patients who present with symptoms with no/low clinical suspicion of prostate cancer is an alternative approach to early diagnosis of prostate cancer. Pre-test counselling, including the discussion of potential bias (such as lead time or length-time bias), is essential. This may hopefully help to improve the short-term outcome for these patients.

All authors have disclosed no conflicts of interest.

1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108. Crossref

2. Center MM, Jemal A, Lortet-Tieulent J, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol 2012;61:1079-92. Crossref

3. Sim HG, Cheng CW. Changing demography of prostate cancer in Asia. Eur J Cancer 2005;41:834-45. Crossref

4. Pu YS, Chiang HS, Lin CC, Huang CY, Huang KH, Chen J. Changing trends of prostate cancer in Asia. Aging Male 2004;7:120-32. Crossref

5. Murphy DG, Ahlering T, Catalona WJ, et al. The Melbourne Consensus Statement on the early detection of prostate cancer. BJU Int 2014;113:186-8. Crossref

6. Schröder FH. Landmarks in prostate cancer screening. BJU Int 2012;110 Suppl 1:3-7. Crossref

7. Alberts AR, Schoots IG, Roobol MJ. Prostate-specific antigen-based prostate cancer screening: past and future. Int J Urol 2015;22:524-32. Crossref

8. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010;102:605-13. Crossref

9. Loeb S, Bjurlin MA, Nicholson J, et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol 2014;65:1046-55. Crossref

10. Stone NN, Crawford ED. To screen or not to screen: the prostate cancer dilemma. Asian J Androl 2015;17:44-5. Crossref

11. Epstein JI. An update of the Gleason grading system. J Urol 2010;183:433-40. Crossref

12. Edge S, Byrd DR, Compton CC, Fitz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York, NY: Springer; 2010.

13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology—Prostate cancer, version 1.2015. Available from: http://www.nccn.org. Accessed 1 Jul 2015.

14. Loeb S, Carter HB. Early detection, diagnosis, and staging of prostate cancer. In: Wein AJ, Kavoussi LR, Novick AC, et al, editors. Campbell-Walsh Urology. 10th ed. Philadelphia, PA: Elsevier Saunders; 2012: 2763-70. Crossref

15. European Association of Urology. Guidelines on the management of non-neurogenic male lower urinary tract symptoms (LUTS), incl. benign prostatic obstruction (BPO). Available from: http://uroweb.org/wp-content/uploads/EAU-Guidelines-Non-Neurogenic-Male-LUTS_LR.pdf. Accessed 1 Jul 2015.

16. Arianayagam M, Arianayagam R, Rashid P. Lower urinary tract symptoms—current management in older men. Aust Fam Physician 2011;40:758-67.

17. Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR, CaPSURE. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (Data from CaPSURE). J Urol 2003;170(6 Pt 2):S21-7. Crossref

18. Crawford ED. Epidemiology of prostate cancer. Urology 2003;62(6 Suppl 1):3-12. Crossref

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20. Patrikidou A, Loriot Y, Eymard JC, et al. Who dies from prostate cancer? Prostate Cancer Prostatic Dis 2014;17:348-52. Crossref

21. Wu JN, Fish KM, Evans CP, Devere White RW, Dall’Era MA. No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period. Cancer 2014;120:818-23. Crossref

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24. Carter HB, Albertsen PC, Barry MJ, et al. Early detection of prostate cancer: AUA Guideline. J Urol 2013;190:419-26. Crossref

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26. European Association of Urology. Guidelines on prostate cancer. Available from: http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LRV2-2015.pdf. Accessed 1 Jul 2015.

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29. Braun K, Sjoberg DD, Vickers AJ, Lilja H, Bjartell AS. A four-kallikrein panel predicts high-grade cancer on biopsy: independent validation in a community cohort. Eur Urol 2016;69:505-11. Crossref

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32. Ng CF, Chiu PK, Lam NY, Lam HC, Lee KW, Hou SS. The Prostate Health Index in predicting initial prostate biopsy outcomes in Asian men with prostate-specific antigen levels of 4-10 ng/mL. Int Urol Nephrol 2014;46:711-7. Crossref

33. Teoh JY, Yuen SK, Tsu JH, et al. Prostate cancer detection upon transrectal ultrasound-guided biopsy in relation to digital rectal examination and prostate-specific antigen level: what to expect in the Chinese population? Asian J Androl 2015;17:821-5.

Sexual violence refers to sexual activity where consent is not obtained or freely given.1 The World Health Organization defines sexual violence as “any sexual act, attempt to obtain a sexual act, or other act directed against a person’s sexuality using coercion, by any person regardless of their relationship to the victim, in any setting”.2 This includes rape, indecent assault, sexual harassment and threats. According to the statistics of ‘Child abuse, spouse/cohabitant battering and sexual violence cases’ from the Social Welfare Department, the majority (88.4%) of newly reported sexual violence cases in Hong Kong are indecent assault and 8.8% are rape or unlawful sexual intercourse. More than 96% of the victims are females. Approximately 70% of the perpetrators are strangers, and the rest are usually someone known to the victim, such as a family member, friend, lover or ex-lover, co-worker, caregiver, neighbour, or teacher.3 Sexual violence is usually underreported because of fear: fear of physical examination, disclosure of sexual history, repeating the traumatic experience in full detail over and over again, complicated legal procedures, not being believed by others, and being harmed by the perpetrator(s).2

Sexual violence may lead to health consequences such as unwanted pregnancy, sexually transmitted disease (STD) infections, physical trauma, depression, and post-traumatic stress disorder.4 Not all victims will seek medical care, however, because the experience of sexual violence is seen as stigmatising and shameful, with possible extreme social consequences.5 Stigmatisation not only from society but also from health care providers, family, and even the intimate partner is common. This leads to minimal support for the victims who may distance themselves by withdrawing from social activities.6

In November 2000, the Association Concerning Sexual Violence Against Women set up the first one-stop crisis centre in Hong Kong, Rainlily, for the protection of female victims of sexual violence. All the social workers at Rainlily are female and trained to provide counselling and care for victims of sexual assault. They will accompany the victim for medical care, police interviews, legal proceedings, and most importantly, the possibly long and difficult recovery period from the incident.

For many years, Rainlily has worked with the accident and emergency department of Kwong Wah Hospital to provide one-stop service to victims of sexual violence including pregnancy prevention, screening and prevention of STDs, forensic medical examination, psychological support, and reporting to the police if desired by the victim. This avoids recalling and repeating the unpleasant experience for different professionals and hence minimises the need for the victim to psychologically re-live the trauma. Since May 2010, Rainlily has also collaborated with the United Christian Hospital and set up an additional rape crisis centre.

We conducted a retrospective analysis of female victims of sexual assault who were seen at either hospital to evaluate the characteristics of the cases and the victims, the use of alcohol and drugs, involvement of violence, and the outcome of the victims. The data are invaluable for health care professionals and policymakers for improving service provision for victims.

All female sexual assault victims who attended the Kwong Wah Hospital or United Christian Hospital from May 2010 to April 2013 were included in this retrospective study. The sexual assault cases were identified from the special case list of the accident and emergency department of each hospital and the designated gynaecology clinic booking list of the United Christian Hospital. The clinical records were reviewed and the demographics of the victims, time lapse from assault to presentation at hospital, characteristics of the assault, investigations and results, treatment and outcome of the victims were analysed.

At Kwong Wah Hospital, the sexual assault cases were managed and followed up in the accident and emergency department, with referral to gynaecologists if clinically indicated, for example, for unwanted pregnancy. At the United Christian Hospital, cases were initially managed in the accident and emergency department with subsequent follow-up in the gynaecology clinic. At initial presentation, victims were screened for the presence of any infection, including STDs. Emergency contraception was prescribed if necessary. Subsequent follow-up was after 2 weeks, 6 weeks, 3 months, and 6 months to exclude pregnancy, to review investigation results and treat any infection.

The study protocol complied with the good clinical practice of ICH (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use). Ethical approval was obtained from Clinical Research Ethics Committee of Hospital Authority.

All statistical analysis of data was performed by PASW Statistics 18, Release Version 18.0.0 (SPSS, Inc, 2009, Chicago [IL], US). For continuous data with a highly skewed distribution such as time from the incident of assault to presentation at the hospital, Mann-Whitney U test was used. The critical level of statistical significance was set at 0.05.

From May 2010 to April 2013, a total of 154 sexual assault victims had attended either hospital; 102 at Kwong Wah Hospital and 52 at United Christian Hospital. The age of victims ranged from 13 to 64 years (mean 24.5 years, median 22 years; Table 1). Most (150 cases; 97.4%) victims were Chinese and four were domestic helpers from other Asian countries. Five (3.2%) victims were mentally disabled and 19 (12.3%) had a history of psychiatric disorder.

The time from the incident of assault to presentation at the hospital ranged from 1 hour to more than 5 months (mean 16 days, median 3 days). Half of the victims (n=77) attended hospital within 3 days of the incident. Approximately half (n=84, 54.5%) of the assailants were strangers (Table 2); the others included friend, internet friend, family member, classmate, colleague, employer, boyfriend, ex-boyfriend, and ex-husband.

The median time from the incident to presentation was 48 hours (interquartile range [IQR], 24-240 hours) for victims with symptoms (except pregnancy), compared with 288 hours for those without (IQR, 48-696 hours) [P<0.001]. Those who were pregnant (median time, 756 hours; IQR, 510-1386 hours) presented later than those who were not (median time, 72 hours; IQR, 24-432 hours) [P<0.001].

In 56 (36.4%) cases, alcohol was involved in the incident. There were 18 (11.7%) cases where drugs were involved, including ketamine, amphetamine, methamphetamine, cocaine, and midazolam. In one victim, multiple drugs were involved. Some victims could not identify which drug they had been given. It had either been added to the victim’s drink, or been given as ‘flu medication’ or an ‘anti-drunk pill’.

There were 133 (86.4%) victims with documented vaginal penetration, of whom 25 had also been exposed to oral penetration, five to anal penetration, and four to all three forms of sexual assault. There were three victims in whom penetration was oral only. The remaining 18 victims had no clear documentation. In only three (1.9%) cases did the assailant use a condom. Verbal threats were reported by six (3.9%) victims, and physical violence with or without verbal threat by 45 (29.2%). Reported physical violence included restraint, strangling, beating, grasping, and biting.

Apart from the incident, 75 (48.7%) victims presented with other associated problems, most (n=44, 28.6%) with pelvic or genitourinary symptoms such as lower abdominal pain, vaginal discharge, or urinary symptoms. There were 17 (11.0%) victims who complained of laceration, contusions, bruises, and pain due to physical violence during the incident. Another 12 (7.8%) victims presented with psychiatric or mood problems: two attempted suicide, one had auditory hallucinations, and the others had mood problems or post-traumatic stress disorder with nightmares and flashbacks. One victim presented with per rectal bleeding due to anal penetration and another presented with recurrent oral ulcers in which oral penetration was involved during the incident. Seven victims had found themselves pregnant before attending the hospital.

Blood testing for hepatitis B surface antigen was performed in 146 victims of whom six (4.1%) were positive. All positive results were obtained within 6 weeks of the sexual assault. Hepatitis B surface antibodies were not present in 85 of 134 victims tested. Hepatitis B immunoglobulin was given to 43 victims and a first dose of hepatitis B vaccination to 52. Only 29 victims completed the course of hepatitis B vaccination, however, and the remainder defaulted from follow-up.

Blood test for syphilis by rapid plasma reagin was positive in one victim and was performed around 4 days after the sexual assault. Treponema pallidum haemagglutination assay was also positive. There was no other positive case in the subsequent screening at 6 weeks and 6 months. A similar result was obtained when testing for anti–hepatitis C virus antibody that was positive in one victim and the test was performed within 1 day of the sexual assault. There was no other positive case identified at subsequent follow-up. Blood tests for anti–human immunodeficiency virus antibody were all negative and a total of 71 victims had negative serology 6 months after the alleged assault.

High vaginal and endocervical swabs were taken for culture and revealed one victim with Trichomonas vaginalis. Urethral, rectal, and throat swabs were taken in selected cases and no infection other than with Candida species was detected. Chlamydia trachomatis was tested by polymerase chain reaction test on a urine sample or endocervical swab in 110 victims, and 12 (10.9%) were positive. Among those with chlamydial infection, four presented with genitourinary symptoms such as perineal pain, vaginal discharge, urinary frequency, and dysuria.

Emergency contraception was provided to 63 of the 77 victims who presented within 3 days of the alleged rape. There were 10 victims who had been prescribed emergency contraception, either by other doctors, or self-prescribed from a pharmacy. Other reasons for not prescribing emergency contraception included a victim with only oral penetration, one victim with a previous hysterectomy, two victims taking reliable regular contraception, and one victim who refused the prescription.

There were a total of 11 pregnancies as a result of the incident, among them one victim had received emergency contraception within the day of assault. The gestational age ranged from 6 weeks to 5 months at presentation. Eight cases underwent termination of pregnancy, one underwent medical evacuation for silent miscarriage, one continued the pregnancy to term, and one defaulted from follow-up with unknown outcome.

Attendance at follow-up was 57.8%, 63.6%, 59.1% and 46.8% at 2 weeks, 6 weeks, 3 months, and 6 months, respectively after the incident. Overall, less than half of the victims completed follow-up care.

Every 2 to 3 minutes, one woman is sexually assaulted somewhere in the world.7 The prevalence of sexual violence differs across populations, but studies have consistently shown there to be underreporting in both developed and developing countries.5 It is believed that Hong Kong is no different. The reported cases may only be the tip of the iceberg. This makes prevention, detection, and proper care difficult.

Comparison with a similar study conducted in Hong Kong from 2001 to 2004 by Chu and Tung8 shows that the age of victims, time between assault and presentation, and the percentage of those lost to follow-up are similar; thus the characteristics appear unchanged over the past decade. This raises the question of whether we are doing enough to promote awareness, prevention, and education in society.

A considerable proportion of victims have a history of psychiatric disorder, and there is emerging evidence of the association.9 Although the causal relationship is not well understood, it might be due to the higher prevalence of alcohol or substance abuse among this population. Nonetheless, a history of alcohol or substance abuse was not always documented in the case notes. Patients having a certain type of psychiatric disorder—such as schizophrenia, bipolar disorder, and heroin addiction—are more likely to adopt risky behaviour,10 and hence are at higher risk of being sexually abused.

The delayed presentation among victims of assault by a known assailant may be due to the fear of being discovered by the assailant and being further harmed. Furthermore, sexual violence is associated with stigma in some communities, even in cases with an unknown assailant; the victims may be afraid of being blamed, and there is also a perceived lack of support from families and friends.11 Delayed presentation may result in loss of forensic evidence, delay in prescription of STD prophylaxis, and a missed chance for emergency contraception.12 This explains why those who were pregnant presented later than those who were not, and those without symptoms may not have sought help until they found themselves pregnant. Public education definitely has a role and must emphasise the importance of seeking medical care early and promote community awareness of prevention, instead of blaming the victims.

The prevalence of sexual assault involving alcohol or drug use in this study was similar to a previous study by Hurley et al.13 Females are more vulnerable to the effects of alcohol because of their smaller body mass and higher proportion of body fat. Compared with drugs, there is a higher rate of alcohol involvement in sexual assault cases because it is easily available, cheap, and legally and socially acceptable. Alcohol can cause disinhibition and impair judgement; most of the victims consumed alcohol voluntarily and therefore there is a strong feeling of self-blame after the incident. Recreational drugs consumed by victims themselves or ‘date rape drug’–spiked drinks given to victims can cause sedation, anterograde amnesia, and incapacitation. The actual prevalence is likely to be more than reported, as the victims may not be aware of the assault or only have patchy recall of events. Some of these victims have an intense fear of internet exposure of their body or the incident, and feel a loss of control and sense of insecurity. If a drug abuser is assaulted, they may worry about being charged and are reluctant to report the incident to the police. Delay in reporting or seeking help results in loss of forensic evidence and delay in prescription of emergency contraception. The current protocol of the two studied units did not include toxicological analysis. Therefore the drug used was based on the victim’s report and recall error is highly likely. In order to improve service provision and to help in crime recollection, blood, urine, and nasal swabs for toxicology screening should be obtained in selected sexual assault cases. Public education should emphasise the harmful effects of excessive alcohol consumption and the effects of combining alcohol and recreational drugs. Ways to avoid spiked drinks include keeping an eye on one’s drink, not leaving a drink unattended or obtaining a new one if it is, and not accepting a drink from strangers.

The most common presenting symptoms were pelvic and genitourinary symptoms or injuries as a result of violence during the incident. Psychiatric symptoms were usually underreported. Common symptoms include low mood, fear, guilt, nervousness, sleeping difficulties, poor appetite, and feelings of shame and anger. Emotional numbness and avoidance are common reasons for not seeking help.14 Moreover, some medical providers do not actively ask about psychiatric symptoms. Even if symptoms are reported, they may be considered a ‘normal reaction’ to rape and then ignored. About half of victims recover from acute psychological effects by 12 weeks, but in others the symptoms persist for years.14 Sexual assault survivors are at increased lifetime risk of post-traumatic stress disorder, major depression, suicidal ideas and attempts.15 Mental state and risk of self-harm should be assessed to identify those who are at risk. Psychosocial support and opportunities to talk about the incident are important. For those who do not recover with time, referral to a psychotherapist or even a psychiatrist is essential.

Some experts discourage testing for STD infections in the acute setting unless clinically indicated by symptoms.15 The positive rate of STD in this study was low with the exception of chlamydial infection. Nucleic acid amplification testing can be carried out on urine samples instead of endocervical samples, minimising the need for invasive vaginal examination using a speculum.14 One may consider omitting the screening test and instead offering prophylactic antibiotics against bacterial STDs.

The rate of pregnancy (7.1%) is slightly higher than the quoted risk of 5%.16 The administration of emergency contraception in the two studied units comes in the form of levonorgestrel and was limited to victims who presented within 3 days of alleged rape. Levonorgestrel is licensed for up to 72 hours after unprotected intercourse, indeed there is still some residual efficacy after 3 days although it diminishes with time. To further decrease the chance of pregnancy, other contraceptive methods can be considered in victims who present more than 3 days after the incident, including a copper intrauterine device or ulipristal acetate. If it is not feasible to insert an intrauterine device in the emergency department, urgent referral to a gynaecology clinic should be considered. Ulipristal acetate may not be readily available in all public hospitals but it could be stocked and prescribed as a patient-financed item.

Limitations of this study include the small sample size, recall bias of alcohol or drug use, loss of some victims to follow-up, and short follow-up periods. A territory-wide case review may offer a better evaluation of the problem in Hong Kong.

Sexual assault is usually underreported and can lead to significant health consequences. Involvement of alcohol and drugs is not uncommon in sexual assault cases. Efforts should be made to enhance coordination and cooperation between medical and social services, and improve the accessibility and availability of clinical care. Health care professionals should be properly trained to understand the physical and mental health consequences, the importance of follow-up care, and to equip the skills to manage sexual assault cases. Public education should target at primary prevention, and publicise the simple ways to access the available services.

The authors gratefully acknowledge Mr Edward Choi for his valuable statistical advice.

All authors have disclosed no conflicts of interest.

1. Understanding sexual violence. National Center for Injury Prevention and Control, Centers for Disease Control and Prevention; 2012.

2. Violence against women: preventing intimate partner and sexual violence against women. Geneva: World Health Organization; 2011.

3. Statistics on child abuse, spouse/cohabitant battering and sexual violence cases. Social Welfare Department, the Government of the Hong Kong Special Administrative Region; 2014.

4. Welch J, Mason F. Rape and sexual assault. BMJ 2007;334:1154-8. Crossref

5. Dartnall E, Jewkes R. Sexual violence against women: the scope of the problem. Best Pract Res Clin Obstet Gynaecol 2013;27:3-13. Crossref

6. Jina R, Thomas LS. Health consequences of sexual violence against women. Best Pract Res Clin Obstet Gynaecol 2013;27:15-26. Crossref

7. Masho SW, Odor RK, Adera T. Sexual assault in Virginia: A population-based study. Womens Health Issues 2005;15:157-66. Crossref

8. Chu LC, Tung WK. The clinical outcome of 137 rape victims in Hong Kong. Hong Kong Med J 2005;11:391-6.

9. Goodman LA, Rosenberg SD, Mueser KT, Drake RE. Physical and sexual assault history in women with serious mental illness: prevalence, correlates, treatment, and future research directions. Schizophr Bull 1997;23:685-96. Crossref

10. Hariri AG, Karadag F, Gokalp P, Essizoglu A. Risky sexual behavior among patients in Turkey with bipolar disorder, schizophrenia, and heroin addiction. J Sex Med 2011;9:2284-91. Crossref

11. Abrahams N, Devries K, Watts C, et al. Worldwide prevalence of non-partner sexual violence: a systematic review. Lancet 2014;383:1648-54. Crossref

12. McCall-Hosenfeld JS, Freund KM, Liebschutz JM. Factors associated with sexual assault and time to presentation. Prev Med 2009;48:593-5. Crossref

13. Hurley M, Parker H, Wells DL. The epidemiology of drug facilitated sexual assault. J Clin Forensic Med 2006;13:181-5. Crossref

14. Cybulska B. Immediate medical care after sexual assault. Best Pract Res Clin Obstet Gynaecol 2013;27:141-9. Crossref

15. Linden JA. Clinical practice. Care of the adult patient after sexual assault. N Engl J Med 2011;365:834-41. Crossref

16. Holmes MM, Resnick HS, Kilpatrick DG, Best CL. Rape-related pregnancy: estimates and descriptive characteristics from a national sample of women. Am J Obstet Gynecol 1996;175:320-4. Crossref

Nephron-sparing surgery (NSS) for renal tumour has been proved to produce similar oncological and superior functional outcome for stage T1 renal masses as radical nephrectomy.1 It is now recommended as the gold standard.2 Various vascular control methods have been described to achieve a bloodless field for tumour dissection and excision, with the traditional way being renal hilar clamping (HC) that results in global renal ischaemia. The importance of minimising ischaemia in NSS to preserve postoperative renal function is well documented.3 While HC is less technically demanding, zero-ischaemia NSS with selective segmental arterial clamping requires high levels of surgical and anaesthetic expertise.1 Furthermore, not all renal masses are amenable to the technique, such as peripherally located tumours without an identifiable feeding segmental artery on preoperative imaging. In such cases, attaining regional renal ischaemia is a feasible way of maintaining a clear operative field while reducing ischaemic insults to the renal parenchyma, and will theoretically better preserve postoperative renal function. Different methods of regional ischaemia have been reported including manual compression and various parenchymal clamps.4 We describe a method of selective renal parenchymal clamping (SRPC) with a kidney clamp that can be adopted in open, conventional, or robot-assisted laparoscopic NSS. In this study, we report the case selection, feasibility, and surgical outcomes in our initial series of SRPC technique with respect to traditional HC NSS.

All patients who underwent NSS for renal tumour from January 2009 to March 2015 were retrospectively reviewed at a tertiary centre in Hong Kong. Since March 2012, selected patients have been prospectively recruited for SRPC after careful review of the computed tomographic imaging during a preoperative planning session. Eligible indications for renal parenchymal clamping included small tumour size, and peripherally located and exophytic tumour; hilar or centrally located tumours were unsuitable. All procedures including open, conventional, and robot-assisted laparoscopic transperitoneal or retroperitoneal approaches were included. Patients with NSS performed using selective segmental artery clamping technique were excluded from the current study. This study was done in accordance with the principles outlined in the Declaration of Helsinki.

The technique of SRPC has been in use at our unit since March 2012. The kidney clamp (Karl Storz, Tuttlingen, Germany) is a 29-cm long, 10-mm wide instrument. It consists of a 120-mm long distal snare comprising nitinol, an outer sheath, and a handle with ratchet (Fig 1). It is reusable and can be inserted through a 10-mm laparoscopic port. It can be used in laparoscopic, robot-assisted, or open NSS in both transperitoneal and retroperitoneal approach. Tightening of the snare across the renal parenchyma surrounding the tumour occludes the blood flow with the ratchet preventing accidental loosening of the snare during dissection. The clamp can be released by rotating the handle 90 degrees. The fine ratchet mechanism of the clamp allows easy fine-tuning of tightness on the parenchymal tissue according to the bleeding encountered during tumour excision, as the ratchet can be further tightened one gear tooth at a time. Furthermore, the clamp release is gradual and can be easily tightened again. This allows further haemostasis procedures to be performed in case bleeding is encountered on clamp release.

The partial nephrectomy procedure was carried out in a standardised way via an open, pure laparoscopic, or robot-assisted laparoscopic approach. Intra-operative ureteric cannulation and catheterisation was performed after general anaesthesia in selected patients whose tumours were considered by the operating surgeon to be closer to the collecting system. With the patient positioned in a lateral bridged position, an open oblique loin or subcostal incision along the 12th rib tip was made or laparoscopic ports were inserted in the standard manner according to the selected approach. After creation of the operative field and exposure of the kidney, the Gerota’s fascia was incised and perirenal fat was dissected from the renal capsule. Hilar dissections were performed in all cases in order to prepare for HC in case excessive bleeding was encountered. The renal tumour was exposed with its circumferential and deep margins confirmed by intra-operative ultrasonography. The perirenal fat was dissected adequately to allow positioning of the parenchymal clamp over the kidney at about 1 to 1.5 cm from the tumour edge so as to achieve optimal vascular control while avoiding slipping of the clamp during repair of the parenchymal defect after tumour excision. In laparoscopic procedures, the clamp was inserted through a 10-mm assistant port directed towards the planned axis of clamping across the polar region (Fig 2). The hilar area and the ureter were always spared from clamping. The snare was then tightened gradually until bluish discolouration of the parenchyma was noted, and the tightness adjusted according to the degree of bleeding during tumour excision. A thermal excision of tumour was performed. Breaching of the collecting system was checked in those patients with retrograde stenting by slightly releasing the clamp and injecting methylene blue dye through the ureteric catheter, and any area of leakage repaired with polydioxanone sutures. Renorrhaphy was done by using a barbed suture in a continuous manner, with reinforcement by sliding polymer clips. Fibrin glue was applied to aid haemostasis in selected patients, and the kidney clamp was loosened once major oozing had stopped, but kept in place providing stability for the renorrhaphy before its final removal, such that regional ischaemic time could be minimised.

Patient demographics (age, gender, Charlson Comorbidity Index score, baseline renal function, co-existing diabetes or hypertension), tumour characteristics (radiological maximum tumour diameter, PADUA [preoperative aspects and dimensions used for an anatomical] nephrometry score), intra-operative data (operating time, ischaemic time, estimated blood loss), and postoperative outcomes (complications, hospital stay, renal function) were assessed for all patients. Estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease study equation was used to measure postoperative renal function.5 Acute kidney injury was defined as either two-fold increase in serum creatinine or 50% reduction in eGFR within the postoperative hospital stay when compared with preoperative baseline, or any requirement for renal replacement therapy. The renal function at 7, 30, 60, and 90 days after operation was assessed. The PADUA nephrometry score6 was used as an objective measure of tumour characteristics and its individual parameters were also analysed. Complications were graded as per the Clavien-Dindo classification system.7 The proportion of high-grade complications (grades 3-5) was reported.

Clinical data were compared between the SRPC series and a larger cohort of conventional HC series. Continuous variables were compared using Mann-Whitney U test while categorical variables were compared using Chi squared test or Fisher’s exact test. Statistical significance was defined as P<0.05. Analysis was performed using the Statistical Package for the Social Sciences (Windows version 20.0; SPSS Inc, Chicago [IL], US).

From January 2009 to March 2015, a total of 93 patients were identified. After excluding one patient who had an infected upper moiety in a duplex system with upper pole nephrectomy, 92 cases with NSS procedures performed with conventional HC (n=72) or SRPC (n=20) techniques were included for analysis. The mean follow-up duration was 27 and 37 months for SRPC and HC groups, respectively. Patient demographics and co-morbidity were similar between the two groups, as was baseline renal function (mean ± standard deviation of eGFR: 79.1 ± 25.9 mL/min vs 76.1 ± 26.5 mL/min; P=0.751; Table 1). Regarding the tumour complexity (Table 2), there were no differences in the mean radiological tumour size (26.1 ± 10.6 mm vs 30.6 ± 15.2 mm; P=0.371), while the mean PADUA nephrometry score was significantly lower in the SRPC group (7.07 vs 8.34; P=0.002). All tumours in the SRPC series were significantly more exophytic to varying extents (P=0.032), laterally located (P=0.015), and over the polar region (P=0.016). Apparently more NSS procedures in the SRPC group were performed by laparoscopic approach (with or without robot assistance), though not reaching statistical significance compared with HC group. (Table 3). Operating time was significantly shorter (207 ± 72 mins vs 306 ± 80 mins; P<0.001) and estimated blood loss was lower (205 ± 191 mL vs 331 ± 275 mL; P=0.045) with SRPC. No open conversions were needed in minimally invasive approaches. The mean length of hospital stay was 6.6 days and complication rate with Clavien-Dindo grade 3 or above was 5% (n=1) for SRPC group.

Overall postoperative renal function was satisfactory in both groups and the changes between preoperative and postoperative eGFR are shown in Table 4. Cold and warm ischaemia was adopted in 50 (69.4%) and 22 (30.6%) patients in the HC group, respectively. The mean clamping time for SRPC was 20 minutes. The reduction in eGFR was significantly more for HC at postoperative day 60 for both cold (P=0.006) and warm ischaemia (P=0.016) when compared with SRPC. No acute kidney injury occurred during the early postoperative period after parenchymal clamping, while there were seven (9.7%) cases of acute kidney injury in HC.

Overall 70% were renal cell carcinoma in SRPC. All tumours were pathological T1 disease with 92.9% in stage T1a. The mean pathological tumour size was 26.8 mm. No patients in the SRPC group had a positive surgical margin or developed local recurrence or metastasis.

This was a feasibility and safety study that showed the initial promising result of regional ischaemia achieved by SRPC using an adjustable kidney clamp. The concept of regional ischaemia is indeed not new and different instruments have been used successfully in other centres for partial nephrectomy. It was first described by Semb8 in 1956 using manual compression. A self-made clamp with two remodelled malleable retractors4 and use of Rumel tourniquet have also been reported.9 More recently open10 and laparoscopic Satinsky vascular clamps11 have been used. A Nussbaum clamp was used by Simon et al in 200812 in open partial nephrectomy, normally intended for intestinal clamping during general surgery. They later modified this to the laparoscopic Simon clamp with a ratchet mechanism similar to ours.13 It consists of a pair of jaws 100-mm long, one straight and the other one curved. Blood loss was minimal and no complications occurred in three cases. Recently the first study comparing parenchymal clamping with HC for robot-assisted laparoscopic partial nephrectomy was published.14 It showed that parenchymal clamping was associated with a shorter operating time and better preserved immediate postoperative renal function. Our method of SRPC using an adjustable kidney clamp has the merit of allowing flexible control with different degrees of tightness on the parenchyma during tumour excision, collecting system repair, and renorrhaphy. The degree of regional ischaemia can thus be minimised. Furthermore, the clamp serves as a mount for controlling the kidney’s position during the procedure, mimicking the surgeon’s hand directly holding the kidney and keeping it in a stable position during tumour excision and renorrhaphy, which is particularly useful in a laparoscopic setting.

Utilisation of the kidney clamp is feasible for tumours with certain characteristics. As illustrated in Table 2, favourable tumour features include laterally located, polar region, and exophytic. Use in tumours that are located near the hilum, mid pole, or medial side is generally contra-indicated.13 Recently, different nephrometry scores have been increasingly used to describe tumour complexity in partial nephrectomies.6 The PADUA nephrometry score takes several variables into account, including the longitudinal location, the rim location, the relationship with the renal sinus and collecting system, percentage of tumour extending into the kidney, the anterior or posterior location, and the tumour diameter. A higher score is associated with greater risk of complications,6 externally validated by other study.15 The PADUA nephrometry score in the SRPC group was significantly lower in this study. It may have been that these tumours were technically less challenging, and reflects the limitations of the clamp as the hilum and ureter have to be spared during clamp application, therefore not all tumour locations are feasible. Nonetheless in selected cases, SRPC offers an easy and safe way of performing NSS. Currently no particular cut-off value of nephrometry score is used to determine the method of vascular control. Future studies are needed to deduce the selection criteria in which SRPC could be feasible and safely performed. This would be more objective and could facilitate the widespread adoption of the technique.

The kidney clamp is reusable and can be used regardless of the surgical approach. In the current study, seven patients had open surgery, nine had robot-assisted laparoscopic surgery, and four had pure laparoscopic surgery. In our experience, no adjustment to its application is required, regardless of surgical approach. This versatility allows the surgeon to be flexible when deciding the surgical approach.

Another obvious benefit with the kidney clamp was the avoidance of whole kidney ischaemia.16 This was especially true for laparoscopic or robot-assisted cases in which only warm ischaemia was permitted. While cold ischaemia can be up to 3 hours, warm ischaemia is classically limited to 30 minutes.17 This is undoubtedly one of the important stresses for the surgeons during partial nephrectomy. Recent studies have even shown that every minute of ischaemia can have a significant impact on postoperative renal function. Longer warm ischaemia is associated with acute kidney failure, with an odds ratio of 1.05 for each 1-minute increase.3 Regional ischaemia spares most of the non–tumour baring area from ischaemic injury. Animal study has reported the change in serum creatinine and intra-operative oxygenation profiles to be improved with parenchymal clamping or partial renal artery clamping, compared with complete renal artery clamping.18 In this study, early postoperative renal function was satisfactory after parenchymal clamping with minimal changes in eGFR. No patients experienced acute kidney injury during the early postoperative period. Postoperative renal function was mostly comparable between the groups (Table 4). There was significant deterioration in eGFR for HC (P=0.006 and 0.016 for cold and warm ischaemia, respectively) at postoperative 60 days when compared with SRPC. This benefit in SRPC, however, failed to translate into a long-term renal function improvement as shown by 90-day renal function. The significance of this apparent transient benefit was not clear and might have been confounded by different factors in this retrospective study. By accumulating more cases and a longer follow-up, we believe the renal parenchymal clamp will be shown to better preserve renal function for partial nephrectomy in the long term.

There was no slippage or accidental loosening of the parenchymal clamp during tumour dissection and renorrhaphy. No cases required any additional hilar control. In terms of the oncological control, the parenchymal clamps did not lead to a higher positive margin rate, local recurrence rate, or metastases. On the contrary, we expect it to be lower, as the parenchymal clamp allows a more comfortable tumour dissection with less time constraints. This may improve the dissection result and lead to reduced positive surgical margin and better tumour control as the surgeon becomes more experienced.

The mean operating time was reasonably short at 207 minutes. This was mainly attributed by the time saved for the tedious and sometimes risky hilar dissection.19 Renal cooling with ice was also unnecessary and further reduced the overall operating time. The lower estimated blood loss could be explained by the avoidance of HC, as vascular injury during HC can lead to profuse bleeding10 or even renal artery dissection.

The study result of a shortened operating time and lower estimated blood loss needs to be interpreted with caution in view of several limitations of our study. First, it was a retrospective study and the sample size for SRPC was small. Moreover parenchymal clamping was done for less complex tumours. This difference in complexity might have contributed to the smaller blood loss and shorter operating time, as well as the preservation of renal function as less volume of renal parenchyma was removed. Another significant limitation was the lack of volumetric analysis, which rendered the renal function comparison between two groups difficult. A randomised, prospective study is required to truly compare the two methods after accumulating more clinical experience.

Recently partial nephrectomy with zero ischaemia was reported, combining the use of selective arterial clamping and controlled hypotension.20 Outcomes were favourable with a mean absolute and percentage change in preoperative and 4-month postoperative eGFR of -11.4 mL/min/1.73 m² and 13%, respectively. Nonetheless, this technique is technically demanding and requires a steep learning curve. Its utilisation is also limited to robot-assisted or laparoscopic surgery as a magnified view is essential for the meticulous vascular dissection. On the contrary, the kidney clamp in our study provides a relatively simpler way to perform partial nephrectomy without HC, with a reasonable postoperative renal function outcome. This kidney clamp is undoubtedly an important addition to the surgical armamentarium in the evolvement of partial nephrectomy with ultimately zero ischaemia.

Partial nephrectomy using parenchymal clamping as a means of vascular control is safe and feasible in selected cases with peripherally located and exophytic tumours. It could be used in various surgical approaches to achieve regional ischaemia. The postoperative renal function and oncological control in this initial experience were satisfactory.

All authors have disclosed no conflicts of interest.

1. Uzzo RG, Novick AC. Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol 2001;166:6-18. Crossref

2. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol 2009;182:1271-9. Crossref

3. Thompson RH, Lane BR, Lohse CM, et al. Every minute counts when the renal hilum is clamped during partial nephrectomy. Eur Urol 2010;58:340-5. Crossref

4. Selikowitz SM. A simple partial nephrectomy clamp. J Urol 1995;154:489-90. Crossref

5. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70. Crossref

6. Ficarra V, Novara G, Secco S, et al. Preoperative aspects and dimensions used for an anatomical (PADUA) classification of renal tumours in patients who are candidates for nephron-sparing surgery. Eur Urol 2009;56:786-93. Crossref

7. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009;250:187-96. Crossref

8. Semb C. Partial resection of the kidney: anatomical, physiological and clinical aspects. Ann R Coll Surg Engl 1956;19:137-55.

9. Gill IS, Munch LC, Clayman RV, McRoberts JW, Nickless B, Roemer FD. A new renal tourniquet for open and laparoscopic partial nephrectomy. J Urol 1995;154:1113-6. Crossref

10. Denardi F, Borges GM, Silva W Jr, et al. Nephron-sparing surgery for renal tumours using selective renal parenchymal clamping. BJU Int 2005;96:1036-9. Crossref

11. Verhoest G, Manunta A, Bensalah K, et al. Laparoscopic partial nephrectomy with clamping of the renal parenchyma: initial experience. Eur Urol 2007;52:1340-6. Crossref

12. Simon J, dePetriconi R, Rinnab L, Hautmann RE, Kurtz F. Optimizing selective renal clamping in nephron-sparing surgery using the Nussbaum clamp. Urology 2008;71:1196-8. Crossref

13. Simon J, Bartsch G Jr, Finter F, Hautmann R, de Petriconi R. Laparoscopic partial nephrectomy with selective control of the renal parenchyma: initial experience with a novel laparoscopic clamp. BJU Int 2009;103:805-8. Crossref

14. Hsi RS, Macleod LC, Gore JL, Wright JL, Harper JD. Comparison of selective parenchymal clamping to hilar clamping during robotic-assisted laparoscopic partial nephrectomy. Urology 2014;83:339-44. Crossref

15. Tyritzis SI, Papadoukakis S, Katafigiotis I, et al. Implementation and external validation of Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score for predicting complications in 74 consecutive partial nephrectomies. BJU Int 2012;109:1813-8. Crossref

16. George AK, Herati AS, Srinivasan AK, et al. Perioperative outcomes of off-clamp vs complete hilar control laparoscopic partial nephrectomy. BJU Int 2013;111:E235-41. Crossref

17. Novick AC. Renal hypothermia: in vivo and ex vivo. Urol Clin North Am 1983;10:637-44.

18. Raman JD, Bensalah K, Bagrodia A, et al. Comparison of tissue oxygenation profiles using 3 different methods of vascular control during porcine partial nephrectomy. Urology 2009;74:926-31. Crossref

19. Mejean A, Vogt B, Cazin S, Balian C, Poisson JF, Dufour B. Nephron sparing surgery for renal cell carcinoma using selective renal parenchymal clamping. J Urol 2002;167:234-5. Crossref

20. Gill IS, Patil MB, Abreu AL, et al. Zero ischemia anatomical partial nephrectomy: a novel approach. J Urol 2012;187:807-14. Crossref

According to the Hong Kong Cancer Registry,1 there were 1797 new cases of rectal/anal cancer in 2013. The incidence rate per 100 000 persons was 25.0 (crude rate) and 13.3 (age-standardised rate). The total number of deaths from rectal/anal cancer was 597, and the mortality rate was 8.3 (crude rate) or 3.7 (age-standardised rate) per 100 000 persons. In Hong Kong, colorectal cancer is the first most common cancer in incidence and the second in mortality rate for both sexes.

Conventional treatment of rectal cancer is mainly surgery. In locally advanced cancer, adjuvant therapy with concurrent chemoradiation has been shown to improve local control and disease-free survival (DFS) in phase III clinical trials.2 3 4 5 The major indication for adjuvant chemoradiation is pathological T3 or T4 and/or regional nodal disease without distant metastasis.

Preoperative radiotherapy with or without concurrent chemotherapy has been shown to reduce the local recurrence rate of locally advanced rectal cancer.6 7 8 9 10 11 12 Preoperative radiotherapy comprises a short or long course.

Short-course preoperative radiotherapy was given in 5 Gy per fraction for five fractions over 1 week, followed by surgery about 1 week after completion of radiotherapy. Since the introduction of total mesorectal excision (TME), the local recurrence rate has been significantly reduced. In the new era of TME surgery, a Dutch rectal trial confirmed that a short course of preoperative radiotherapy, followed by TME surgery, was also beneficial in reducing local recurrence rate from 8.2% to 2.4% over 2 years compared with TME surgery alone in locally advanced rectal cancer.13 14

Long-course preoperative radiotherapy involves a conventional fractionation of 1.8 Gy per fraction, five fractions per week, up to a total dose of 45 to 50 Gy. It is given with concurrent chemotherapy consisting of mostly a fluoropyrimidine-containing regimen. Surgery is usually performed approximately 4 to 10 weeks after completion of chemoradiation.

A randomised German trial (CAO/ARO/AIO 94)10 compared preoperative long-course chemoradiation with postoperative chemoradiation. At a median follow-up of 4 years, no significant difference was reported in the 5-year overall survival (OS). Nonetheless, treatment compliance, grade 3/4 acute and late toxicity profile, tumour and nodal downstaging, and rates of pelvic recurrence all favoured the preoperative chemoradiation arm. In addition, the sphincter preservation rate in the 194 patients with low-lying tumours declared by the surgeon prior to randomisation requiring an abdominoperineal resection (APR) was enhanced with preoperative treatment (39% vs 19%; P=0.004).

Since 2005, our hospital has adopted a treatment policy of long-course neoadjuvant (or preoperative) chemoradiation (nCRT) for selected cases of locally advanced rectal cancer. The objective of this study was to review the clinical outcome of these patients with locally advanced rectal cancer treated with nCRT in our department from November 2005 to October 2014 and to elucidate the prognostic factors for treatment outcome retrospectively.

Eligible patients included those without distant metastasis and who were staged preoperatively on radiological grounds with T3 or T4 disease and/or having nodal involvement. There might have been other extra specific reasons for recommending nCRT, including threatened circumferential resection margin (CRM), sphincter-sparing surgery, avoidance of pelvic exenteration, and unresectability (Table 1). Patients were required to be medically fit and agree to the nCRT.

The nCRT scheme adopted in our department consisted of the following.

Simulation procedure was done in an immobilised prone position with full bladder, using simulation computed tomography (CT) scan. The three-dimensional conformal radiotherapy planning was performed on the simulation CT scan imaging, using three coplanar fields with shielding conformal to the target volume. The radiotherapy was given in two phases. Phase 1 included the whole pelvis. A total dose of 45 Gy was delivered at 1.8 Gy per day, five fractions per week over 5 weeks. Phase II included only the gross tumour and the enlarged pelvic nodes with margins. A booster dose of 5.4 Gy was administered in the same fractionation as phase 1.

Concurrent chemotherapy was given in the first and fifth weeks of radiation. It comprised an intravenous (IV) bolus of 5-fluorouracil (5-FU; 400 mg/m²) and leucovorin (20 mg/m²) on days 1 to 4.

The surgery was scheduled about 4 to 10 weeks after completion of nCRT. Adjuvant chemotherapy with four cycles of 5-FU and leucovorin was administered to most patients. In some selected cases with pathological node-positive disease following surgery, four cycles of capecitabine and oxaliplatin (‘XELOX’ regimen) were given.

In this study, clinical data were collected retrospectively from the medical records of all patients who had undergone nCRT for locally advanced rectal cancer in the Department of Clinical Oncology at the Prince of Wales Hospital, Hong Kong from November 2005 to October 2014. The surgery was performed either at Prince of Wales Hospital or the referring hospital. There was variation in practice for pretreatment staging method, re-staging on completion of nCRT (follow-up CT scan was arranged to exclude distant metastasis at least 2 weeks after nCRT; optional magnetic resonance imaging [MRI] was considered at least 4 weeks after nCRT), and follow-up among different hospitals. The patients’ demographic information, tumour characteristics, and treatment details were retrieved. The initial type of surgery recommended by the referring surgical team at presentation and any extra specific reasons (intentions) for referral for nCRT were reviewed. The final pathology at the definitive surgery (the pathological T and N staging, the tumour size, any pathological complete response [pCR], the resection margins), the treatment-related toxicity (radiation- or chemotherapy-related, surgical complications), recurrence (local, regional, distant relapse), and disease status at follow-up were reviewed.

The key study endpoints included loco-regional recurrence–free survival, distant metastasis–free survival, DFS, and OS. Other secondary endpoints included the rate of pCR, tumour downstaging (T and N staging), conversion of threatened CRM to clearance of margins (R0), conversion to sphincter-sparing surgery for lower rectal cancers, conversion from a potential pelvic exenteration to non-exenterating surgery, and the rate of conversion from unresectable to resectable tumour. For toxicity endpoints, the rate of grade 3 or above acute toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, and the rate of grade 3 or above late radiation toxicity according to the Toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer, and perioperative complications as represented by rate of 30-day postoperative mortality and morbidity (delayed wound healing, anastomotic complication, reoperation) were also assessed.

Descriptive statistics were used to report the incidence rates of secondary endpoints that were calculated directly. The survival rates and time-to-event rates were estimated with the Kaplan-Meier method. Univariate analysis based on the proportional hazard model was performed to investigate the relationship between different outcome (survival) and prognostic factors. The hazard ratio and the corresponding 95% confidence interval were shown. The prognostic factors included pretreatment T stage, pretreatment N stage, histological grade, threatened CRM, completion of nCRT, time from nCRT to surgery, pathological T stage, pathological N stage, pathological group stage, pCR, pathological margin, number of involved nodes, and completion of adjuvant chemotherapy. For those significant prognostic factors, multivariate analysis using Cox regression with stepwise selection was performed.

This study was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee with informed consent waived. The principles outlined in the Declaration of Helsinki have also been followed.

A total of 135 patients who had received nCRT in our department from November 2005 to October 2014 were reviewed, of whom 130 had completed nCRT and surgery with or without adjuvant chemotherapy. Of the five patients who did not have surgery, two refused surgery after nCRT and three progressed after nCRT without undergoing surgery.

Patient characteristics are shown in Table 2. The mean age was 60.9 (standard deviation [SD], 9.23) years. The male-to-female ratio was 3.2:1. For the pretreatment stage, 80% and 20% were T3 and T4 respectively, while 13.8%, 40.0% and 45.4% were N0, N1 and N2 stage, respectively. For the overall group stage, the incidences of stage IIA, IIB/C, and III were 8.5%, 6.1%, and 85.4%, respectively. A total of 65.4% cases had threatened CRM at pretreatment imaging.

Of the 130 patients who had surgery, 128 (98.5%) completed nCRT. For the radiotherapy-related toxicities, the combined incidence of grade 3 or above acute toxicity to the skin, bowel, and urinary toxicity was 6.2%. Similarly, the radiotherapy-related grade 3 or above late toxicity to the bowel and urinary tract was 6.2%. For chemotherapy-related grade 3 or above acute toxicity, the incidences of neutropenia, anaemia, and thrombocytopenia were 14.6%, 1.5%, and 1.5%, respectively. The most common non-haematological grade 3 or above acute toxicities were hand-foot-mouth syndrome (0.8%), mucositis (1.5%), and diarrhoea (0.8%). Adjuvant chemotherapy was given to 103 (79.2%) patients, of whom 92 (89.3%) received the regimen of IV bolus 5-FU and leucovorin. With regard to surgical complications, 22 (16.9%) patients had delayed wound healing (>30 days after operation), six (4.6%) had anastomotic complication, and six (4.6%) required reoperation. There was no 30-day postoperative mortality reported (Table 3).

Of the 130 cases, 124 (95.4%) underwent TME surgery and 114 (87.7%) had laparoscopic surgery. The mean time from the date of completion of nCRT to surgery was 7.2 (SD, 4.8) weeks. Comparing the type of surgery recommended before starting nCRT and those finally carried out after nCRT, the rate of anterior resection/low anterior resection increased to 65.4% from 50.8%, and the rate of APR/pelvic exenteration decreased to 27.7%/3.8% from 32.3%/12.3% respectively. The overall rate of surgical conversion was reported in several clinical contexts: (1) percentage achieving a R0 resection, (2) percentage undergoing sphincter-sparing surgery, and (3) percentage avoiding pelvic exenteration. First, of the total number of patients who were found to have threatened CRM before treatment, 90.6% finally achieved a R0 resection. Of the 42 patients who were initially deemed on presentation to require an APR, 35.7% underwent sphincter-sparing surgery. In a subgroup of the 15 patients who had received nCRT with the intention of sphincter preservation, 86.7% (n=13) underwent sphincter-sparing surgery rather than APR. Among these 13 cases with successful sphincter-sparing surgery, one had pCR and all had clear resection margins. They remained alive and free of loco-regional and distant recurrence at the end of this study. Of the 16 patients who were initially assessed to require pelvic exenteration, 62.5% (n=10) underwent non-exenterating surgery. There were six patients in whom tumour was deemed unresectable and who were referred for nCRT to improve resectability. Complete resection with negative margins was subsequently achieved in four (66.7%) of the six patients while the other two had a positive margin in the palliative surgery.

The final pathological staging in the surgical specimen is reported (Table 4). The rates of pCR and clear resection margin were 13.8% and 89.2%, respectively. The rate of T downstaging was 49.2% and that for N stage was 63.1% (Table 3).

The median follow-up time was 35.1 months. Of the 130 patients, local recurrence, loco-regional recurrence, distant metastasis, disease recurrence, and death occurred in 10 (crude rate, 7.7%), 15 (11.5%), 30 (23.1%), 34 (26.2%), and 23 (17.7%) patients, respectively. The Kaplan-Meier estimates of the 3-year local recurrence–free survival, regional recurrence–free survival, loco-regional recurrence–free survival, distant metastasis–free survival, DFS, and OS were 91.8%, 92.6%, 87.9%, 73.9%, 70.1%, and 86.5%, respectively. The respective 5-year survival rates were 86.7%, 85.3%, 81.0%, 72.1%, 64.6%, and 68.4%. The corresponding Kaplan-Meier curves for local recurrence-free survival and OS is also shown in the Figure (the curves for loco-regional recurrence–free survival, distant metastasis–free survival, and DFS are shown in the Appendix).

The variables (factors including age and gender were tested but not significant in univariate model) in the univariate analysis included the pretreatment T stage, pretreatment N stage, histological grade, presence of threatened CRM, completion of nCRT, time from nCRT to surgery (continuous variable), pathological T stage, pathological N stage, pathological group stage, pCR, pathological margin, number of involved nodes (continuous variable), and completion of adjuvant chemotherapy. Those significant prognostic factors were studied by multivariate analysis.

In the multivariate analysis, the pathological clear margin, completion of nCRT, and the number of involved nodes were significantly associated with local recurrence–free survival. The number of involved nodes, pathological clear margin, and time from nCRT to surgery were significantly associated with loco-regional recurrence–free survival. The number of involved nodes, the pretreatment T4, pathological stage III/IV, and completion of adjuvant chemotherapy were significantly associated with distant metastasis–free survival. The number of involved nodes, pathological stage III/IV, and completion of adjuvant chemotherapy were significantly associated with DFS. Finally, the number of involved nodes, the pretreatment T4, and pathological stage III/IV were significantly associated with OS (Table 5).

Although the current study was retrospective, survival data were comparable with figures reported in international studies. In the major randomised trials, 5-year local recurrence rate in the arm with preoperative short-course radiotherapy was in the range of 11% to 14%, and OS was in the range of 42% to 76%.6 7 8 9 In the randomised trials that had an arm with nCRT, the 4- or 5-year local recurrence rates were 5.7% to 15.6% and the OS were 66.2% to 76%.10 15 16 17 18 In this study, the 5-year local recurrence rate and loco-regional recurrence rate was 13.3% and 19%, respectively. These were close to the reported figures from randomised studies.10 15 16 17 18 The 5-year OS in this study was 68.4% and is comparable with international studies.10 15 16 17 18

The pCR rate was 13.8% in this study, again comparable with randomised trials10 15 16 17 18 and reviews.19 Together with the favourable downstaging effects, the completion resection rate was high (89.2%). This is the primary aim of nCRT in advanced rectal cancer. The role of nCRT in sphincter preservation for low-lying tumours has been a controversial issue in some randomised trials,10 11 15 16 and critical reviews.20 21 In a German study,10 among the 194 patients with tumours that were determined by the surgeon before randomisation to require an APR, a statistically significant increase in sphincter preservation was achieved among patients who received nCRT compared with those who received postoperative chemoradiation (39% vs 19%; P=0.004). Although long-course nCRT is expected to result in tumour downsizing, a Polish trial11 did not find that long-course chemoradiation was superior to short-course preoperative radiotherapy in reducing the APR rate. The possible explanations for this finding include the possibility that the degree of downsizing was not sufficient to alter the surgical approach, due to surgeon’s concern about residual microscopic disease despite an apparently good response after nCRT, or the surgeons had made their clinical decision based on the pretreatment staging information. In our study the overall rate of conversion from APR to sphincter-sparing surgery was 35.7% and was comparable with that (39%) in the German trial10; and for the subgroup of patients with an intention to spare the sphincter, the conversion rate was even higher, up to 86.7%, with a good clinical outcome.

The extent of extramural tumour spread and lymph node and CRM status are powerful predictive factors for local recurrence, distant metastases, and OS in patients with rectal cancer.22 23 24 25 26 27 28 From our study, it was evident that the number of involved nodes in the final pathology was an independent factor in OS, DFS, local or loco-regional recurrence–free survival, and distant metastasis–free survival. For local or loco-regional recurrence, the pathological clear margin, the completion of nCRT, and the time from nCRT to surgery were independent prognostic factors. Although in this study there was an attempt to find the optimal cut-off time for surgery after the completion of nCRT, this was not possible because of the small sample size. Increasing the time interval from completion of nCRT to surgery was associated with a detrimental effect on loco-regional recurrence (hazard ratio=1.348).

In this study, completion of adjuvant chemotherapy was a prognostic factor for distant metastasis. This implies that adjuvant chemotherapy might be important in reducing distant metastasis. It remains controversial whether adjuvant chemotherapy should be given after nCRT and surgery. A 2x2 factorial randomised trial (EORTC trial 22921)29 30 31 32 that assessed the value of preoperative chemo-radiotherapy versus preoperative radiotherapy and postoperative chemotherapy versus no postoperative chemotherapy in patients with cT3-4 disease could not demonstrate any prolonged progression-free or OS from adjuvant chemotherapy in patients with resectable T3-T4 rectal cancer. Its follow-up report of 785 eligible patients who underwent R0 resection showed that patients with a good prognosis (ypT0-2) seemed to benefit from adjuvant chemotherapy, especially if the tumour was located in the mid-rectum.33 Nonetheless, an updated analysis of the EORTC 22921 trial18 recently failed to confirm the benefit of adjuvant chemotherapy for ypT0-2 patients after a median follow-up of 10.4 years. In the I-CNR-RT phase III randomised trial,34 there was no benefit of adjuvant chemotherapy (6 cycles of 5-FU and folinic acid) compared with observation only after nCRT. The result may be partly attributed to the low compliance to complete the planned number of chemotherapy cycles. The British Chronicle trial35 is unique in comparing XELOX postoperatively against observation alone in locally advanced rectal cancer treated with nCRT. After a median follow-up of 44.8 months, there was no statistically significant benefit of adjuvant XELOX in the 3-year DFS rate. A Korean study reported the results of ADORE phase II study in which 321 patients of ypT3-4/ypN0 or ypTx/ypN1-2 after nCRT with 5-FU alone were randomised to receive adjuvant chemotherapy with 5-FU or FOLFOX.36 37 After a median follow-up of 38.2 months, the 3-year DFS rate was better in the FOLFOX arm (P=0.047). Although adjuvant treatment of patients with rectal cancer remains controversial, the National Comprehensive Cancer Network guidelines recommend 5-FU–based chemotherapy with oxaliplatin as the preferred adjuvant treatment for all patients with rectal cancer, who receive neoadjuvant 5-FU–based chemoradiation, regardless of surgical pathology results. The recently reported German CAO/ARO/AIO-04 trial also revealed the benefit of adding oxaliplatin to both neoadjuvant and adjuvant treatment with significant improvement in DFS of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with conventional 5-FU–based combined modality regimen.38

There were limitations to this study. The data were collected retrospectively and there was no blinding during data collection. It is possible that potential confounding factors like smoking and co-morbidity were inadequately controlled for. Toxicity data were not collected systematically and thus could be underreported. If the data can be collected prospectively, a tailor-made toxicity form will be designed and more toxicity can be captured. The median follow-up time was relatively short. Magnetic resonance imaging is now a standard staging tool in rectal cancer. The use of MRI as initial staging was only 66.1% in this cohort. Therefore, pretreatment staging might not accurately reflect the true staging at presentation. In this study, there was limited reporting of late toxicity of radiation such as sexual and sphincter dysfunction. The full extent of the late toxicity of radiation requires longer follow-up. Due to the small sample size, the adjustment of the potential confounding factors for survival was a limitation of the study.

The treatment outcome following nCRT for locally advanced non-metastatic rectal cancer in our experience was comparable with overseas data in terms of local control rate and OS. The high conversion rate from having a threatened circumferential margin to clear resection margin, and the high T and N downstaging rates, suggest that this approach is effective in facilitating surgery to obtain complete surgical clearance. In the subgroup with an intention of sphincter preservation, the conversion rate from APR to sphincter-sparing surgery was high. The rate of acute toxicities was within expectations and manageable and there were no treatment-related deaths.

Although not named in the author list, we thank the other colleagues who contributed to the treatment of this group of patients and those who helped with data collection.

All authors have disclosed no conflicts of interest.

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11. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 2012;30:1926-33. Crossref

12. Sebag-Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009;373:811-20. Crossref

13. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-46. Crossref

14. Van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 2011;12:575-82. Crossref

15. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93:1215-23. Crossref

16. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012;30:3827-33. Crossref

17. Gérard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24:4620-5. Crossref

18. Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014;15:184-90. Crossref

19. Damin DC, Lazzaron AR. Evolving treatment strategies for colorectal cancer: a critical review of current therapeutic options. World J Gastroenterol 2014;20:877-87. Crossref

20. Gerard JP, Rostom Y, Gal J, et al. Can we increase the chance of sphincter saving surgery in rectal cancer with neoadjuvant treatments: lessons from a systematic review of recent randomized trials. Crit Rev Oncol Hematol 2012;81:21-8. Crossref

21. Bujko K, Kepka L, Michalski W, Nowacki MP. Does rectal cancer shrinkage induced by preoperative radio(chemo)therapy increase the likelihood of anterior resection? A systematic review of randomised trials. Radiother Oncol 2006;80:4-12. Crossref

22. Dukes CE, Bussey JH. The spread of rectal cancer and its effect on prognosis. Br J Cancer 1958;12:309-20. Crossref

23. Gunderson LL, Sosin H. Areas of failure found at reoperation (second or symptomatic look) following “curative surgery” for adenocarcinoma of the rectum: clinicopathologic correlation and implications for adjuvant therapy. Cancer 1974;34:1278-92. Crossref

24. Rich T, Gunderson LL, Lew R, Galdibini JJ, Cohen AM, Donaldson G. Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer 1983;52:1317-29. Crossref

25. Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet 1986;2:996-9. Crossref

26. Merkel S, Mansmann U, Siassi M, Papadopoulos T, Hohenberger W, Hermanek P. The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 2001;16:298-304. Crossref

27. Birbeck KF, Macklin CP, Tiffin NJ, et al. Rates of circumferential resection margin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Ann Surg 2002;235:449-57. Crossref

28. Wibe A, Rendedal PR, Svensson E, et al. Prognostic significance of the circumferential resection margin following total mesorectal excision for rectal cancer. Br J Surg 2002;89:327-34. Crossref

29. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114-23. Crossref

30. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results—EORTC 22921. J Clin Oncol 2005;23:5620-7. Crossref

31. Bosset JF, Calais G, Mineur L, et al. Preoperative radiation (Preop RT) in rectal cancer: effect and timing of additional chemotherapy (CT) 5-year results of the EORTC 22921 trial. Proc Am Soc Clin Oncol 2005;23:247S (abstract no. 3505).

32. Bosset JF, Calais G, Daban A, et al. Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients: assessment of acute toxicity and treatment compliance. Report of the 22921 randomised trial conducted by the EORTC Radiotherapy Group. Eur J Cancer 2004;40:219-24. Crossref

33. Collette L, Bosset JF, den Dulk M, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007;25:4379-86. Crossref

34. Sainato A, Cernusco Luna Nunzia V, Valentini V, et al. No benefit of adjuvant fluorouracil leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): long term results of a randomized trial (I-CNR-RT). Radiother Oncol 2014;113:223-9. Crossref

35. Glynne-Jones R, Counsell N, Quirke P, et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol 2014;25:1356-62. Crossref

36. Hong YS, Nam B, Kim K, et al. Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin for rectal cancer patients whose postoperative yp stage 2 or 3 after preoperative chemotherapy: updated results of 3-year disease-free survival from a randomized phase II study (The ADORE). J Clin Oncol 2014;32(5 Suppl):abstract no. 3502.

37. Hong YS, Nam BH, Kim KP, et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol 2014;15:1245-53. Crossref

38. Rödel C, Graeven U, Fietkau R, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2015;16:979-89. Crossref

Over the past century, kidney stones have become increasingly prevalent, particularly in more developed countries. The incidence of urolithiasis in a given population is dependent on the geographic area, racial distribution, socio-economic status, and dietary habits.1 In general, patients with a history of gout are at greater risk of forming uric acid stones, as are patients with obesity, diabetes, or complete metabolic syndrome.2 Moreover, elevated serum urate levels are known to lead to gouty arthritis, tophi formation, and uric acid kidney stones.3 The incidence of uric acid stones varies between countries and accounts for 5% to 40% of all urinary calculi.4 Certain risk factors may be involved in the pathogenesis of uric acid nephrolithiasis, including low urinary volume and persistently low urinary pH.5

Calcium oxalate stones may form in some patients with gouty diathesis due to increased urinary excretion of calcium and reduced excretion of citrate. In addition, relative hypercalciuria in gouty diathesis with calcium oxalate stones may be due to intestinal hyperabsorption of calcium.6 Most urinary uric acid calculi are not pure in composition and complex urates, sodium, potassium, and calcium have been found together in various proportions.7 An analysis of stones in gout patients in Japan showed that the incidence of common calcium salt stones was over 60%, while that of uric acid stones was only 30%.8 This implies that the disruption of uric acid metabolism promotes not only uric acid stones, but also calcium salt stones. Therefore, a high serum urate level might be associated with nephrolithiasis and this provided the rationale for this study.

Overall, 120 male gouty arthritis patients with newly diagnosed gout and serum urate concentration of >7 mg/dL, and without previous kidney stone disease were allocated to one of the two groups according to their serum uric acid level: <10 mg/dL (group 1, n=80) and ≥10 mg/dL (group 2, n=40). Patients were recruited from the rheumatology clinic of Taipei City Hospital (Renai and Zhongxing branches), a tertiary community hospital in Taiwan, from March 2015 to February 2016. They had been newly diagnosed with gout but had no clinical suggestions of renal stone disease. The exclusion criteria included previously treated gouty arthritis and current prescription of urate reabsorption inhibitors. The patient’s age, duration of gout arthritis, presence of tophi, body mass index (BMI), blood urea nitrogen (BUN), creatinine, urinary pH, and kidney ultrasonography were all measured and analysed. This study has been approved by the hospital’s Institutional Review Board with informed consent waived.

Results for continuous variables were given as means ± standard deviations. Student’s t test was used to compare the physical characteristics that were continuous in nature among the different subject groups and the Chi squared test was used to compare the difference in the stone detection rate between the two groups. A P value of <0.05 was regarded as statistically significant for two-sided tests. The Statistical Package for the Social Sciences (Windows version 12.0; SPSS Inc, Chicago [IL], US) was used for all statistical analyses.

The mean age of the two study groups was similar (40 years). Family history of gout was present in 67.5% and 90% of groups 1 and 2, respectively. The time elapsed since onset of gout was less than 4 years in both groups. Tophaceous gout was found in 8.8% in group 1 and 10.0% in group 2. The prevalence of patients with a BMI of ≥30 kg/m² was not statistically significant between the two groups. Only 6% of group 2 patients with kidney stones had a BMI of >95th percentile. In most cases, urinary pH was less than 5.5 in both groups and there were no abnormal changes to BUN or creatinine levels. Interestingly, the prevalence of kidney stones detected by ultrasonography was 6.3% in group 1 and 82.5% in group 2 (P<0.05). The sensitivity and specificity of high serum urate level (>10 mg/dL) in predicting kidney stones was 87% and 91%, respectively (Table).

Gout is a common metabolic disorder characterised by chronic hyperuricaemia, and serum urate level of >6.8 mg/dL that exceeds the physiological threshold of saturation. Urolithiasis is one of the well-known complications of gout. We hypothesise that serum urate level can be used as a predictive marker for urolithiasis. Uric acid, a weak organic acid, has very low pH-dependent solubility in aqueous solution. Approximately 70% of urate elimination occurs in urine, and the kidney plays a dominant role in determining plasma level.9 A serum urate level of >7 mg/dL is recognised as leading to gouty arthritis and uric acid stone formation. Moreover, recent epidemiological studies have identified serum urate elevation as an independent risk factor for chronic kidney disease, cardiovascular disease, and hypertension.3 Impaired renal uric acid excretion is the major mechanism of hyperuricaemia in patients with primary gout.10 The molecular mechanisms of renal urate transport are still incompletely understood. Urate transporter 1 is an organic anion transporter with highly specific urate transport activity, exchanging this anion with others including most of the endogenous organic anions and drug anions that are known to affect renal uric acid transport.10 11

Uric acid stones account for 10% of all kidney stones and are the second most common cause of urinary stones after calcium oxalate and calcium phosphate. The most important risk factor for uric acid crystallisation and stone formation is a low urine pH (<5.5) rather than an increased urinary uric acid excretion.12 The proportion of uric acid stones varies between countries and accounts for 5% to 40% of all urinary calculi.4 Uric acid homeostasis is determined by the balance between its production, intestinal secretion, and renal excretion. The kidney is an important regulator of circulating uric acid levels by reabsorbing about 90% of filtered urate and being responsible for 60% to 70% of total body uric acid factor underpinning hyperuricaemia and gout.13 Pure uric acid stones are radiolucent but well visualised on renal ultrasound or non-contrast helical computed tomographic scanning; the latter is especially good for detection of stones which are <5 mm in size.14 Nonetheless the reason why most patients with gout present with acidic urine, even though only 20% have uric acid stones, remains unclear. In a US study, the prevalence of kidney stone disease was almost two-fold higher in men with a history of gout than in those without (15% vs 8%).15 Higher adiposity and weight gain are strong risk factors for gout in men, while weight loss is protective.15 An analysis by Shimizu8 of stones in gout patients revealed that the proportion of common calcium salt stones was over 60%, while that of uric acid stones was only about 30%. Overweight/obesity and older age associated with low urine pH were the principal characteristics of ‘pure’ uric acid stone formers. Impaired urate excretion associated with increased serum uric acid is also another characteristic of uric acid stone formers and resembles patients with primary gout. Patients with pure calcium oxalate stones were younger; they had a low proportion of obese subjects and higher urinary calcium.16

Conventionally, BMI was stratified as normal (<25 kg/m²), overweight (25-29.9 kg/m²), or obese (≥30 kg/m²). In males, the proportion of uric acid stones gradually increased with BMI, from 7.1% in normal BMI to 28.7% in obese subjects.17 The same was true in females, with the proportion of uric acid stones rising from 6.1% in normal BMI to 17.1% in obese subjects.17 Studies found that BMI is associated with an increased risk of kidney stone disease, but with a BMI of >30 kg/m², further increases do not appear to significantly increase the risk of stone disease.17 18 An independent association between kidney stone disease and gout strongly suggests that they share common underlying pathophysiological mechanisms.19

Three major conditions control the potential for uric acid stone formation: the quantity of uric acid, the volume of urine as it affects the urinary concentration of uric acid, and the urinary pH.20 Two major abnormalities have been suggested to explain overly acidic urine: increased net acid excretion and impaired buffering caused by defective urinary ammonium excretion, with the combination resulting in abnormally acidic urine.21 Urinary alkalisation, which involves maintaining a continuously high urinary pH (pH 6-6.5), is considered by some or many to be the treatment of choice for uric acid stone dissolution and prevention.20 In general, gout is caused by the deposition of monosodium urate crystals in tissue that provokes a local inflammatory reaction. The formation of monosodium urate crystals is facilitated by hyperuricaemia. In a study by Sakhaee and Maalouf,21 being overweight and of older age were associated with low urine pH and one of the principal characteristics of pure uric acid stone formation. Impaired urate excretion associated with increased serum uric acid was another characteristic of uric acid stone formation that resembles patients with primary gout.

The limitations of this current study included the lack of measurement of uric acid concentration of urine in the participants, no further computed tomographic scanning for kidney stones, no analysis of stone composition, and limited representativeness of the study subjects. For example, there were only 10 obese patients (BMI ≥30 kg/m²) in the analysis. In this study, hyperuricaemia was a risk factor for kidney stone formation. Patients with serum urate level of >10 mg/dL should undergo ultrasound examination to look for any nephrolithiasis.

All authors have disclosed no conflicts of interest.

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