Editorial

Management of acute paracetamol poisoning

Hong Kong Med J 2015 Oct;21(5):388

DOI: 10.12809/hkmj154680

EDITORIAL

Management of acute paracetamol poisoning

Matthew SH Tsui, FRCP (Edin), FHKAM (Emergency Medicine)

Department of Accident and Emergency, Queen Mary Hospital, Pokfulam, Hong Kong

Corresponding author: Dr Matthew SH Tsui (tsuish@ha.org.hk)

Full paper in PDF

Since 2010, paracetamol has been the most common agent used in Hong Kong for deliberate self-harm by overdose and poisoning.1 It is readily available over-the-counter and is commonly prescribed by doctors. There are more than 900 registered pharmaceuticals that contain paracetamol in Hong Kong. Paracetamol overdose can result in delayed, sometimes life-threatening, liver injury and dose-dependent damage. N-acetylcysteine (NAC) is well known to be an effective antidote that can prevent liver injury if administered in time. The decision to give NAC can be facilitated by plotting the serum paracetamol concentration against time since ingestion on the Rumack-Matthew nomogram.2 Serum concentration above the treatment line on the nomogram indicates the need for NAC therapy.

There are three treatment lines on the Rumack-Matthew nomogram: 100-treatment line, 150-treatment line, and 200-treatment line. Currently, the 150-treatment line is commonly used in most parts of the world including the US, Australia, and New Zealand. The 150-treatment line is parallel to the original 200-treatment line but has been arbitrarily lowered by 25% to improve sensitivity. The Hong Kong Poison Information Centre also recommends the 150-treatment line and most clinicians in Hong Kong follow this recommendation. In the UK, the original 200-treatment line was used for normal-risk patients and the 100-treatment line reserved for high-risk patients. Over the years, cases of liver failure accumulated when patients were treated according to the 200-treatment line. Thus in 2012 the health department in the UK decided to abandon the two-level approach and apply one treatment line of 100 mg/L for all patients.3

In the article written by Chan et al,4 the 150-treatment line has been evaluated and identified a failure rate of 0.45%. All four index patients developed chemical hepatitis that responded to supportive treatment. The incidence of 150-treatment line failures in the US has been reported as 1% to 3% and thought to be predominantly due to inaccurate ingestion history.5 Looking closely at the four cases presented in Chan et al’s study,4 two of them presented late, and in most cases there was an apparent discrepancy between the dose taken and the achieved paracetamol level. Similar to the US experience, an inaccurate ingestion history might explain treatment-line failure for some of these cases. Further evidence from more robust studies is needed before a recommendation can be made to lower the treatment threshold to the UK standard.

Obtaining an accurate history from patients who deliberately self-harm is known to be difficult. Patients may be unwilling or unable to provide accurate information to the clinician. According to the author’s own experience in managing such patients, history taking must be done tactfully and sometimes repeatedly from different sources of information. An astute physician should make the decision to give NAC after analysing all the available evidence including the best-gathered history, the clinical presentation, and the remaining treatment-time window, together with the serum paracetamol level. Laboratory tests may help but can never replace clinical skill, clinical judgement, and experience in patient management.

Previously, the responsibility for managing such time-critical overdosed patients was often borne by interns and junior residents. The quality of care provided may not have been optimal. Over the past 10 years emergency physicians and trainees have received intensive training in the management of toxicology cases based on updated evidence and standards. In addition, groups of interested emergency physicians have formed toxicology teams to oversee and support the management of poisoning patients in individual hospitals. This model of care improves patient outcome and shortens the length of stay for medical treatment.6 7 Such improvements might explain the observed good outcome for Chan et al’s cohort4 of patients with paracetamol overdose.

References

1. Chan YC, Tse ML, Lau FL. Hong Kong Poison Information Centre: Annual Report 2013. Hong Kong J Emerg Med 2014;21:249-59.

2. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871-6.

3. Paracetamol overdose: new guidance on use of intravenous acetylcysteine. Commission of Human Medicine, United Kingdom. Available from: http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con178654.pdf. Accessed Aug 2015.

4. Chan ST, Chan CK, Tse ML. Paracetamol overdose in Hong Kong: is the 150-treatment line good enough to cover patients with paracetamol-induced liver injury? Hong Kong Med J 2015;21:389-93. Crossref

5. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 2002;40:3-20. Crossref

6. Chung AH, Tsui SH, Tong HK. The impact of an emergency department toxicology team in the management of acute intoxication. Hong Kong J Emerg Med 2007;14:134-43.

7. Ko S, Chan HY, Ng F. The impact of Emergency Medicine Ward in acute intoxication management. Hong Kong J Emerg Med 2010;17:323-31.

Is the Hong Kong Medical Journal having an impact? Impact factor and beyond

Hong Kong Med J 2015 Aug;21(4):298

DOI: 10.12809/hkmj154655

EDITORIAL

Is the Hong Kong Medical Journal having an impact? Impact factor and beyond

Ignatius TS Yu, FHKAM (Community Medicine)

Editor-in-Chief, Hong Kong Medical Journal

Full paper in PDF

The Hong Kong Medical Journal (HKMJ) has recently received the first official impact factor in the 2014 edition of the Journal Citation Reports in the ISI Web of Knowledge published by Thomson Reuters. We acquired a very modest impact factor of 0.872, placing us 104 out of 153 journals in the category of ‘Medicine, General and Internal’. Cites in 2014 of items published in 2012 and 2013 were 88 and 55 respectively.

The HKMJ was first indexed on MEDLINE in 2000, making articles published known and more accessible to the international medical community. After several years of deliberations by the Editorial Board, the decision was taken to join the Science Citation Index (SCI) and HKMJ was listed in the Science Citation Index Expanded (SCIE) in 2012. Citations of articles published in HKMJ were then systematically tracked. This helps inform us of the frequency with which our papers are cited in the international medical literature, and is considered to reflect the importance and quality of the research work reported in our journal.

Citations are a measurement of the impact of published articles, but they are not the only one. We do not publish for the sake of publication per se, but to have an impact on medical practice.1 We also strive to ensure the validity of research results published in HKMJ to attract more citations of our published work. The Editorial Board agreed on a new requirement for original articles submitted after August 2011, in that there should be two highlighted boxed texts: ‘New Knowledge Added by This Study’ and ‘Implications for Clinical Practice or Policy’.2 Prior to submission of papers, authors were particularly asked to consider the implications (applications) of their research work on clinical practice or policy, as these would reflect the potential impacts of published research work in the HKMJ on medical practice.

To further enhance the impact of the journal on medical practice, two senior editors, Prof Michael Irwin and Dr TW Wong have been taking the lead in soliciting high-quality reviews and medical practice papers, respectively. We hope that readers will find such papers relevant to their daily practice. The Editorial Board meets on a regular basis to identify papers suitable for continuing medical education (CME) and the Senior Editor Prof PT Cheung is leading efforts to gain the support of authors in the provision of questions and answers for CME. Senior Editors, Dr Albert Chui and Prof Martin Wong, and all members of the Editorial Board have also contributed substantially to improving the quality of papers published in HKMJ. They have invited appropriate reviewers for manuscripts as well as carried out critical reviews. In 2013, we introduced online-first publication of original articles and review papers following satisfactory completion of the review and editing process.3 This enables the potential impact of papers to be realised in a timely manner.

Is the HKMJ having an impact? We believe the answer is yes. To further enhance the impact of HKMJ, we would like to call upon the continued support from readers, authors, reviewers, international advisors, and colleagues on the editorial board and in the editorial office to take HKMJ to the next stage.

References

1. Yu IT. Calling on your continued love and support [editorial]. Hong Kong Med J 2011;17:4.

2. Yu IT. New blood, new initiatives [editorial]. Hong Kong Med J 2011;17:88.

3. Yu IT. From strength to strength [editorial]. Hong Kong Med J 2013;19:100.

Recent advances in preimplantation genetic diagnosis

Hong Kong Med J 2015 Aug;21(4):296–7

DOI: 10.12809/hkmj154638

EDITORIAL

Recent advances in preimplantation genetic diagnosis

KY Leung, MD, FHKAM (Obstetrics and Gynaecology)

Department of Obstetrics and Gynaecology, Queen Elizabeth Hospital, Jordan, Hong Kong

Corresponding author: Dr KY Leung (leungky1@ha.org.hk)

Full paper in PDF

Preimplantation genetic diagnosis (PGD) gives couples who are at risk of having a child with an inherited genetic disorder or chromosome abnormality, a chance to have an unaffected child without undergoing termination or miscarriage of an affected pregnancy. Embryos obtained from in-vitro fertilisation (IVF) with or without intracytoplasmic sperm injection are tested genetically prior to selective transfer of unaffected ones into the uterus. The physical and psychological complications of a termination or miscarriage, especially in repeated situations, should not be underestimated.

In PGD, DNA can be obtained by blastomere biopsy at the cleavage stage, trophectoderm cell biopsy when an embryo has developed to the blastocyst stage or biopsy of one or both polar bodies. Compared with cleavage stage biopsy, trophectoderm biopsy does not adversely impact the embryo, although vitrification and cryopreservation of the embryo may be required to allow time for genetic analysis.1 Although polar body biopsy is less invasive, it is less predictive of actual clinical outcome than direct embryo assessment.2

Genetic laboratories have developed their own protocols to perform different molecular tests on the limited amount of DNA obtained from biopsy. Traditionally, fluorescent in-situ hybridisation is used for cytogenetic diagnosis, and polymerase chain reaction for molecular diagnosis. New technologies, including array comparative genomic hybridisation (CGH) and single nucleotide polymorphism (SNP) microarrays, can improve diagnostic accuracy.3 4 The single-cell whole genome amplification (WGA) method allows subsequent mutation study, directly by minisequencing and/or indirectly by linkage analysis alongside the mutation test. It also allows simultaneous PGD for more than one indication.5

The indications for PGD are increasing. Common ones include single-gene disorders, X-linked diseases, and inherited chromosome abnormalities. Preimplantation genetic diagnosis of predisposition to inherited cancer such as breast cancer (BRCA mutation) is also emerging.6 Nonetheless, social sexing is prohibited in Hong Kong and Europe. Legislation and regulation of PGD also vary among different countries.

Aneuploidy is the most common cause of repeated implantation failure and recurrent miscarriage. As such, preimplantation genetic screening (PGS), using similar technology to PGD, is offered to improve delivery rates in patients of advanced maternal age, and in those with repeated implantation failure, repeated miscarriages, and severe male factor infertility. Evidence that PGS can help improve delivery rates is conflicting, however.7 Whether PGS using array CGH or SNP microarrays can increase delivery rates requires further study.

In 2006, a tertiary centre in London reported their experience of 330 PGD cycles including 96 cycles for single-gene disorders and 62 cycles for X-linked disorders.8 In 62% of the cycles, there was at least one unaffected embryo available for transfer, resulting in 90 pregnancies, 68 clinical pregnancies, and 58 live births. The clinical pregnancy rate and live birth rate was 33% and 28% per cycle started, respectively.8 This result was similar to a clinical pregnancy rate of 30.2% per transfer reported by the European Society of Human Reproduction and Embryology PGD Consortium in 2014.9

In this issue, authors in a local tertiary centre reported their 6-year experience of 124 PGD cycles for monogenetic diseases in 76 couples using WGA and linkage analysis.10 The ongoing pregnancy rate was 28.2% per initiated cycle and 38.0% per fresh embryo transfer.10 These pregnancy rates were similar to those of PGD using frozen-thawed embryo transfer cycles and for IVF for routine infertility treatment. Approximately 19% of the cycles for PGD were cancelled after initiation of stimulation. Approximately 70% of PGD was performed for thalassaemia (α or β), and the remaining 30% for 19 other monogenetic diseases that included spinocerebellar ataxia type 3 and Huntington’s disease. No misdiagnosis was found in this small series according to the available data.10

In clinical practice, thalassaemia is the most common single-gene disorder in Hong Kong. When both parents are a β-thalassaemia carrier, there is a 25% risk of having a fetus affected by homozygous β-thalassaemia. Conventional prenatal diagnosis is an option but couples will face termination of pregnancy if an affected pregnancy is detected. For an unaffected pregnancy, human leukocyte antigen (HLA) typing can subsequently be performed but may not be compatible with a previously affected child. On the other hand, PGD allows at-risk couples the chance to have an unaffected child without undergoing termination or miscarriage of an affected pregnancy. In addition, PGD can be offered to at-risk couples even in the absence of a previously affected pregnancy. It can also allow selection of an unaffected and HLA-compatible embryo simultaneously before transfer into the uterus. This results in subsequent availability of HLA-matched cord blood at birth for transplant to an affected elder sibling.

In a local study of women at risk,11 in particular those with subfertility problems or with a child affected by major thalassaemia, PGD provided an acceptable alternative to conventional prenatal diagnosis. Couples also had a positive attitude to the use of PGD/HLA typing to reproduce a ‘saviour child’ to save an affected sibling.12 It is unknown, however, whether Hong Kong women at risk of other genetic disorders share this view.

Preimplantation genetic diagnosis requires close collaboration between different specialists including obstetricians, fertility specialists, IVF laboratory, and human geneticists. It needs intensive effort and expensive techniques, and is demanding for the patients. In Hong Kong, the high costs of PGD and IVF must be borne by the patient. It is important to inform patients about the success rate and potential risks of IVF and PGD, possible complications of ovarian hyperstimulation, and the risk of multiple pregnancy.

Because of the possibility of mosaicism related to blastomere or trophectoderm cell biopsy and the false-negative rate due to allelic dropout or contamination related to the limited amount of DNA obtained from PGD, prenatal diagnosis is still recommended after PGD. Prenatal diagnosis is made following an invasive test such as chorionic villus sampling or amniocentesis or, in suitable situations, by a non-invasive approach such as testing of cell-free fetal DNA in maternal plasma for chromosomal abnormalities or by serial ultrasound examinations to exclude haemoglobin Bart’s disease.

There are ethical concerns that arise with new technologies such as microarrays and WGA that generate more detailed and complex genetic information than previous conventional approaches, and make preconception carrier testing feasible.13 Genetic laboratories should report their results according to internationally accepted accreditation standards.14 Adequate pre-testing counselling is important.

With a multidisciplinary approach and advances in technology, PGD is a great opportunity for couples at risk. It allows them to have an unaffected child while avoiding the need to terminate an affected pregnancy, and makes HLA-matched cord blood available at birth for transplantation to a previously affected child. Nonetheless, the process is expensive, demanding for couples, not always successful, and not without risks. Couples at risk should be well informed about the two reproductive options, namely PGD and prenatal diagnosis, in pre-pregnancy counselling.

References

1. Zhang S, Tan K, Gong F, et al. Blastocysts can be rebiopsied for preimplantation genetic diagnosis and screening. Fertil Steril 2014;102:1641-5. Crossref

2. Salvaggio CN, Forman EJ, Garnsey HM, Treff NR, Scott RT Jr. Polar body based aneuploidy screening is poorly predictive of embryo ploidy and reproductive potential. J Assist Reprod Genet 2014;31:1221-6. Crossref

3. Rubio C, Rodrigo L, Mir P, et al. Use of array comparative genomic hybridization (array-CGH) for embryo assessment: clinical results. Fertil Steril 2013;99:1044-8. Crossref

4. Tobler KJ, Brezina PR, Benner AT, Du L, Xu X, Kearns WG. Two different microarray technologies for preimplantation genetic diagnosis and screening, due to reciprocal translocation imbalances, demonstrate equivalent euploidy and clinical pregnancy rates. J Assist Reprod Genet 2014;31:843-50. Crossref

5. Vendrell X, Bautista-Llácer R. A methodological overview on molecular preimplantation genetic diagnosis and screening: a genomic future? Syst Biol Reprod Med 2012;58:289-300. Crossref

6. Derks-Smeets IA, Gietel-Habets JJ, Tibben A, et al. Decision-making on preimplantation genetic diagnosis and prenatal diagnosis: a challenge for couples with hereditary breast and ovarian cancer. Hum Reprod 2014;29:1103-12. Crossref

7. Mastenbroek S, Twisk M, van der Veen F, Repping S. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Hum Reprod Update 2011;17:454-66. Crossref

8. Grace J, El-Toukhy T, Scriven P, et al. Three hundred and thirty cycles of preimplantation genetic diagnosis for serious genetic disease: clinical considerations affecting outcome. BJOG 2006;113:1393-401. Crossref

9. Moutou C, Goossens V, Coonen E, et al. ESHRE PGD Consortium data collection XII: cycles from January to December 2009 with pregnancy follow-up to October 2010. Hum Reprod 2014;29:880-903. Crossref

10. Chow JF, Yeung WS, Lee VC, Lau EY, Ho PC, Ng EH. Experience of more than 100 preimplantation genetic diagnosis cycles for monogenetic diseases using whole-genome amplification and linkage analysis in a single centre. Hong Kong Med J 2015;21:299-303. Crossref

11. Hui PW, Lam YH, Chen M, et al. Attitude of at-risk subjects towards preimplantation genetic diagnosis of alpha- and beta-thalassaemias in Hong Kong. Prenat Diagn 2002;22:508-11. Crossref

12. Hui EC, Chan C, Liu A, Chow K. Attitudes of Chinese couples in Hong Kong regarding using preimplantation genetic diagnosis (PGD) and human leukocyte antigens (HLA) typing to conceive a ‘Saviour Child’. Prenat Diagn 2009;29:593-605. Crossref

13. Hens K, Dondorp W, Handyside AH, et al. Dynamics and ethics of comprehensive preimplantation genetic testing: a review of the challenges. Hum Reprod Update 2013;19:366-75. Crossref

14. Harper J, Geraedts J, Borry P, et al. Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. Hum Reprod 2014;29:1603-9. Crossref

Biological safety in the medical laboratory

Hong Kong Med J 2015 Jun;21(3):200

DOI: 10.12809/hkmj154581

EDITORIAL

Biological safety in the medical laboratory

Janice Lo, FRCPA, FHKCPath

Public Health Laboratory Centre, Department of Health, 382 Nam Cheong Street, Shek Kip Mei, Kowloon, Hong Kong

Corresponding author: Dr Janice Lo (janicelo@dh.gov.hk)

Full paper in PDF

Medical laboratories primarily process and perform testing on human specimens to provide results and interpretation for individual patient management, infection control, and public health purposes. Any clinical specimen potentially contains biological agents, such as viruses, bacteria, fungi, or parasites. It is therefore essential to ensure biological safety in the medical laboratory to prevent laboratory-acquired infections by laboratory staff and dissemination of any infectious agent from the laboratory.

Micro-organisms have generally been categorised into four Risk Groups, and medical laboratories are classified into four Biosafety Levels (BSLs).1 Each BSL has designated requirements in terms of architectural features and ventilation, safety equipment such as biological safety cabinets, use of personal protective equipment, and adoption of safe microbiological practices by qualified and trained personnel. Human specimens, which potentially contain human pathogens, are required to be handled at least at BSL-2. Pathogens that pose a high individual and community risk, with the potential to cause serious disease and that can be readily transmitted, with no effective treatment or preventive measures, are generally recommended to be handled with BSL-4 precautions. Nevertheless, such classifications, with only four levels, cannot be implemented mechanically. Risk assessment must incorporate various factors, such as the specific laboratory procedures and route of transmission of the pathogen.

In March 2014, the world was first alerted to the ongoing outbreak of Ebola virus disease (EVD) in West Africa.2 As of 19 April 2015, 26 044 confirmed, probable, and suspected cases of EVD had been reported in the countries with widespread and intense transmission (namely in Guinea, Liberia, and Sierra Leone), with 10 808 reported deaths.3 The Ebola virus, first described in 1976, has been generally regarded as a Risk Group 4 agent, and handling of live cultures needs to be undertaken at BSL-4. Globally, there are few BSL-4–certified laboratories, and such facilities require significant financial and human resources in order to operate effectively. Hong Kong does not have BSL-4 facilities. With the efficiency of modern travel, there is a possibility that a patient at the incubation stage of EVD (incubation period 2 to 21 days) could arrive in Hong Kong and develop the disease. Medical laboratories in Hong Kong thus need to be prepared for supporting the diagnosis and management of EVD patients while ensuring laboratory safety. An article in this issue of the Hong Kong Medical Journal describes the effect of heating plasma specimens at 60°C for 60 minutes on the results of chemical pathology tests.4 The authors concluded that heat inactivation did not significantly affect electrolytes, glucose or renal function test results, but caused a significant bias for many analytes, especially enzymes. Thus for safety and diagnostic accuracy in suspected or confirmed cases of EVD, it was proposed to use point-of-care devices for blood gases, electrolytes, troponin, liver and renal function tests within a biosafety cabinet with BSL-3 practices.

Ebola virus can infect normal healthy persons, with a high fatality rate. There is no effective treatment or vaccine. Nevertheless it is not transmitted via inhalation but by direct contact of non-intact skin or mucous membranes with infected bodily fluids. As such, precautions against infection are targeted at prevention of exposure of non-intact skin or mucous membranes to the virus. In a diagnostic medical laboratory, nucleic acid testing is the investigation of choice to detect Ebola virus in clinical specimens, preferably blood, that are inactivated by extraction of nucleic acids prior to the test proper. Without the need for performing virus isolation, which yields high concentrations of the live virus, and based on the above principles and practical considerations, BSL-4 containment facilities should not be mandatory to undertake testing of specimens from EVD cases.

As elaborated above, while the medical laboratory must support patient diagnosis and management, as well as public health measures, it is essential to maintain biological safety in the laboratory to protect both the laboratory worker and the environment. This can only be achieved when quality standards in medical laboratories, in terms of facilities, equipment and specialist supervision, are duly enforced and continually maintained.

References

1. Laboratory biosafety manual. 3rd ed. Geneva: World Health Organization; 2004.

2. Ebola virus disease. April 2015. Available from: http://www.who.int/mediacentre/factsheets/fs103/en/. Accessed 25 Apr 2015.

3. Ebola situation report. 22 April 2015. Available from: http://apps.who.int/iris/bitstream/10665/162795/1/roadmapsitrep_22Apr2015_eng.pdf. Accessed 25 Apr 2015.

4. Chong YK, Ng WY, Chen SP, Mak CM. Effects of a plasma heating procedure for inactivating Ebola virus on common chemical pathology tests. Hong Kong Med J 2015;21:201-7. Crossref

Current developments in imaging for deep vein thrombosis

Hong Kong Med J 2015 Apr;21(2):96–7

DOI: 10.12809/hkmj154545

EDITORIAL

Current developments in imaging for deep vein thrombosis

Yolanda Lee, FHKCR, FHKAM (Radiology)

Department of Imaging and Interventional Radiology, Prince of Wales Hospital, Shatin, Hong Kong

Corresponding author: Dr Yolanda Lee (yolandalyp@hotmail.com)

Full paper in PDF

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is believed to be less common in Asian countries than in the West. However, recent studies on the incidence of VTE in Asian population have shown that the frequency is comparable to that of the West. Historically, conventional diagnostic catheter venography was the imaging modality of choice for diagnosis of DVT. With the introduction of ultrasound (US) in the 1980s, it has been widely adopted as the preferred imaging investigation for its non-invasive nature and accuracy.

Most cases of DVT are believed to begin around the leaflets of venous valves in the calves and propagate cranially. A smaller portion begins in the upper thigh, pelvis, or lower abdomen due to obstruction and can propagate caudally. The incidence of DVT in the upper limbs has been on the rise with increasing use of central venous catheters, pacemakers, and automated implanted defibrillators, but the overall incidence remains low. Moreover, the prevalence of PE in patients with upper extremity (UE) DVT (2%) is much lower than that of lower extremity (LE) DVT (14.5%).1 A multicentre report of 5451 patients revealed an incidence of unilateral LEDVT in 77%, bilateral LEDVT in 12%, and UEDVT in 11%.2 In a local regional hospital in Hong Kong, US diagnosis of DVT (UEDVT and LEDVT) was seen in 822 (7.6%) patients, of which UEDVT was seen in 4.1% and LEDVT in 95.9%.3

Ultrasound is widely recognised as the preferred imaging of choice for suspected proximal LEDVT and UEDVT.4 5 It is cost-effective, non-invasive, readily available, portable for critically ill patients, and devoid of ionising radiation. In a recent meta-analysis, US was shown to have a high sensitivity (range, 93.2-95.0%) and specificity (range, 93.1-94.4%) for diagnosis of proximal DVT.6 On the other hand, US is much less accurate for the diagnosis of calf DVT but the significance of and therapy for isolated calf vein DVT remain controversial. The major sonographic criterion for DVT is failure of complete luminal collapse on probe pressure. Therefore, grey-scale US is routinely supplemented by colour flow and spectral Doppler to avoid false-positive results in areas where probe pressure is ineffective. Colour Doppler US is also useful in showing the degree of venous occlusion (ie partial vs complete occlusion). Spectral Doppler US could serve as an indicator of proximal venous obstruction when monophasic waveform is detected in the common femoral vein. The augmentation method, previously believed to increase sensitivity of diagnosing proximal DVT, has recently been shown to be of limited value in the diagnosis of proximal DVT in a series of almost 2000 examinations.7

Potential pitfalls of US include false-positive findings in the adductor canal, in portions of the subclavian vein deep to the clavicle, in severely oedematous limbs, and in patients with large body habitus when probe pressure is ineffective. Colour and spectral Doppler US could help in establishing patency of the vein in these conditions. Other potential pitfalls of US include false-negative results in cases of duplicated femoral vein (when only the patent limb is identified), obscured inferior vena cava and iliac veins (which is always a challenge on routine US), and failure to differentiate between acute-on-chronic DVT and chronic DVT (up to 50% of patients with DVT have residual abnormality on follow-up US).

Magnetic resonance venography (MRV) is recommended in the American College of Radiology Appropriateness Criteria4 to be the imaging investigation of choice for evaluation of pelvic or thigh DVT if US is non-diagnostic and as an initial imaging investigation of choice for suspected central vein thrombosis in the thorax. Magnetic resonance has the advantage of not exposing patients to ionising radiation or iodinated contrast compared with computed tomography (CT). Magnetic resonance venography is also superior to US in evaluating veins above the inguinal ligament and is able to show potential sources of extrinsic venous compression in the pelvis. The main limitation to the use of MRV is its lower cost-effectiveness and limited availability, especially in acute clinical settings. In general, contrast media–enhanced MRV is preferred because of higher reproducibility and lower possibility of image artefacts. When gadolinium is contra-indicated, non-contrast MRV remains a useful tool for diagnosing DVT by the use of a variety of pulse sequences and techniques such as spin echo, fast-spin echo, time-of-flight, phase contrast, and steady-state free precession, when the limitations of reproducibility and artefacts being understood.

Computed tomography venography (CTV) has been shown to be comparable to US in diagnosing proximal DVT. A recent meta-analysis showed CTV has sensitivity and specificity ranging from 71% to 100% and from 93% to 100%, respectively, for the diagnosis of proximal DVT.8 For diagnosis of DVT in the calf veins, CTV may be superior to US. Due to significantly higher radiation dose and the risk of iodinated contrast media, CTV should be reserved for when MRV is not available or is contra-indicated. In selected patients, CTV could be incorporated into CT pulmonary angiography (CTPA) for evaluation of both PE and proximal DVT, but it should not be routinely performed for all patients undergoing CTPA.

Given the invasive nature and risks similar to CT (exposure to ionising radiation and iodinated contrast medium), the use of conventional venography in the diagnosis of DVT is limited to a few specific scenarios: inconclusive non-invasive imaging result, when thrombolysis is planned, prior to placement of inferior vena cava filters, and evaluation of central DVT in the proximal arms and thorax.

In summary, US is the most cost-effective non-invasive imaging method for suspected DVT in proximal LEs and in UEs. In cases of a negative initial US result but with persistent symptoms, follow-up US would be helpful to exclude proximal extension of DVT, if any. In addition, MRV and CTV can be used as alternative imaging methods for patients with a non-diagnostic US, who are unable to undergo US, or who are highly suspected to have pelvic DVT. Conventional venography is reserved for a few specific scenarios in modern day practice, usually as a prelude to thrombolysis.

References

1. Levy MM, Albuquerque F, Pfeifer JD. Low incidence of pulmonary embolism associated with upper-extremity deep venous thrombosis. Ann Vas Surg 2012;26:964-72. Crossref

2. Goldhaber SZ, Tapson VF; DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol 2004;93:259-62. Crossref

3. Chung AS, Luk WH, Lo AX, Lo CF. Duplex sonography for detection of deep vein thrombosis of upper extremities: a 13-year experience. Hong Kong Med J 2015;21:107-13.

4. Hanley M, Donahue J, Rybicki FJ, et al. American College of Radiology: ACR Appropriateness Criteria®. Clinical condition: suspected lower-extremity deep vein thrombosis. Available at: https://acsearch.acr.org/docs/69416/Narrative. Accessed 28 Feb 2015.

5. Dill KE, Bennett SJ, Hanley M, et al. American College of Radiology: ACR Appropriateness Criteria®. Clinical condition: upper extremity swelling. Available at https://acsearch.acr.org/docs/69417/Narrative. Accessed 28 Feb 2015.

6. Lewis BD, James EM, Welch TJ, Joyce JW, Hallett JW, Weaver AL. Diagnosis of acute deep venous thrombosis of the lower extremities: prospective evaluation of color Doppler flow imaging versus venography. Radiology 1994;192:651-5. Crossref

7. Lockhart ME, Sheldon HI, Robbin ML. Augmentation in lower extremity sonography for the detection of deep venous thrombosis. AJR Am J Roentgenol 2005;184:419-22. Crossref

8. Thomas SM, Goodacre SW, Sampson FC, van Beek EJ. Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis. Clin Radiol 2008;63:299-304. Crossref

The Third Term

Hong Kong Med J 2015 Feb;21(1):4

DOI: 10.12809/hkmj144506

EDITORIAL

The Third Term

Ignatius TS Yu, FHKAM (Community Medicine)

Editor-in-Chief, Hong Kong Medical Journal

Full paper in PDF

Thanks to the support of Fellows of the Hong Kong Academy of Medicine (HKAM), the current Editorial Board is entering its third term of office.

We recently reviewed the mix of specialty backgrounds of Editorial Board members with reference to those of the manuscripts submitted to HKMJ. We then invited new blood among the fellowship of the Academy to serve on the Editorial Board. We are delighted to welcome the following new members: (in alphabetical order) Dr Gavin Jehim CHAN (Dermatology), Dr Wah CHEUK (Pathology), Dr Paul Cheung-lung CHOI (Pathology), Prof Ellis Kam-lun HON (Paediatrics), Dr Chor-yin LAM (Orthopaedics), Prof Keith Kwong-hung LAU (Paediatrics), Dr Pui-yau LAU (Orthopaedics), Dr Andrea On-yan LUK (Endocrinology), and Dr Arthur Dun-ping Mak (Psychiatry). Welcome on board!

Doctors Chun-bong Chow and Po-chor Tam left us after serving 10 years on the Board and Dr Ronald Ma left after 4 years of active contributions. Please join me in giving them a big THANK YOU for their dedication and past contributions!

Prof Martin Wong, who has been coordinating the Doctor for Society section since its inception, is now senior editor looking after that section as well as supporting Dr Albert Chui in managing the Case Reports. Responsibilities of other senior editors continue as before, with Dr TW Wong handling submissions to Medical Practice, Commentaries and Pictorial Medicine, Prof Michael Irwin focusing on Review Articles, and Prof PT Cheung managing the CME papers.

Two ‘soft’ sections have been introduced over the past two and a half years—Doctor for Society, and Reminiscence: Artefacts from The Hong Kong Museum of Medical Sciences. Both have been well received by readers and thanks are due to the medical students who helped with interviewing the doctors and writing the manuscripts for the former, and the Education and Research Committee of Hong Kong Museum of Medical Sciences Society for the latter. The Editorial Board has decided to continue these two sections.

Our Online First papers (original articles and reviews) have attracted much attention from readers: a hit rate approaching five thousand and more than two thousand full text downloads. It is reassuring that we are moving in the right direction.

The question has periodically been asked whether HKMJ should continue with a hard copy format when all papers are freely accessible on the HKMJ website. The June/July 2013 Readers Survey revealed that 71% of respondents read the print journal, compared with 11% who read the e-version.1 There are benefits for retaining the print version and we shall continue printing and distributing the hard copy for the time being.

From the beginning of this year, HKMJ has been offering its ‘mobile website’. This re-styled website is based on the ‘responsive web’ technology that can automatically adjust according to the device that is browsing the website, thus making the content user-friendly and easily accessible. It is hoped that provision of the full text of all HKMJ papers in print format, as well as a free file format compatible with many smartphones, e-readers, and tablets will reap most benefit for the journal.

Papers published in the HKMJ are attracting a lot of media attention and some local journalists use HKMJ as their prime source to identify new developments in medical practice in Hong Kong. We hope that papers published in the HKMJ will continue to benefit the general public when highlighted by the media, and not just be read by the medical community.

A number of colleges of the Academy have set requirements for trainees to publish papers in peer-reviewed journals before sitting the exit examinations. HKMJ should serve as a suitable vehicle to achieve this.

To assist novice authors, HKMJ has prepared some simple templates for submissions of different types of manuscript. Potential authors may find the following links handy:

• Template for Original Article: HKMJ-template-OA.docx

• Template for Review Article: HKMJ-template-RA.docx

• Template for Medical Practice paper: HKMJ-template-MP.docx

• Template for Case Report: HKMJ-template-CR.docx

• Template for Pictorial Medicine paper: HKMJ-template-PM.docx

The Editorial Board will continue to work hard over the next 2 years to ensure that the quality of papers published in HKMJ meet the highest standards and that new knowledge of medical developments in Hong Kong is disseminated efficiently. This will not be possible without the unstinting support from you, manuscript reviewers and authors, as well as Fellows of the HKAM, to ensure the continued success of your journal. Let us work together to bring HKMJ to a new stage!

Reference

1. HKMJ Editorial Board. Report on the 2013 Readers Survey. Hong Kong Med J 2013;19:374-6.

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Multidisciplinary care with deep brain stimulation for Parkinson’s disease patients

Hong Kong Med J 2014 Dec;20(6):472–3

DOI: 10.12809/hkmj144426

EDITORIAL

Multidisciplinary care with deep brain stimulation for Parkinson’s disease patients

YF Cheung

Department of Medicine, Queen Elizabeth Hospital, Hong Kong; Hong Kong Movement Disorder Society

Corresponding author: Dr YF Cheung (cyfz02@ha.org.hk)

Full paper in PDF

Since Benabid et al’s introduction in 1987,1 deep brain stimulation (DBS) has emerged as a standard therapeutic option for various movement disorders when they become refractory to pharmacological treatment. The commonest clinical indications for DBS include Parkinson’s disease (PD), dystonia, and essential tremor.2 3 In Hong Kong, more than 200 patients have received DBS therapy since 1997 when the procedure was first introduced to Hong Kong. Apart from PD, which accounts for most patients,4 5 successful treatment has been reported locally in patients with dystonia6 and Tourette’s syndrome.7 Deep brain stimulation devices are expensive. In the Hospital Authority, these devices for advanced PD and severe dystonia are covered under standard services for improving the standard of care, provided that certain selection criteria have been fulfilled. This programme has facilitated provision of DBS services to those patients in need, but who cannot afford the devices themselves.

In this issue of the Hong Kong Medical Journal, the Prince of Wales Hospital/Chinese University of Hong Kong Movement Disorder Group5 report their experience of 41 PD patients who received bilateral subthalamic nucleus DBS over 12 years. The group has demonstrated both efficacy and safety of the procedure by improvement of Unified Parkinson’s Disease Rating Scale part II and III scores of 32.5% and 31.5%, respectively and improvement in PD diary parameters, as well as its low surgical complication rate and zero perioperative mortality.

The authors5 also compared the outcomes of patients operated on before mid-2005 with those operated on after that date, and showed significant improvement in the latter group. They attributed the difference to multiple factors, one of which is the dedicated, multidisciplinary approach that they adopted. Deep brain stimulation is a procedure that emphasises multidisciplinary teamwork. Expertise from various disciplines contributes to patient management, including neurologists, neurosurgeons, nurse specialists, clinical psychologists, radiologists, physiotherapists, occupational therapists, and speech therapists. Each team member has a specific role to play, yet coordination and communication between disciplines is key to the best outcome.

From a patient journey perspective, PD patients are first assessed by neurologists who check for the indications and contra-indications for DBS (eg does the patient really have advanced PD? Are there any physical or psychiatric illnesses that might increase the risks and adversely affect the outcomes?). Neurosurgeons determine whether a patient is a suitable surgical candidate and evaluate the surgical risks. Nurse specialists act as case managers to liaise with different parties and offer education and counselling to patients and their caregivers. Meticulous preoperative assessment is then performed, which is protocol-driven and includes detailed neuropsychological tests by clinical psychologists, magnetic resonance imaging of the brain by radiologists, and levodopa challenge test and video recording by neurologists and nurse specialists.

On the day of DBS, both the neurosurgeons and the radiologists are responsible for precise target localisation and trajectory planning. After the burr hole is created under local anaesthesia, microelectrode recording is performed by neurologists, who verify characteristic neuronal signals from the brain target. Once the quadripolar DBS electrode has been implanted, macrostimulation can be delivered and neurologists can assess the therapeutic responses and the thresholds for inducing side-effects. When the electrodes are optimally placed, an impulse generator is inserted under general anaesthesia by neurosurgeons. During the operation, nurse specialists play an important role in patient reassurance and alleviation of their anxiety.

Postoperative stimulation and DBS programming is usually delayed for a few weeks to allow for the microlesioning effects to resolve. Regular adjustment of pulse generator settings is performed by neurologists and nurse specialists to sustain clinical improvement, which can last for years. Rehabilitation is contributed to by physiotherapists, occupational therapists, and speech therapists. Ad-hoc troubleshooting is provided by nurse specialists. Finally, multidisciplinary clinics co-attended by clinicians, nurses, and allied health care professionals can enhance communication, care coordination, and patient accessibility.

The concept of multidisciplinary care in PD has evolved over many years. Parkinson’s disease is a heterogeneous condition, with both motor and non-motor manifestations, which vary considerably from one individual to another. As the disease progresses, new symptoms emerge that are levodopa-resistant and become the dominant causes of death and disability.8 9 Modern health care also underscores patient-centred care and patient empowerment, which highlights patient preferences and their own decision-making. Hence, it is generally accepted that a multidisciplinary health care model is preferable to a monodisciplinary model. In a recent review, van der Marck and Bloem10 have pointed out the challenges associated with the implementation of multidisciplinary care in PD. Due to the lack of high-quality conclusive evidence, the optimal composition of the team and the relative contribution of specialists remain unknown. The degree of collaboration between team members (ie multidisciplinary care, interdisciplinary care, or integrative care) that can translate into the most robust benefits is still unclear. It is also uncertain at what stage of the disease the application of an organised team approach can yield the best results. Finally, the setting of service delivery varies from centre to centre (ie in-patient, specialised out-patient centre, or regional community-based network).

Despite the challenges and the uncertainties mentioned above, multidisciplinary care will continue to be one of the pillars in the management of DBS patients. According to a survey in The Netherlands, barriers that impede the implementation of multidisciplinary care for PD include insufficient expertise, poor interdisciplinary collaboration, inadequate communication, and lack of financial support.11 We are probably facing similar problems in Hong Kong. While we wait for more evidence, efforts should be made in our local centres to develop rehabilitation protocols, provide training for movement disorder specialists, functional neurosurgeons, nurse specialists and allied health care professionals, and optimise delivery of DBS service in a streamlined and well-coordinated fashion.

References

1. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery for the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 1987;50:344-6.

2. Okun MS. Deep-brain stimulation for Parkinson’s disease. N Engl J Med 2012;367:1529-38. CrossRef

3. Machado AG, Deogaonkar M, Cooper S. Deep brain stimulation for movement disorders: patient selection and technical options. Cleve Clin J Med 2012;79 Suppl 2:S19-24. CrossRef

4. Cheung YF, Chan HF, Poon TL, et al. The efficacy of deep brain stimulation for advanced Parkinson’s disease. Hong Kong Med J 2011;17 Suppl 5:S5.

5. Movement Disorder Group; Chan AY, Yeung JH, Mok VC, et al. Subthalamic nucleus deep brain stimulation for Parkinson’s disease: evidence for effectiveness and limitations from 12 years’ experience. Hong Kong Med J 2014;20:474-80.

6. Woo PY, Chan D, Zhu XL, et al. Pallidal deep brain stimulation: an effective treatment in Chinese patients with tardive dystonia. Hong Kong Med J 2014;20:455-9. CrossRef

7. Lee MW, Au-Yeung MM, Hung KN, Wong CK. Deep brain stimulation in a Chinese Tourette’s syndrome patient. Hong Kong Med J 2011;17:147-50.

8. Auyeung M, Tsoi TH, Mok V, et al. Ten year survival and outcomes in a prospective cohort of new onset Chinese Parkinson’s disease patients. J Neurol Neurosurg Psychiatry 2012;83:607-11. CrossRef

9. Hely MA, Morris JG, Reid WG, Trafficante R. Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 2005;20:190-9. CrossRef

10. van der Marck MA, Bloem BR. How to organize multispecialty care for patients with Parkinson’s disease. Parkinsonism Relat Disord 2014;20 Suppl 1:S167-73. CrossRef

11. Post B, van der Eijk M, Munneke M, Bloem BR. Multidisciplinary care for Parkinson’s disease: not if, but how! Postgrad Med J 2011;87:575-8. CrossRef

Evolving standards in preoperative staging and treatment of rectal cancer

Hong Kong Med J 2014 Oct;20(5):364–5

DOI: 10.12809/hkmj144370

EDITORIAL

Evolving standards in preoperative staging and treatment of rectal cancer

Jensen TC Poon, FCSHK, FHKAM (Surgery)

Division of Colorectal Surgery, Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong

Corresponding author: Dr Jensen TC Poon (jp@hkma.org)

Full paper in PDF

Colorectal cancer has become the commonest cancer in Hong Kong since 2011 and rectal cancer constitutes about one third of all colorectal cancers.1 Rectal cancer has a much higher local recurrence rate of about 10% than colon cancer.2 Hence, stern efforts must be made to safeguard patients from recurrence during the management of rectal cancer. In current practice, good oncological outcome with low local recurrence rate for rectal cancer treatment relies on careful exercise of total mesorectal excision (TME) technique which is the standard for mid- and low-rectal cancer resection3 and perioperative radiotherapy with/without chemotherapy.

In the Dutch rectal cancer trial, combination of TME and preoperative short-course radiotherapy (5 Gy for 5 days) was associated with a significantly lower recurrence rate of 2.4% at 2 years versus 8.2% with TME only (P<0.001).4 A combination of long-course radiotherapy (usually 50.4 Gy over 6 weeks) and fluorouracil offers additional benefit of tumour downstaging to improve sphincter preservation rate or even complete tumour remission in about 15% to 20% of patients.5 Radiotherapy, given after operation, can also reduce local recurrence rate. However, a randomised trial showed that, compared with postoperative chemoradiation, preoperative chemoradiation was associated with significantly better local control and less toxicity for locally advanced rectal cancer, which is defined as T3 or T4 or lymph node–positive rectal cancer.6 Hence, most colorectal centres adopt the policy of offering neoadjuvant (preoperative) chemoradiation to locally advanced rectal cancer.

As the preoperative local staging of rectal cancer affects the management plan, the accuracy of staging is very important. Preoperative local staging usually relies on endorectal ultrasound or magnetic resonance imaging (MRI). Recently, MRI has emerged as the preferred modality for local staging of rectal cancer by colorectal surgeons. Apart from having high reproducibility and accuracy in assessing T stage and regional lymph node status, high-resolution MRI can predict circumferential resection margin (CRM) of the rectal tumour. In pathology terms, a positive CRM is defined as presence of tumour within 1 mm of radial surgical margin and it is associated with high chance of local recurrence. High-resolution MRI can accurately measure the closest distance between the tumour and mesorectal fascia and, hence, predict CRM. In a multicentre European trial (the MERCURY study), assessment of CRM by MRI was shown to be superior to TMN-based criteria in predicting local recurrence. After multivariate analysis, CRM was the only parameter that predicted local recurrence and patient survival in the preoperative stage.7 This finding suggested that MRI-predicted CRM assessment should be routinely incorporated into preoperative planning of rectal cancer treatment. The MERCURY study group proposed that the treatment plan of stage I to III rectal cancer can be guided by MRI assessment of rectal tumour.8 Good tumour prognosis by MRI is defined as predicted CRM of <1 mm, T1, T2 or T3 disease with depth of invasion of < 5 mm beyond muscularis propria (T3a/b), irrespective of regional lymph node stage. Poor tumour prognosis by MRI is defined as predicted CRM of <1 mm or T3 disease with depth of invasion of >5 mm beyond muscularis propria (T3c/d) or presence of extramural venous invasion. The centres involved in the MERCURY study had the policy of offering upfront surgery to tumours showing good prognosis by MRI and neoadjuvant chemoradiation to the tumours showing poor prognosis by MRI. The MERCURY study recorded local recurrence rate of only 3% in the tumours showing good prognosis by MRI and suggested omitting preoperative treatment in some stage III tumours. If the favourable results of the MERCURY study can be reproduced in other clinical trials, the MRI-predicted tumour prognosis system may become a new standard for deciding preoperative treatment of rectal cancer. However, the prerequisite for the success of a more selective approach in preoperative therapy is good TME technique by colorectal surgeons to avoid breaching of mesorectal fascia which may, otherwise, result in spillage of tumour cells and, subsequently, local recurrence. This is a serious concern when the tumour is covered and protected from exposure by only a few millimetres of CRM.

In the current issue of our journal, Wong et al9 report that the thickness of mesorectum in the Chinese is relatively thin and less than 15 mm in the majority of patients at most levels. As a result, the distance between the tumour and mesorectal fascia is intrinsically short. The CRM in Chinese patients with rectal cancer is reduced and, hence, more patients may have CRM which is involved or threatened by the tumour. This is a small series with only 25 patients and there is no similar report involving different ethnic groups for us to compare and ascertain if the mesorectum of the Chinese is thinner than that in patients of other ethnicities. However, we know that ultra-low rectal cancer (tumour within 5 cm from the anal verge) has a worse prognosis than higher tumour because the mesorectum tapers and thins out as it descends and approaches the pelvic floor. As a result, the chances of positive CRM and local recurrence increase.10 Neoadjuvant chemoradiation to downstage the tumour is particularly important in this group of patients with ultra-low tumours. It is also the policy of this author’s centre to routinely offer neoadjuvant chemoradiation for ultra-low rectal cancer. Therefore, the hypothesis proposed by Wong et al9 is reasonable and underscores the importance of CRM during preoperative assessment.

The modern high-resolution MRI allows assessment of several characteristics of rectal cancer including the depth of tumour invasion, CRM, regional lymph node status, and extramural vascular invasion. These are features with prognostic value and serve to guide a more selective approach in neoadjuvant therapy of rectal cancer. In parallel with advances in chemoradiation and surgery, optimal care for rectal cancer is sophisticated and involves contribution from several specialists including radiologists, oncologists, pathologists, and colorectal surgeons. It is important that we keep abreast of advances in this field and manage patients within a multidisciplinary setting.

References

1. Hong Kong Cancer Registry, Hospital Authority. Summary of cancer statistics in Hong Kong in 2011. Available from: http://www3.ha.org.hk/cancereg. Accessed Aug 2014.

2. Poon JT, Law WL. Laparoscopic resection for rectal cancer: a review. Ann Surg Oncol 2009;16:3038-47. CrossRef

3. Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 1998;133:894-9. CrossRef

4. 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

5. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol 2011;29:4633-40. CrossRef

6. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-40. CrossRef

7. Taylor FG, Quirke P, Heald RJ, et al. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol 2014;32:34-43. CrossRef

8. Taylor FG, Quirke P, Heald RJ, et al. Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study. Ann Surg 2011;253:711-9. CrossRef

9. Wong EM, Lai BM, Fung VK, et al. Limitation of radiological T3 subclassification of rectal cancer due to paucity of mesorectal fat in Chinese patients. Hong Kong Med J 2014;20:366-70.

10. West NP, Finan PJ, Anderin C, Lindholm J, Holm T, Quirke P. Evidence of the oncologic superiority of cylindrical abdominoperineal excision for low rectal cancer. J Clin Oncol 2008;26:3517-22. CrossRef

Treat the patient, not just the eye pressure

Hong Kong Med J 2014 Aug;20(4):272–3

DOI: 10.12809/hkmj144309

EDITORIAL

Treat the patient, not just the eye pressure

Dexter YL Leung, FRCS, FHKAM (Ophthalmology); Alvin KH Kwok, MD, PhD

Department of Ophthalmology, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong

Corresponding author: Dr Alvin Kwok (alvinkwok@hksh.com)

Full paper in PDF

Worldwide, glaucoma is regarded as one of the commonest causes of irreversible blindness.1 The global burden of glaucoma continues to rise: in 2010, at least 60.5 million people suffered from glaucoma, and by 2020, this is estimated to reach 79.6 million, of whom 11.2 million will be irreversibly blind in both eyes.1

Quality of life (QoL) includes dimensions such as physical health, mental health, general health perceptions, social functional status, and independence.2 It has been shown that vision is consistently regarded as one of its key determinants.3 In a chronic disease such as glaucoma, the impact on vision, and hence QoL is, naturally, a very important subject.

Traditionally, research in glaucoma focuses on outcome parameters important for the ophthalmologists such as intra-ocular pressure (IOP), vertical cup-to-disc ratio (CDR), visual field status, and optical coherence tomography parameters such as the mean retinal nerve fibre layer (RNFL) thickness. No doubt these are important to the patients, but are no more than abstract ideas to them. Patients are more likely to be interested in their QoL. Unfortunately, some of the treatment modalities in glaucoma, while successful in preserving the optic nerve function, may sometimes have side-effects, diluting the gain in QoL.4 Even more unfortunately, in the past, few major ophthalmic clinical trials included QoL as part of their study protocol. So, a new treatment modality can be hugely successful in lowering IOP, preserving CDR, visual field, mean RNFL thickness and vision, and yet result in an unacceptable drop in QoL in the long term. In the year 2010, the US Food and Drug Administration endorsed that QoL assessment be included in all glaucoma clinical trials.5

Broadly speaking, there are currently four major categories of validated QoL analysis questionnaires used for glaucoma patients: the general health-related, vision-specific, glaucoma-specific, and utility value assessments. They differ in their internal consistency (as indicated by their Cronbach’s alpha values), test-retest reliability, and correlation with severity of glaucoma. No matter what category of tools we choose, one unique challenge we face is that none of these validated QoL questionnaires is in Chinese (in fact, all are in English, thereby, creating a language barrier).

The study by Lee et al6 represents a nice attempt to address these issues. Firstly, the authors translated the Glaucoma Quality of Life–15 questionnaire (GQL-15) into traditional Chinese via a careful back-translation procedure. The questionnaire is a relatively easy-to-use, glaucoma-specific QoL tool addressing four aspects: (1) central and near vision; (2) peripheral vision; (3) dark adaptation and glare; and (4) outdoor mobility.

Secondly, they correlate this Chinese version of GQL-15 with a relatively new and important glaucoma clinical parameter, namely, the visual field index (VFI). First devised by Bengtsson and Heijl7 in 2008, VFI is automatically calculated using the newer Humphrey visual field analyser. Visual field index has been shown to reliably correlate with visual field loss from glaucoma, and be considerably less affected by visual loss as a result of concurrent cataract, which is also common in the same age-group of patients with glaucoma.7 Using VFI also allows the clinician to determine glaucoma disease progression (ie worsening) using a trend-based algorithm in addition to the traditional event-based algorithm. It has been demonstrated that trend-based determination of disease progression may be more robust than an event-based one, and incorporating both trend and event-based analyses can improve detection of glaucoma progression.8 Visual field index is increasingly being used in large clinical glaucoma trials and, clinically, is convenient to measure. The choice of studying the correlation between VFI and GQL-15 is a good way forward as currently there are few similar published data on this topic.

In this study,6 the authors found that a lower VFI correlated well with poorer GQL-15 scores and, hence, a lower QoL. The most problematic activities affecting QoL in these patients were “adjusting to bright lights”, “going from a light to a dark room or vice versa”, and “seeing at night”. While these difficulties may seem immediately obvious to the eye doctors, the findings may have greater implications to the architectural lighting design specialists. It is high time now for Hong Kong to have a more mature discussion on the design of the city’s exterior and interior lighting to facilitate the visually impaired citizens. Some of the suggested lighting engineering measures are, for example, plenty of floor lamps and table lamps in recreation and reading areas; usage of adjustable blinds, sheer curtains, or draperies for window coverings to allow adjustment of natural light; choice of brightly coloured vases and lamps near the furniture to make them easier to locate; elimination of hazards such as electrical cords in the pathway; avoiding waxing the floor; lighting the stairways clearly and uniformly; installation of grab bars; placing signs at eye level, with large lettering and braille signage according to guidelines, for example, from the Americans with Disabilities Act, etc.9 A concerted effort from all stakeholders of the society, from the Government to the architectural societies including the lighting specialists, to various blindness prevention organisations including the ophthalmologists, is needed to effect positive changes.

The ultimate goal of glaucoma treatment is to maximise QoL and patient satisfaction, not just creating a beautiful set of numerical figures in IOP/CDR/visual field/RNFL thickness. Addressing issues relating to QoL will allow both the clinicians and patients to re-orientate themselves towards a common realistic therapeutic programme, leading to a more harmonious partnership in care. So here is an old truth newly understood: we care for the patient as a human, not just for the parameters.

References

1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:262-7. CrossRef

2. Felce D, Perry J. Quality of life: its definition and measurement. Res Dev Disabil 1995;16:51-74. CrossRef

3. Spaeth G, Walt J, Keener J. Evaluation of quality of life for patients with glaucoma. Am J Ophthalmol 2006;141(1 Suppl):S3-14. CrossRef

4. Leung DY, Tham CC. Management of bleb complications after trabeculectomy. Semin Ophthalmol 2013;28:144-56. CrossRef

5. Varma R, Richman EA, Ferris FL 3rd, Bressler NM. Use of patient-reported outcomes in medical product development: a report from the 2009 NEI/FDA Clinical Trial Endpoints Symposium. Invest Ophthalmol Vis Sci 2010;51:6095-103. CrossRef

6. Lee JW, Chan CW, Chan JC, Li Q, Lai JS. The association between clinical parameters and glaucoma-specific quality of life in Chinese primary open-angle glaucoma patients. Hong Kong Med J 2014;20:274-8. CrossRef

7. Bengtsson B, Heijl A. A visual field index for calculation of glaucoma rate of progression. Am J Ophthalmol 2008;145:343-53. CrossRef

8. Medeiros FA, Weinreb RN, Moore G, Liebmann JM, Girkin CA, Zangwill LM. Integrating event- and trend-based analyses to improve detection of glaucomatous visual field progression. Ophthalmology 2012;119:458-67. CrossRef

9. Information and Technical Assistance on the Americans with Disabilities Act, Civil Rights Division, United States Department of Justice. Available from: http://www.ada.gov/2010_regs.htm. Accessed 1 Jun 2014.

Comparison is beyond IPASS and OPTIMAL

Hong Kong Med J 2014;20:176–7 | Number 3, June 2014

DOI: 10.12809/hkmj144267

EDITORIAL

Comparison is beyond IPASS and OPTIMAL

KC Lam, FHKAM (Medicine)¹; Tony SK Mok, FHKCP, FHKAM (Medicine)²

¹ Department of Clinical Oncology, Prince of Wales Hospital, Shatin, Hong Kong

² Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong

Corresponding author: Dr KC Lam (kc_lam@clo.cuhk.edu.hk)

Full paper in PDF

Now that first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is recognised as a standard therapy for non–small-cell lung cancer (NSCLC) with activating mutations,1 2 3 4 5 6 7 it is only natural for some of us to ask which TKI is the best. In the absence of a direct head-to-head randomised controlled study, Lee et al8 used an indirect comparison method to compare the efficacy and cost-effectiveness of gefitinib and erlotinib, results of which are published in this issue. The authors concluded that erlotinib has better efficacy and is more cost-effective than gefitinib.8 Is this a trustworthy conclusion?

For reason that is not entirely clear to us, authors chose to use data from only the OPTIMAL and IPASS studies. Truth is that there are four randomised studies on gefitinib (IPASS, FIRST-SIGNAL, NEJ-002, and WJTOG 345) and three randomised studies on erlotinib (OPTIMAL, EURTAC, and ENSURE) in patients with activating EGFR mutation–positive NSCLC. The authors excluded EURTAC study from the comparison because of the differences in baseline demographic data and ethnicity. Similar to IPASS, EURTAC is a registration study using stringent criteria for documentation of treatment outcomes and toxicity. The OPTIMAL study was not considered a registration study by the China Food and Drug Administration, and that was exactly the reason for the replication of OPTIMAL study (ENSURE study) in China. Grade 3 or above skin rash rate was higher in the EURTAC study (13%) as compared with IPASS study (3.1%), and this is a fact that should not be ignored. The median progression-free survival (PFS) and hazard ratio were comparable between EURTAC and IPASS and, again, this fact was ignored. Lee et al8 should incorporate data from more relevant clinical trials into the indirect comparison to provide a non-biased estimate of the true treatment effect. As erlotinib is slightly more expensive than gefitinib in the Hong Kong public health care system, it will be unrealistic to conclude a better cost-effectiveness if the two drugs were shown to have similar efficacy in an honest manner.

Kim et al9 conducted a prospective open-label randomised non-comparative parallel study in a single Korean hospital to evaluate the efficacy of erlotinib and gefitinib in those EGFR mutation–positive NSCLC patients or patients with at least two out of three clinical factors associated with higher incidence of EGFR mutations who failed platinum-based chemotherapy. In this exploratory comparison, there were no statistically significant differences in response rate and median PFS between the two drugs. More treatment-related grade-3 or -4 adverse events were observed with erlotinib versus gefitinib (12.4% vs 4.2%). Wu et al10 conducted a retrospective study to evaluate the difference in efficacy between erlotinib and gefitinib in Taiwanese patients with advanced-stage EGFR mutation–positive NSCLC. They also found no statistically significant difference in response rate and PFS between the two drugs. Lim et al11 performed a retrospective review to examine the treatment outcomes with two EGFR TKIs with a match-pair case-control study design. Again, there were no statistically significant differences in response rates, PFS, and overall survival between the two drugs. An ongoing prospective randomised trial in China compares erlotinib with gefitinib in NSCLC patients harbouring EGFR exon 21 mutation. This will be the only true head-to-head comparison between gefitinib and erlotinib in this setting.

While we argue about which is a better EGFR TKI, treatment paradigm is shifting to second and third generations of EGFR TKIs. Afatinib, an irreversible pan-HER inhibitor, has been proven to be superior to standard platinum-based chemotherapy.12 LUX–Lung 7 trial, a randomised phase IIb study comparing afatinib to gefitinib in EGFR mutation–positive NSCLC, is completed and results are pending. Furthermore, ARCHER 1050 will be the first randomised phase III study comparing dacomitinib with gefitinib in patients with either exon 19 or 21 mutations. Phase I studies on third-generation EGFR TKIs including AZ9291 and CO1686 have also reported high tumour response rate in patients with resistant T790M mutation. Its role as first-line EGFR TKI remains to be explored.

Treatment of advanced-stage lung cancer is rapidly evolving. Instead of asking the question of which is a better EGFR TKI, perhaps we should focus on how to improve outcomes for our future patients.

References

1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. CrossRef

2. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8. CrossRef

3. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG345): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8. CrossRef

4. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42. CrossRef

5. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46. CrossRef

6. Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012;30:1122-8. CrossRef

7. Wu YL, Zhou C, Wu G, et al. Quality of Life (QoL) analysis from ENSURE, a phase 3, open-label study of first-line erlotinib versus gemcitabine/cisplatin (gp) in Asian patients with EGFR mutation-positive NSCLC. J Thorac Oncol 2014;9:7S-52S.

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