HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Keyvan Moghissi Andrew Thorpe Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moghissi, K. Articles by Brown, S. Search for Related Content PubMed PubMed Citation Articles by Moghissi, K. Articles by Brown, S.

Eur J Cardiothorac Surg 1999;15:1-6
© 1999 Elsevier Science NL

The place of bronchoscopic photodynamic therapy in advanced unresectable lung cancer: experience of 100 cases¹

^a The Yorkshire Laser Centre, Goole and District Hospital, Woodland Avenue, Goole, East Yorkshire, UK
^b Department of Applied Physics, The University of Hull, Hull, UK
^c Centre for Photobiology and Photodynamic Therapy, The University of Leeds, Leeds, UK

Received 25 August 1998; received in revised form 19 October 1998; accepted 20 October 1998.

^* Corresponding author. Tel./fax: +44-1724-290-456.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion Appendix A. Conference... References

 
Objectives: The objectives of the study were: (1) to evaluate effectiveness of photodynamic therapy (PDT) for symptom palliation in patients with inoperable lung cancer; (2) to determine survival benefit in a subset of patients. Methods: One hundred patients, 68 male, 32 female, aged 44–81 years (mean 62.5) with advanced inoperable bronchogenic cancer and endobronchial luminal obstruction were prospectively studied. Eighty-two percent had previous chemo/radiotherapy. The pre-treatment protocol consisted of: clinical, radiological and bronchoscopic examination, pulmonary function testing, assessment of WHO performance status and clinical staging. Treatment protocol was: intravenous injection of 2 mg/kg body weight of photofrin/polyhaematoporphyrin and interstitial illumination using 630 nm laser light 24–72 h later. Follow-up was at 6–8 weeks for 1 year. Then every 3–6 months if applicable. Repeat PDT as necessary. Results: All patients were stage IIIa–IV. The histology of the tumour was: non small cell in 90 and small cell in 10. There was no treatment related mortality. Mean endoluminal obstruction fell from 85.8% to 17.5%, mean forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) improvement was 430 ml and 280 ml, respectively. Ninety patients died from 6 weeks to 37 months, mean and median survival: 9 months and 5 months, respectively. Ten patients are alive from 13 to 72 months, mean 36 months, median 29 months. Overall 2-year survival was 19%. Multivariant analysis indicated that age, sex, histology and stage of disease did not influence survival significantly but performance status did. Patients with WHO<2 had mean and median survival of 17.8 and 14 months versus WHO>2, 6.9 mean and 4 months median survival (log-rank P<0.0001). Conclusions: (1) PDT is effective in palliation of inoperable advanced lung cancer. (2) Subset of patients with a better performance status have added survival benefit.

Key Words: Photodynamic therapy • Lung cancer

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion Appendix A. Conference... References

 
Lung cancer is the commonest cancer affecting the male population in the Western World. In the UK alone between 30 000 and 32 000 cases are diagnosed and about the same number die from the disease annually.

Although resectional surgery is acknowledged to be the treatment of choice and the only therapy with any prospect of cure or long survival, in practice only a small number of patients are referred to the surgeon or submitted to surgical resection. In the UK the rate of resection is no more than 10–12% [1] [2] [3] and in many of the European countries this does not exceed 20% [3] [4]. It therefore follows that at least 80% of lung cancer sufferers will have to be managed by treatment other than resectional surgery principally for palliation of symptoms.

Traditionally, and for the past 40–50 years, such palliative therapy has meant differing regimens of radiotherapy, chemotherapy and/or supportive care. In recent years some of the patients with substantial endoluminal obstructive lesions, amongst this vast inoperable population, have been treated by bronchoscopic laser treatment. For this the neodymium yttrium aluminium garnet (Nd:YAG) laser has been employed extensively and its usefulness is universally accepted [5] [6]. More recently the development of photodynamic therapy (PDT) with its target orientated mode of action has encouraged its application to endobronchial cancer [7] [8] [9].

Our group has been involved in PDT for bronchial cancer since 1990 and in this paper we review our experience in the first 100 patients in a series with inoperable and advanced bronchial carcinoma. The aim is, in the first place, to evaluate the safety and efficacy of PDT with respect to symptom relief in advanced bronchial carcinoma and secondly to identify subgroups which, in addition to palliation, might gain survival benefit from this therapy.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion Appendix A. Conference... References

 
From May 1990 to May 1997, 100 patients with advanced inoperable broncho-pulmonary cancer and endoluminal malignant obstructive lesions received bronchoscopic PDT and were studied prospectively. The majority of these (92%) had been investigated, diagnosed and rejected for surgical resection prior to referral to our team. Some, in fact, had exploratory thoracotomy. The protocol of the study involved recording of: clinical history and symptoms, notably cough, dyspnoea and haemoptysis; routine clinical and laboratory examination; evaluation of performance status using WHO scale (Table 1), and measurement of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1); plain chest radiography and CT of the thorax and upper abdomen.

Treatment protocol
Informed consent was obtained from all patients prior to PDT. Treatment protocol has previously been reported in detail [11] and consisted of intravenous administration of 2 mg/kg body weight of photosensitizer, photofrin (or equivalent polyhaematoporphyrin). After an interval of 24–72 h bronchoscopic illumination of the tumour was carried out.

All bronchoscopic treatments were undertaken under general anaesthetic. A rigid, open ended, Negus type bronchoscope was first placed into the trachea to allow ventilation. The flexible fibre optic bronchoscope was next introduced through the rigid instrument to precisely locate the tumour. The laser delivery fibre with its end diffuser was then passed through the biopsy channel of the fibreoptic bronchoscope and the diffuser was placed into the mass of the tumour for interstitial laser therapy ( Fig. 1 a,b). Depending on the topography and extent of the tumour, single or multiple placements of the diffuser into the tumour (i.e. single/multiple site treatment) was undertaken.

View larger version (57K): [in this window] [in a new window]   Fig. 1. (a) The obstructing tumour in the bronchus. (b) Interstitial placement of the cylindrical diffuser into the tumour.

Assessment of results was made on the basis of symptom relief, patient satisfaction to treatment, change in performance status and pulmonary function, bronchoscopic evidence of alteration in luminal obstruction expressed as percentage of total bronchial luminal diameter and patient survival. Based on post treatment bronchoscopic findings and biopsy results, response to treatment was graded as complete (CR) when there was absence of tumour macroscopically and microscopically and partial response (PR) when the mass of the tumour was <50% of that at the pretreatment bronchoscopy.

The above parameters were recorded at each out-patient and bronchoscopy attendance. Multivariant analysis was done to evaluate the influence on survival of age, sex and performance status of the patients (WHO scale 2 vs. >2), as well as histology and stage of the tumour.

Statistics
Values are presented as mean±standard error. Statistical comparison was performed using log-rank test. A value of P<0.05 was considered as significant. The Kaplan–Meier method was employed to present survival curves.

	Results

Top Abstract Introduction Patients and Methods Results Discussion Appendix A. Conference... References

 
Prior to PDT all patients were symptomatic, predominantly with dyspnoea and haemoptysis. Eighty-two (82%) had previous EBR/chemotherapy and nine (9%) had endoscopic YAG laser. Patients' characteristics are shown in Table 2 which also indicates the histology and stage of tumours. The primary locations of the tumour within the tracheo-bronchial tree are shown in Fig. 2 . The number of treatments in all patients was 147 (mean 1.47/patient range 1–4 treatments). There was no treatment related mortality or morbidity. There were, however, five episodes of mild skin photosensitivity reaction in four patients, an incidence of 3.4% of treatments or 4% of patients. In all five, there was redness of face and hands and in one incidence there was also oedema of both hands which subsided within 72 h with application of steroid skin ointment. Patients satisfaction to treatment was 100% and symptomatic improvement was recorded in all.

View larger version (20K): [in this window] [in a new window]   Fig. 2. Site and distribution of obstructing tumours within the bronchial tree and the number of cases in a particular site. The arrow indicates extension of the tumour from the primary to other sites.

Table 4 reports the distribution of N1/N2 disease and the histology, i.e. small cell lung cancer (SCLC) versus non small cell lung cancer (NSCLC) in patients with WHO PS2 and those with WHO PS>2. This indicates, firstly, that the two groups were matched. Secondly, it suggests that survival benefit afforded to patients with better performance status in this series is independent of N factor or the histology.

View this table: [in this window] [in a new window]   Table 4. Number (%) of patients with N1 or N2 disease and histology (SCLC or NSCLC) in patients with WHO PS>2 and those with WHO PS2

View larger version (21K): [in this window] [in a new window]   Fig. 3. (a) Overall survival curve for 98 patients (two patients data not available). (b) Upper curve: survival curve for patients WHO 2 performance status (n=43). Lower curve: survival curve for patients >2 (n=54).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion Appendix A. Conference... References

Originally Dougherty et al. [12] reported the feasibility and potential benefits of endo bronchial PDT in cases of bronchogenic carcinoma. Other investigators since have shown the efficacy of PDT in palliation of symptoms in patients with advanced lung cancer [7] [8] [9] [11] [13] [14]. Hayata and Colleagues [15] in Japan have focused their attention primarily on patients with early stage lung cancer. They have shown that bronchoscopic PDT in such cases can achieve complete response and remission accompanied by long survival. Review of the literature concerned with bronchoscopic PDT in lung cancer seems to suggest that some investigators [16] [17] have continued to use endobronchial PDT in advanced and inoperable patients for palliation, many of whom had previously received other specific cancer therapy. Other workers [18] [19] uphold the view that PDTs primary indication in lung cancer is in its application to bronchial mucosal and submucosal malignant lesions. Whilst agreeing with the argument that the best results of PDT belong to early lung cancer cases, we believe that at this moment in time, the aim should be to target inoperable and advanced cases. This view is based on the fact that, with advances in anaesthetic and surgical techniques such as minimal access and bronchoplastic procedures, many early stage cancer patients, even with limited pulmonary function, can be offered surgical resection; present day mortality of pulmonary resection is around 5% and 5-year survival of early stage cancer is over 70% [4] [20] [21]. Also, as at presentation 80% or more of lung cancer patients are unresectable it is more reasonable to focus attention primarily on this unresectable cohort of population who are in need of novel therapeutic methods. Additionally, early in the course of our experience with PDT we became aware that some patients with advanced stage lung cancer had survival advantage in addition to symptom relief after bronchoscopic PDT. The present study has identified this subgroup to be those with a good performance status (WHO 2). It is interesting to refer to a recent publication of McCaughan and Williams [17] who surveyed their 14 years experience in 175 patients with bronchogenic carcinoma receiving bronchoscopic PDT. Whilst they point out that the most significant influence on long-term survival in their cases was the stage of the tumour, their data also appears to show that, in those of their patients with advanced tumour stage (Stage IIIa–IV), the performance status became an important determinant of length of survival. In our series we had only patients with Stage III and IV tumours and it would seem that in these the pretreatment performance status had a definite influence on survival. It is relevant to emphasise that in our series 23/43 (53%) patients with pretreatment performance status (2 survived 2 years or more, whereas two patients amongst 54 (3.7%) with performance status >2 survived more than 2 years. Clearly this finding suggests that PDT can have a major therapeutic role for this category of lung cancer patient. It could also be argued that those unresectable patients with good performance status should be given the chance of PDT instead of, or at the same time as, their referral to chemo/radiotherapy before further deterioration in their PS occurs. It is relevant to point out that over 80% of our patients had chemo/radiotherapy prior to referral for PDT. We have experienced no technical difficulties in these patients, particularly as all of our treatments were interstitial.

Our study suggests that neither the histology nor the stage of tumour influenced survival. Nevertheless it is worthwhile to mention that, of the two patients with recurrence of adenoid cystic tumours following External beam radiotherapy (EBR), one survived 29 months and died of bladder carcinoma of different histology whilst in complete remission for 16 months and the other patient is living 35 months after PDT. It must also be emphasised that since all our patients had stage III and IV tumours, it has not been possible to evaluate the influence on survival of less advanced tumour stages. The fact that ten patients had SCLC and appear to have benefited from PDT in the same way as patients with NSCLC tends to suggest that such patients should not be deprived of PDT for the reason of their lung cancer cell type.

Our conclusions are that PDT can play an important therapeutic role in advanced bronchogenic carcinoma. This role is confined to palliation in those with poor general condition translated, in this study, to performance status >2. In patients with good performance status (2) there is also a definite survival benefit in addition to palliation.

A large multi centre clinical trial is warranted for PDT to establish its rightful place amongst the therapeutic armamentarium for lung cancer patients.

	Acknowledgments

 
We are grateful to the Laser Trust Fund (Moghissi) Appeal and the Yorkshire Cancer Research Campaign for their support of this work.

	Footnotes

 
Presented at the 12th Annual Meeting of the European Association for Cardio-thoracic Surgery, Brussels, Belgium, September 20–23, 1998.

	Appendix A. Conference discussion

Top Abstract Introduction Patients and Methods Results Discussion Appendix A. Conference... References

 
Mr P. Goldstraw (London, UK): It is not surprising that performance status had an impact on survival. It would be more impressive if performance status after treatment was improved and if the performance status after palliative treatment was shown to correlate with survival. Did you look at that?

Mr Thorpe: Certainly, yes, there was an improvement in performance status after PDT.

Mr Goldstraw: But did that correlate with survival or was it only preoperative performance data?

Mr Thorpe: Yes. The pre- and post-performance did correlate with survival.

Mr Goldstraw: So the patients who had their performance status improved moved into a better prognostic group?

Mr Thorpe: Yes.

Mr Goldstraw: That's very impressive. The other point, for a non-laser person, could you tell me why you used photosensitization technique with all the after effects for the patient, rather than a simple laser disobliteration?

Mr Thorpe: There is a logic in trying to kill the tumor cell with PDT. With Nd:YAG laser or cryoablation you can disobliterate the lumen. Nd:YAG laser is just basically a `superdiathermy' that is actually opening up the airway. I think with PDT you have at least a chance of killing tumor cells from within.

Mr Goldstraw: But it's still a palliative technique, isn't it? And using photoporphyrins will have a cost implication, it will have an implication on quality of life. Has it ever been shown that the addition of photosensitizers is worthwhile?

Mr Thorpe: That is something we have not really looked into as yet, but I think this is obviously an important point.

Dr F. Venuta (Rome, Italy): I would like to go back to a technical point. I understood that you don't clean the airway of patients with a complete obstruction before treating them with photodynamic therapy. Do you stick the probe inside the tumor? Is there any reason why you don't clean the airway with Nd:YAG laser before using photodynamic therapy. This would give a result immediately after the procedure without waiting for the effects of photodynamic therapy.

Mr Thorpe: Yes, I think that's a very pertinent comment. In certain cases, you can debride the airway prior to applying the probe. I think you've got to select the cases carefully. If you cannot easily place the probe, you may have to debride the airway beforehand. You can do this quite easily with forceps or with the tip of the bronchoscope. Tracheobronchial toilet is essential prior to the application of PDT.

Dr. J. Kolodziej (Wroclaw, Poland): Most of your patients were IIIa. Why are you not qualifying for operation?

Mr Thorpe: Reasons for inoperability in these patients were previous chemoradiotherapy and poor performance status in terms of previous myocardial history, etc.

	References

Top Abstract Introduction Patients and Methods Results Discussion Appendix A. Conference... References

 

1. Whitehouse, J.M.A. Management of lung cancer. Report of working group. Curr Clin Pract 1994;1.
2. Joslin C, Rider L, eds. Cancer in Yorkshire, Cancer Registry. Special Report Series 1; Lung Cancer 1994;22-2.
3. Moghissi K., Connolly C.K. Resection rates in lung cancer patients. Eur Respir J 1996;9:5-6.[Medline]
4. Damhuis R.A.M., Schutte P.R. Resection rates and post-operative mortality in 7,899 patients with lung cancer. Eur Respir J 1995;9:8-11.
5. Personne C., Colchen A., Leroy M., Vourch G., Toty L. Indication and technique for YAG laser resection in bronchology, a critical analysis based on 2285 resections. J Thorac Cardiovasc Surg 1986;91:710-715.[Abstract]
6. Hetzel M.R., Smith S.G.T. Endoscopic palliation of tracheo-bronchial malignancies. Thorax 1991;46:325-333.[Abstract]
7. Vincent R., Dougherty T. Photoradiation therapy in the treatment of advanced carcinoma of the trachea and bronchus. Proc Clin Biol Res 1984;170:759-766.
8. McCaughan JS Jr, Hawley PC, Bethel BH, Walker J. Photodynamic Therapy of endobronchial malignancies. Cancer 1988;62:691–701.
9. Moghissi K., Parsons R.J., Dixon K. Photodynamic therapy (PDT) for bronchial carcinoma with use of rigid bronchoscope. Lasers Med Sci 1991;7:381-385.
10. Mountain CF. A new international staging system for lung cancer. Chest 89;(Suppl.):225–233.
11. Moghissi K., Dixon K., Parsons R.J. A controlled trial of Nd:YAG laser vs. photodynamic therapy for advanced malignant bronchial obstruction. Lasers Med Sci 1993;8:269-273.
12. Dougherty T.J., Kaufman J.E., Goldfarb A., Weishaupt K.R., Boyle D., Mittleman A. Photoradiation therapy for the treatment of malignant tumours. Cancer Res 1978;38:2628-2635.[Abstract/Free Full Text]
13. Cortese D.A., Kinsey G.H. Endoscopic management of lung cancer with haematoporphyrin phototherapy. Mayo Clin Proc 1982;57:543-547.[Medline]
14. Balchum O.J., Doiron D.R., Hutch G.C. Photoradiation therapy of endobronchial lung cancer employing the photodynamic action of haematoporphyrin derivative. Lasers Surg Med 1984;4:13-30.[Medline]
15. Hayata Y., Kato H., Konaka C., Amemiya R., Ono J., Ogawa I., Kinoshita K., Sakai H., Takahashi H. Photoradiation therapy with haematoporphyrin derivative in early and stage I lung cancer. Chest 1984;86:169-177.[Abstract/Free Full Text]
16. Moghissi K., Dixon K., Hudson E., Stringer M., Brown S. Endoscopic laser therapy in malignant tracheobronchial obstruction using sequential Nd:YAG laser and photodynamic therapy. Thorax 1997;52:281-283.[Abstract]
17. McCaugham J.S., Williams T.E. Photodynamic therapy for endobronchial malignant disease. A prospective fourteen years study. J Thorac Cardiovasc Surg 1997;114:940-947.[Abstract/Free Full Text]
18. Cortese D.A. Bronchoscopic photodynamic therapy of early lung cancer. Chest 1986;90:629-631.
19. Okunaka, T., Kato, H., Konaka, C. A clinical trial of photodynamic therapy for early stage lung cancer. Int Photodyn 1995;March 4–6.
20. Martini N, Ginsberg RJ. Surgical management (lung cancer). In: Deslaurie RS, Hiebert CA, Ginsberg RJ, McKneally MF, Urschel CH Jr, eds. Thoracic surgery. New York: Churchill Livingstone, 1995:690–705.
21. D'Amico TA, Sabiston DC Jr. Neoplasms of the lung: I. Carcinoma of the lung. In: Sabiston DC Jr, Spencer FC, eds. Surgery of the chest, 6th edn. Philadelphia: WB Saunders, 1995;634–648.

This article has been cited by other articles:

				P. A. Kvale, P. A. Selecky, and U. B. S. Prakash Palliative Care in Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition) Chest, September 1, 2007; 132(3_suppl): 368S - 403S. [Abstract] [Full Text] [PDF]

				K. Moghissi, K. Dixon, J. A. C. Thorpe, M. Stringer, and C. Oxtoby Photodynamic therapy (PDT) in early central lung cancer: a treatment option for patients ineligible for surgical resection Thorax, May 1, 2007; 62(5): 391 - 395. [Abstract] [Full Text] [PDF]

				M. M. Wahidi, F. J. F. Herth, and A. Ernst State of the Art: Interventional Pulmonology Chest, January 1, 2007; 131(1): 261 - 274. [Abstract] [Full Text] [PDF]

				M. Triesscheijn, P. Baas, J. H. M. Schellens, and F. A. Stewart Photodynamic Therapy in Oncology Oncologist, October 1, 2006; 11(9): 1034 - 1044. [Abstract] [Full Text] [PDF]

				K. D. Mortman and K. M. Frankel Pulmonary Resection After Successful Downstaging with Photodynamic Therapy Ann. Thorac. Surg., August 1, 2006; 82(2): 722 - 724. [Abstract] [Full Text] [PDF]

				J-M. Vergnon, R. M. Huber, and K. Moghissi Place of cryotherapy, brachytherapy and photodynamic therapy in therapeutic bronchoscopy of lung cancers. Eur. Respir. J., July 1, 2006; 28(1): 200 - 218. [Abstract] [Full Text] [PDF]

				G. Asimakopoulos, J. Beeson, J. Evans, and M. O. Maiwand Cryosurgery for Malignant Endobronchial Tumors: Analysis of Outcome Chest, June 1, 2005; 127(6): 2007 - 2014. [Abstract] [Full Text] [PDF]

				P. Ross Jr, C. M. Magro, and M. A. King Endobronchial histoplasmosis: a masquerade of primary endobronchial neoplasia--a clinical study of four cases Ann. Thorac. Surg., July 1, 2004; 78(1): 277 - 281. [Abstract] [Full Text] [PDF]

				A. Ernst, D. Feller-Kopman, H. D. Becker, and A. C. Mehta Central Airway Obstruction Am. J. Respir. Crit. Care Med., June 15, 2004; 169(12): 1278 - 1297. [Abstract] [Full Text] [PDF]

				D. E. Maziak, B. R. Markman, J. A. MacKay, and W. K. Evans Photodynamic therapy in nonsmall cell lung cancer: a systematic review Ann. Thorac. Surg., April 1, 2004; 77(4): 1484 - 1491. [Abstract] [Full Text] [PDF]

				K. Moghissi and K. Dixon Is bronchoscopic photodynamic therapy a therapeutic option in lung cancer? Eur. Respir. J., September 1, 2003; 22(3): 535 - 541. [Abstract] [Full Text] [PDF]

				K. Moghissi, K. Dixon, and J.A. C. Thorpe A method for video-assisted thoracoscopic photodynamic therapy (VAT-PDT) Interactive CardioVascular and Thoracic Surgery, September 1, 2003; 2(3): 373 - 375. [Abstract] [Full Text] [PDF]

				B. Kiani, C. M. Magro, P. Porcu, M. Starns, N. Heerema, and P. Ross Jr Polypoid endobronchial Hodgkin lymphoma with an initial response to photodynamic therapy Ann. Thorac. Surg., September 1, 2003; 76(3): 940 - 942. [Abstract] [Full Text] [PDF]

				B. Kiani, C. M. Magro, and P. Ross Jr Endobronchial presentation of Hodgkin lymphoma: a review of the literature Ann. Thorac. Surg., September 1, 2003; 76(3): 967 - 972. [Abstract] [Full Text] [PDF]

				P. A. Kvale, M. Simoff, and U. B. S. Prakash Palliative Care Chest, January 1, 2003; 123(1_suppl): 284S - 311S. [Abstract] [Full Text] [PDF]

				G. A. Silvestri, C. Sherman, T. Williams, S.-S. Leong, P. Flume, and A. Turrisi Caring for the Dying Patient With Lung Cancer* Chest, September 1, 2002; 122(3): 1028 - 1036. [Full Text] [PDF]

				F. Tomaselli, A. Maier, H. Pinter, H. Stranzl, and F. M. Smolle-Juttner Photodynamic therapy enhanced by hyperbaric oxygen in acute endoluminal palliation of malignant bronchial stenosis (Clinical pilot study in 40 patients) Eur. J. Cardiothorac. Surg., May 1, 2001; 19(5): 549 - 554. [Abstract] [Full Text] [PDF]

				L. M. Seijo and D. H. Sterman Interventional Pulmonology N. Engl. J. Med., March 8, 2001; 344(10): 740 - 749. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Keyvan Moghissi Andrew Thorpe Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moghissi, K. Articles by Brown, S. Search for Related Content PubMed PubMed Citation Articles by Moghissi, K. Articles by Brown, S.