Tumour pH

342

vaccine, but the evidence suggests that it needs 50-100-fold more viable organisms to be of value to travellers. It has the obvious advantages of being easily taken by mouth, with no adverse effects of any consequence, and could potentially stimulate local intestinal immunity, which is generally held to be important in protecting against infection. However, travellers are responsible for their own vaccination through the long schedule of three (worldwide) or four (USA) alternate-day doses and the necessity of maintaining the vaccine at 4°C. This requirement has been associated with compliance difficulties in the USA, where the vaccine was licensed in December, 1989.16 The purified Vi-antigen vaccine has a protective efficacy of 60-72% against disease in field trials conducted in populations in endemic regions of Nepal and South Africa. 17,18 This preparation is immunogenic in healthy North American subjects, but has never been evaluated for its likely protective efficacy in this proposed target group. The Vi-antigen vaccine has all the disadvantages of a parenterally administered vaccine: apart from the unpleasantness of an injection, there are frequent local and rare systemic reactions (albeit condsiderably milder than those associated with the heat-killed vaccine), and no stimulation of local intestinal immunity. The vaccine is convenient; with a single injection, the health-care provider can be confident that the traveller has been vaccinated. Despite many misgivings about the existing heatkilled typhoid vaccine and the doubts concerning the efficacy of this and the newer preparations, many hundreds of thousands of vaccine doses will be sold to travellers from developed countries during the coming year. Before deciding to embark on the travel vaccination ritual, travellers and their health-care providers should consider carefully the necessity of these vaccinations. Many vaccines are associated with adverse effects, especially the parenterally administered formulations. It is worth recalling that the abolition of cholera vaccination, even for travellers visiting endemic areas, has not been associated with a noticeable increase in travel-related cholera. Travellers should be provided with the opportunity to be vaccinated should they so choose, but they should be made aware (a) of the low risk of acquiring typhoid fever through travel; (b) that of the three available typhoid vaccines, none has proven any ability to confer protection against typhoid in healthy previously unexposed adults with the doses or schedules approved by licensing authorities; and (c) that the only differences between the vaccines are routes of administration, dose schedules, and adverse effects. 1.

Ryan CA, Hagrett-Bean NT, Blake PA. Salmonella typhi infections in the United States, 1975-1984: increasing role of foreign travel. Rev Infect Dis 1989; 11: 1-8.

2. Yugoslav Typhoid Commission. A controlled field trial of the effectiveness of phenol and alcohol typhoid vaccines: final report. Bull WHO 1962; 26: 357-69.

Commission. A controlled field trial of the effectiveness of acetone-dried and inactivated and heat-phenolinactivated typhoid vaccines in Yugoslavia. Bull WHO 1964; 30: 623-30. 4. Ashcroft MT, Singh B, Nicholson CC, Ritchie JM, Sobryan E, Williams F. A seven-year field trial of two typhoid vaccines in Guyana. Lancet 1967; ii: 1056-59. 5. Hejfec LB. Results of the study of typhoid vaccines in four controlled field trials in the USSR. Bull WHO 1965; 32: 1-14. 6. Hejfec LB, Levina LA, Kuz’minova ML, Salmin LV, Slavina AM, Vasil’eva AV. Controlled field trials of paratyphoid B vaccine and evaluation of the effectiveness of a single administration of typhoid vaccine. Bull WHO 1968; 38: 907-15. 7. Forrest BD, LaBrooy JT, Dearlove CE, Shearman DJC. Effect of parenteral immunisation on the intestinal immune response to Salmonella typhi Ty21a in humans. Infect Immun 1992; 60: 465-71. 8. Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins AT, Snyder MJ. Typhoid fever: pathogenesis and immunologic control, part 2. N Engl J Med 1970; 283: 739-46. 9. Wahdan MH, Serie C, Cerisier Y, Sallam S, Germanier R. A controlled field trial of live Salmonella typhi strain Ty21a oral vaccine against typhoid: three-year results. J Infect Dis 1982; 145: 292-95. 10. Levine MM, Ferreccio C, Black RE, Germanier R, Chilean Typhoid Committee. Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation. Lancet 1987; i: 1049-52. 11. Simanjuntak CH, Paleologo FP, Punjabi NH, et al. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet 1991; 338: 1055-59. 12. Gilman RH, Hornick RB, Woodward WE, DuPont HL, Levine MM, Libonati JP. Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhi as a live oral typhoid vaccine. J Infect Dis 1977; 136: 716-23. 13. Forrest BD, LaBrooy JT, Beyer L, Dearlove CE, Shearman DJC. The human humoral immune response to Salmonella typhi Ty21a. J Infect Dis 1991; 163: 336-45. 14. Murphy JR, Grez L, Schlesinger L, et al. Immunogenicity of Salmonella typhi Ty21a for young children. Infect Immun 1991; 59: 4291-93. 15. Schwartz E, Shlim DR, Eaton M, Jenks N, Houston R. The effect of oral and parenteral typhoid vaccination on the rate of infection with Salmonella typhi and Salmonella paratyphi A among foreigners in Nepal. Arch Intern Med 1990; 150: 349-51. 16. Kaplan DT, Hill DR. Compliance with live, oral Ty21a typhoid vaccine. JAMA 1992; 267: 1074. 17. Klugman KP, Gilbertson IT, Koornhof HJ, et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987; ii: 165-69. 18. Acharya IL, Lowe CU, Thapa R, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi: a preliminary report. N Engl J Med 1987; 317: 1101-04.

3. Yugoslav Typhoid

Tumour

pH

As reported in The Lancet nearly sixty years ago,1 a Nobel prize was awarded to Otto Warburg in recognition of work2 that included the discovery of "the remarkable extent to which living tumour cells are able to convert carbohydrate into lactic acid". For many years afterwards it was assumed that tumours relied largely on the glycolytic pathway, produced large amounts of lactic acid, and consequently had an acidic intracellular pH (pHi). In the intervening years, microelectrode measurements of tumour pH seemed to confirm this assumption. However, we now know that these measurements largely reflect pHe, the interstitial (or extracellular) fluid pH (range 5.5-7.3).3-5 With the advent of magnetic resonance spectroscopy (MRS), a non-invasive in-vivo measure of tissue pH became available, and in 1983 the pH of a human tumour was measured for the first time.6 The pHMRS measurement is based on the pH-dependent chemical shift difference between the 31 PI (inorganic phosphate) signal and an endogenous reference signal. At physiological pH, the Pi signal reflects the

343

relative concentrations of the two phosphate species (H2PO4- and HPO42-) present. The MRS measurement of tissue pH is a composite value of pH, and pHe. In normal tissues it is believed that pH measured in this way is intracellular. This assumption might not hold for tumours, since their extracellular volume can be much larger than in normal tissues. The proportion of Pi signal coming from the intracellular volume can be calculated if total tissue water content and the fractional volume of extracellular water are known. In animal tumours, if the extracellular volume does not exceed 50%, pHMRS largely represents intracellular pH.8 Many human tumours, especially brain tumours and sarcomas (pH 7-01—7 35), have a similar or even slightly higher pH, than their respective normal tissues.3,9 Positron emission tomography studies support the findings of high brain tumour pH.lO These pHMRS values mean that human tumours are alkaline in comparison to their extracellular fluid-the exact opposite of normal tissues. Because it was widely assumed that microelectrode measurements of acidic pHe implied acidic pH,, there have been many proposalsll for the development of drugs that would localise in these supposedly acidic tumour cells. Since it is now clear that pH; is more alkaline than pHe, drugs intended to partition preferentially across the cell membrane will actually partition into the acidic extracellular fluid. For some purposes this may not matter. Conjugates that release free drug at acid pH12 would benefit from being localised in the extracellular fluid. Ionising radiation and hyperthermia are more effective in cultured cell lines at low pH, although treatment of human tumours in vivo by these methods suggests that the converse may occur.13 High lactate concentrations are observed concurrently with high pH, and this finding can be attributed to the fact that tumour cells readily extrude protons from the cell but retain the lactate ion. According to Spencer and Lehninger 14 and V eech, 15 this is to be expected, since lactate distributes across the cell membrane as a reciprocal of H distribution, which means that high pH, in comparison to pHe would be expected to be accompanied by high intracellular lactate. Thus, after 60 years of "acidic tumours", we have to be more precise and be aware that tumours have a neutral to alkaline pHi in comparison with their extracellular environment, which is often acidic. It may be possible to exploit this difference to develop new

approaches to cancer therapy.

1. Anon. The Nobel prizeman. Lancet 1931; ii: 1035. 2. Warburg O. The metabolism of tumours. English translation by F. Dickens. London: Constable, 1930. 3. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumours: a review. Cancer Res 1989; 49: 6449-65. 4. Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984; 2: 343-66. 5. Griffiths JR. Review: Are cancer cells acidic? Br J Cancer 1991; 64: 425-27.

6. Griffiths JR, Cady E, Edwards RHT, McCready VR, Wilkie DR, Wiltshaw E. 31P-NMR studies of a human tumour in situ. Lancet 1983; i: 1435-36. 7. Prichard JW, Alger JR, Behar KL, Petroff OAC, Shulman RG. Cerebral metabolic studies in vivo by 31P NMR. Proc Natl Acad Sci USA 1983; 80: 2748-51. 8. Stubbs M, Bhujwalla ZM, Tozer GM, et al. An assessment of31P MRS as a method of measuring pH in rat tumours. NMR Biomed (in press). 9. Oberhaensli RD, Hilton-Jones D, Bore PJ, Hands LJ, Rampling RP, Radda GK. Biochemical investigation of human tumours in vivo with

phosphorus-31 magnetic

resonance

spectroscopy. Lancet 1986; ii:

8-11. 10.

Ginos JZ, Kearfott KJ, Junck L, Bigner D. In vivo of regional brain tissue pH using positron emission tomography. Ann Neurol 1984; 15 (suppl): 98-102. Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 1989; 49: 4373-84. Lavie E, Hirschberg DL, Schreiber G, et al. Monoclonal antibody L6-daunomycin conjugates constructed to release free drug at the lower pH of tumor tissue. Cancer Immunol Immunother 1991; 33: 223-30. Van Den Berg AP, Wike-Hooley JL, Broekmeyer-Reurink MA, Van der Zee J, Reinhold HS. The relationship between the unmodified initial tissue pH of human tumours and the response to combined radiotherapy and local hyperthermia treatment. Eur J Cancer Clin Oncol 1989; 25: 73-78. Spencer TL, Lehninger A. L-Lactate transport in Ehrlich ascites tumour cells. Biochem J 1976; 154: 405-14. Veech RL. The metabolism of lactate. NMR Biomed 1991; 4: 53-58.

Rottenberg DA, measurements

11.

12.

13.

14. 15.

Magnetic

resonance

imaging

in

epilepsy Advances in magnetic resonance imaging (MRI) techniques have led to considerable improvements in the detection of lesions in patients with epilepsy; MRI also offers new insights into the aetiology of this condition. Scars, tumours, and vascular and atrophic lesions are the most common abnormalities detected on neuroimaging studies. Use of volumetric data acquisition, a technique that generates fine slices of high anatomical resolution, has revealed a high frequency of embryofetal lesions (eg, neuronal migration abnormalities1-5) in extratemporal epilepsies. These abnormalities are common in childhood but were thought to be uncommon in adult cases. Similar techniques have shown a high frequency of hippocampal lesions in temporal lobe epilepsy.‘ Surgical treatment for epilepsy is becoming increasingly popular; in some series researchers have found a relation between resection of lesions displayed by neuroimaging and postoperative seizure control.9,10 In many centres providing surgery for epilepsy, the emphasis of preoperative assessment has shifted from invasive electrophysiology to imaging

techniques. Temporal lobe epilepsy, the most common partial epilepsy in adult practice, is usually a consequence of hippocampal sclerosis; other causes are vascular, dysembryoplastic, and neoplastic lesions. MR abnormalities in hippocampal sclerosis are a high signal on T2 weighted studies," and hippocampal volume loss in volumetric studies. T2 weighted studies show high signal when tissue water content is increased whereas volumetric studies allow fine slices of high anatomical resolution that are suitable for accurate volume estimates. Both techniques have a