Cervical intraepithelial neoplasia, cervical carcinoma, and risk for patients with HLA-DQB1 *0602, *301, *0303 alleles

1215

bileduct injury would be found were this operation to be analysed to the same degree as has been the case with LC. LC is probably better than MC in terms of improved postoperative recovery, but is clearly not worse. We are convinced that it is a technically easier operation in most cases, and thus likely to be safer. Nevertheless, bileduct injuries are occurring from technical errors. Efforts should be directed not to addressing the question "exactly how much money, time, or discomfort may be saved by LC?" but towards improving the quality of surgery for this new treatment of choice.

J. J. T. TATE W. Y. LAU K. L. LEUNG A. K. C. LI

Department of Surgery, Prince of Wales Hospital, Shatin, New Territories, Hong Kong

JS, Barkun AN, Sampalis JS, et al. Randomised controlled trial of laparoscopic mini cholecystectomy. Lancet 1992; 340: 1116-19. 2. Assalia A, Schein M, Kopelman D, Hashmonai M. Laparoscopic versus mini-incision cholecystectomy. Lancet 1993; 341: 47. 1. Barkun

versus

Cervical

intraepithelial neoplasia, cervical

carcinoma, and risk for patients with HLA-DQB1*0602,*301,*0303 alleles SIR,-Dr Vandenvelde and colleagues (Feb 13,

p 442) and the importance of the major histocompatibility complex linked class II allele HLA-DQB1 *0303 as a risk factor in cervical intraepithelial neoplasia grade III (CIN III). In these two studies patients’ DNA was amplified by polymerase chain reaction (PCR) and hybridised with one or several sequence-specific oligonucleotides (SSO) that distinguish the various DQBl alleles. Vandenvelde et al compare HPV-positive and HPV-negative patients with various grades of CIN with healthy blood donors with only one SSO that identifies the HLA-DQB1*0303 allele. These workers found in a Belgian population a significant increase in the frequency of HLA-DQB1 *0303 in the CIN I + II HPV-positive patients, but not in HPV-positive women with CIN III. In patients from London tested for all frequent HLA-DQB1* alleles including SSOs that could distinguish among the HLA-DQB 1 *03 alleles, *0301, *0302, and *0303,1 a significant increase in the frequency of DQB1 *0303 was recorded only in those with CIN III (relative risk 25). The results of both these studies provide important information which should be considered together with other observations and used in the design of future studies. We first discovered with serological HLA typing that certain alleles of the DQB1 gene (ie, HLA-DQw3) served as markers of a risk factor in the development of squamous cell carcinoma of the cervix (SCC).’ The patients were also investigated by molecular typing with DQA and DQB oligonucleotide probes (llth histocompatibility workshop).3 This analysis’ revealed a predominance of HLA-DQB1 *0301 and *0303 alleles: 40 of 57 SCC patients had a *0301 allele (relative risk 871, p 0 0001) and 9 of 57 carried a *0303 allele (relative risk 45, p = 0 0012). Vandenvelde and colleagues’ finding of an increased frequency of the HLA-DQBl *0303 allele in CIN III patients strengthens our hypothesis that an immunogenetic component determines susceptibility to cervical cancer. On the other hand, why an increase in the frequency of the HLA-DQBl *0301 allele was not seen in their patient is unclear. DQ alleles are also implicated in disease susceptibility by the increase in DQB1 *0303 in some Belgian patients, but unfortunately the investigators did not screen for *0301. In our SCC patients 5 of the 7 individuals who were HLA-DQB 1 *03 negative had an HLA-DQB1*0602 allele. The overall frequency of this allele was increased in the patient group (19% vs 12% in controls, p= 0-124). Furthermore, we have now found a high prevalence of the HLA-DQB1 *0602 allele in 22 SCC patients from Tanzania, with the use of all the llth International HLA Workshop SSOs for DQA and DQB.3 11 of these 22 SCC patients had *0602 allele. We do not have Tanzanian controls so we can only compare this frequency with that of a population of 387 healthy

others1

have

discussed

=

ASSOCIATION BETWEEN SQUAMOUS CELL CARCINOMA TYPES OF CERVIX WITH GOOD PROGNOSIS AND NON-DQB1*0301, *0303,*0602 ALLELESt

tfisher’s exact test, p = 00049. #Two *0301, *0303, *0602 negative as well as eighteen of nineteen *0301, *0303, *0602 positive cervical carcinomas were SCCs of the keratinismg type, with an intermediate prognosis; in one of two SCCs with a poor prognosis, no alleles could be defined; the second SCC was *0303 positive.

donors from four South African tribes. Here an HLA-DQB 1 *0602 frequency of 22-7% was recorded,s showing that the significant DQBl*0602 increase in SCC patients is probably important (p=00041). In the 22 Tanzanian patients no significant increases in DQB1*0301 or *0303 alleles were recorded. Even more noteworthy is the significant association between HPV16 and/or HPV18 positive SCC and presence of the HLA-DQB 1 *0602 allele: 9 of 11 patients with cervical carcinoma positive for HPV 16, 18, or both, had a DQB 1 *0602 allele but only 2 of 8 HPV 16/18 negative patients had this allele (p = 0-0204, Fisher’s exact test). The importance of the association between HPV16 and an HLA DQB1 is supported by the finding that all three SCC with the best prognosis-ie, those with large, non-keratinising cell type-were negative for the *0602, *0301, and *0303 alleles (table). We suggest that full understanding of the involvement of various DQ alleles in susceptibility to CIN and SCC will only be revealed by analysing associations between HPV types and HLA-DQB1* alleles in various ethnically distinct populations and by studying other MHC linked alleles, such as HLA-DR, HLA-DP, and TAP genes.6 In particular, it will be important to determine the haplotypic combinations of alleles, which would enable researchers to identify the specific role of the HLA-DQB 1 *0301, *0302, *0303, *0602 alleles and other linked genes in the immune response against HPV and other viruses, and their contribution to the development to this cancer. Institute of Immunology, University of Munich, D-8000 Munich 2, Germany

RUDOLF WANK

Department of Virology, Bernhard Nocht Institute,

Hamburg

JAN TER MEULEN

Tanzania Tumour Centre, Dar-Es-Salaam, Tanzania

JEFF LUANDE

Landfriedstraße 10,

HANS-CHRISTOPH EBERHARDT

Heidelberg Deutsches

Krebsforschungszentrum, MICHAEL PAWLITA

Heidelberg 1.

David ALM, Taylor GM, Gokhale D, Aplin JD, Seif MW, Tindall VR. HLA-DQB1 *03 and cervical intraepithelial neoplasia type III. Lancet 1992; 340: 52. 2. Wank R, Thomssen C. High risk of squamous cell carcinoma of the cervix for women with HLA-DQw3. Nature 1991; 352: 723-25. 3. Kimura A, Sasazuki T. Eleventh International Histocompatibility Workshop reference protocol for the HLA DNA-typing technique. In: Tsuji K, Aizawa M, Sasazuki T, eds. HLA 1991. Tokyo: Oxford University Press, 1992: 397-419. 4. Wank R, Schendel DJ, Thomssen C. HLA antigens and cervical carcinoma. Nature 1992; 356: 22-23. MG, Du Toit ED, Sachs JA, Kaplan C, Mbayo K. HLA in southern African populations. In: Tsuji K, Aizawa M, Sasazuki, eds. HLA 1991. Tokyo: Oxford University Press, 1992: 636-38. 6. Bodmer JG, Marsh SGE, Albert Ed, et al. Nomenclature for factors of the HLA system, 1991. In: Tsuji K, Aizawa M, Sasazuki, eds. HLA 1991. Tokyo: Oxford University Press, 1992: 17-31. 5. Hammond

Microscopic air embolism and cerebral angiography SIR,-Dr Markus and colleagues (March 27, p 784) reach some

disquieting conclusions on the basis of the fact that small air-bubbles usually accompany intravascular injections of liquids and, to my knowledge, are the first to recommend that standard angiographic technique should be changed because of this. They recommend that, for cerebral angiography, contrast media should be left to settle before injection and that injections of saline should be slow. The

new

non-ionic

contrast

media that

are most