Infection with oncogenic types of human papillomavirus (HPV) is the main causal factor of cervical cancer and its precursor lesion (cervical intraepithelial neoplasia [CIN]). Cellular immunity may be critical in the elimination of HPV-harboring cells. Interleukin-10, a T-helper type 2 cytokine, has a suppressive effect on cell-mediated immunity. Resistance to apoptosis through the Fas pathway might enable many cancers to escape the immune system. We examined in a large study population whether three polymorphisms in the IL-10 gene and a polymorphism at position -670 of the Fas promotor affect susceptibility for cervical cancer or its precursor. In addition, it was studied whether these polymorphisms were causal and not merely associated by typing microsatellite markers in the region surrounding both genes. A total of 311 CIN, 695 cervical cancer patients, and 115 family-based and 586 unrelated controls were analyzed. Association analysis revealed an increased CIN (II-III) (OR 1.44 [1.06-1.97]) and squamous cell carcinoma of the cervix (OR 1.35 [1.04-1.75]) for individuals heterozygous for the A-allele of the IL-10-592 polymorphism. In contrast to previous findings, no association was found for the IL-10-1082 polymorphism. While an increased risk for adenocarcinoma (AC) in heterozygotes (OR 1.59 [1.02-2.48]) was observed. Our study shows a possible role for the IL-10 gene in CIN and squamous cell cervical cancer susceptibility in the Caucasian population; simultaneously, there might be a role for the Fas gene in the development of AC of the cervix. Further investigations with a higher density of markers are necessary to find the causal mutation.

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme regulating the metabolism of folate and methionine. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair presents MTHFR as a candidate for being a cancer-predisposing gene. In the present study, we have examined a large study population to determine whether the C677T polymorphism at the MTHFR locus affects susceptibility for cervical cancer or its precursor, cervical intraepithelial neoplasia (CIN). In addition, we have investigated whether this polymorphism is causal, and not merely associated, by typing microsatellite markers in the region surrounding the MTHFR gene. A total of 311 CIN and 695 cervical cancer patients and 115 family-based and 586 unrelated controls was analysed. Association analysis showed a decreased cervical cancer risk for individuals heterozygous or homozygous for the T-allele, both for squamous cell carcinoma (heterozygous odds ration [OR] 0.66 [0.51-0.86]; homozygous OR 0.76 [0.49-1.16]) and adenocarcinoma (heterozygous OR 0.71 [0.49-1.03]; homozygous OR 0.34 [0.14-0.81]). No difference was found for high grade CIN (heterozygous OR 1.03 [0.76-1.40]; homozygous OR 0.91 [0.54-1.55]). A microsatellite haplotype containing the C allele was associated with an increased risk for cervical cancer and CIN (both among squamous cell carcinomas, adenocarcinomas and CIN II-III; OR = 2.61 [1.59-4.27]). Our study thus lends further support to the hypothesis that the MTHFR C677T polymorphism is involved in susceptibility cervical cancer but also illustrates that, despite the large sample size analysed, still larger studies are needed to establish fully the nature of this association.

Question 4Cryopreserved platelets are currently stored at -65 to -90°C (-80°C) in a mechanical freezer. A frozen shelf life of 2 years has been applied for platelets for the CLIP trial and for the Australian Defence Force. We have allocated a post-thaw shelf life of 6 h for platelets for the Australian Defence Force to minimize risk of bacterial growth. This is

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Background Cryopreserved platelet products can be stored for years and are mainly used in military settings. Following thawing, cryopreserved platelets are activated, resulting in faster clot formation but reduced aggregation in vitro, rendering their efficacy in bleeding unknown. Also, concerns remain on the safety of these products. The aim was to investigate the efficacy and safety of cryopreserved platelets in a rat model of traumatic hemorrhage. Study Design and Methods After 1 hour of shock, rats (n = 13/group) were randomized to receive a balanced transfusion pack (1:1:1 red blood cell:plasma:platelet) made from syngeneic rat blood, containing either liquid stored platelets or cryopreserved platelets. Primary outcome was the transfusion volume required to obtain a mean arterial pressure (MAP) of 60 mmHg. Secondary outcomes were coagulation as assessed by thromboelastometry (ROTEM®) and organ failure as assessed by biochemistry and histopathology. Results The transfusion volume to obtain a MAP of 60 mmHg was lower in animals receiving cryopreserved platelets (5.4 [4.1‐7.1] mL/kg) compared to those receiving liquid stored platelets (7.5 [6.4‐8.5] mL/kg, p < 0.05). ROTEM® clotting times were shorter (45 [41‐48] vs. 49 [45‐53]sec, p < 0.05), while maximum clot firmness was slightly lower (68 [67‐68] vs. 69 [69‐71]mm, p < 0.01). Organ failure was similar in both groups. Conclusions Use of cryopreserved platelets required less transfusion volume to reach a targeted MAP compared to liquid stored platelets, while organ injury was similar. These results provide a rationale for clinical trials with cryopreserved platelets in (traumatic) bleeding.

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We report three Dutch families with familial clustering of (pre)neoplastic cervical disease, review the literature on familial risks of cervical intraepithelial neoplasia (CIN) and cervical cancer, and discuss possible practical guidelines for women with a family history of cervical cancer. Daughters and sisters of women with cervical cancer have been reported to have a relative risk of 1.5-2.3 to develop this type of cancer. From a practical clinical point of view, we suggest that as in women with an increased non-genetic risk to develop cervical cancer (e.g. because of immunosuppressive therapy) increased surveillance to detect this tumour should be considered in women with an increased risk based on family history. Cessation of smoking should be advised. As the use of condoms at least prevents HPV re-infection its use can be recommended as a way to lower the cervical cancer risk. Future studies to determine the genetic contribution to the development of cervical cancer should include the paternal family history of cancer and, because genetic predisposition might express itself as a higher risk to develop precursors of cervical cancer, carcinoma in situ and CIN grade II-III.