Do intervertebral discs degenerate before they herniate, or after?

The belief that an intervertebral disc must degenerate before it can herniate has clinical and medicolegal significance, but lacks scientific validity. We hypothesised that tissue changes in herniated discs differ from those in discs that degenerate without herniation. Tissues were obtained at surgery from 21 herniated discs and 11 non-herniated discs of similar degeneration as assessed by the Pfirrmann grade. Thin sections were graded histologically, and certain features were quantified using immunofluorescence combined with confocal microscopy and image analysis. Herniated and degenerated tissues were compared separately for each tissue type: nucleus, inner annulus and outer annulus. Herniated tissues showed significantly greater proteoglycan loss (outer annulus), neovascularisation (annulus), innervation (annulus), cellularity/inflammation (annulus) and expression of matrix-degrading enzymes (inner annulus) than degenerated discs. No significant differences were seen in the nucleus tissue from herniated and degenerated discs. Degenerative changes start in the nucleus, so it seems unlikely that advanced degeneration caused herniation in 21 of these 32 discs. On the contrary, specific changes in the annulus can be interpreted as the consequences of herniation, when disruption allows local swelling, proteoglycan loss, and the ingrowth of blood vessels, nerves and inflammatory cells. In conclusion, it should not be assumed that degenerative changes always precede disc herniation. Cite this article: Bone Joint J 2013;95-B:1127-33.

Transglutaminase 2 protects against ischemic stroke.

Transglutaminase 2 (TG2) is a multifunctional protein that modulates cell survival and death pathways. It is upregulated in numerous ischemic models, and protects primary neurons from oxygen and glucose deprivation. TG2 binds to the hypoxia inducible factor (HIF) 1beta and decreases the upregulation of hypoxic-induced proapoptotic genes. To investigate the role of TG2 in ischemic stroke in vivo, we used the murine, permanent middle cerebral artery (MCA) ligation model. TG2 mRNA levels are increased after MCA ligations, and transgenic mice that express human TG2 in neurons had significantly smaller infarct volumes than wild type littermates. Further, TG2 translocates into the nucleus within 2h post ligation. Nuclear-localized TG2 is also apparent in human stroke cases. TG2 suppressed the upregulation of the HIF-induced, proapoptotic gene, Noxa. The findings of this study indicate that TG2 plays a role in attenuating ischemic-induced cell death possibly by modulating hypoxic-induced transcriptional processes.

A non-calcemic sulfone version of the vitamin D(3) analogue seocalcitol (EB 1089): chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin.

Novel side-chain diene sulfones 5, analogues of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Company's drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9-->10) and Horner-Wadsworth-Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1alpha,3beta-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 microg/kg of rat body weight.

Role of phase 2 enzyme induction in chemoprotection by dithiolethiones.

One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, terpenoids and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B(1) (AFB(1))-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of AFB(1) can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the "antioxidant response element" (ARE), leading to transcriptional activation of a score of genes involved in carcinogen detoxication and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to dithiolethiones; moreover, basal expression of these genes is typically repressed. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, PR China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB(1), AFM(1), when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population.

Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice.

Induction of phase 2 enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, appears to be an effective means for achieving protection against a variety of carcinogens in animals and humans. Transcriptional control of the expression of these enzymes is mediated, at least in part, through the antioxidant response element (ARE) found in the regulatory regions of their genes. The transcription factor Nrf2, which binds to the ARE, appears to be essential for the induction of prototypical phase 2 enzymes such as glutathione S-transferases (GSTs) and NAD(P)H:quinone oxidoreductase (NQO1). Constitutive hepatic and gastric activities of GST and NQO1 were reduced by 50-80% in nrf2-deficient mice compared with wild-type mice. Moreover, the 2- to 5-fold induction of these enzymes in wild-type mice by the chemoprotective agent oltipraz, which is currently in clinical trials, was almost completely abrogated in the nrf2-deficient mice. In parallel with the enzymatic changes, nrf2-deficient mice had a significantly higher burden of gastric neoplasia after treatment with benzo[a]pyrene than did wild-type mice. Oltipraz significantly reduced multiplicity of gastric neoplasia in wild-type mice by 55%, but had no effect on tumor burden in nrf2-deficient mice. Thus, Nrf2 plays a central role in the regulation of constitutive and inducible expression of phase 2 enzymes in vivo and dramatically influences susceptibility to carcinogenesis. Moreover, the total loss of anticarcinogenic efficacy of oltipraz in the nrf2-disrupted mice highlights the prime importance of elevated phase 2 gene expression in chemoprotection by this and similar enzyme inducers.

The external calcium-dependent NADPH dehydrogenase from Neurospora crassa mitochondria.

We have inactivated the nuclear gene coding for a putative NAD(P)H dehydrogenase from the inner membrane of Neurospora crassa mitochondria by repeat-induced point mutations. The respiratory rates of mitochondria from the resulting mutant (nde-1) were measured, using NADH or NADPH as substrates under different assay conditions. The results showed that the mutant lacks an external calcium-dependent NADPH dehydrogenase. The observation of NADH and NADPH oxidation by intact mitochondria from the nde-1 mutant suggests the existence of a second external NAD(P)H dehydrogenase. The topology of the NDE1 protein was further studied by protease accessibility, in vitro import experiments, and in silico analysis of the amino acid sequence. Taken together, it appears that most of the NDE1 protein extends into the intermembrane space in a tightly folded conformation and that it remains anchored to the inner mitochondrial membrane by an N-terminal transmembrane domain.

Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1alpha,25-dihydroxyvitamin D(3): synthesis and biological evaluation.

New C,D-ring side-chain-modified sulfone 4a, with natural 1alpha, 3beta-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1), has been prepared and characterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermediate and (2) smooth reductive etherification without interference by a neighboring sulfonyl group. Sulfone 4a, but not its 1beta, 3alpha-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resemble Leo Pharmaceutical Co.'s KH-1060 (3), is recognized by catabolic enzymes, the selective biological profile of sulfone 4a is likely not due to its metabolites that are formed in only minor amounts.

Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis.

Development of vitamin D analogs (deltanoids) as chemopreventive agents requires separation of desirable antiproliferative and pro-differentiating activities from the undesirable calcemic activity also found in the hormone calcitriol (1 alpha, 25-dihydroxyvitamin D(3)). Therefore, several conceptually new deltanoids were synthesized with modifications to the 1alpha- and/or 25-hydroxyl groups, positions traditionally considered essential for stimulating biological responses. In this study, 1 beta-hydroxymethyl-3-epi-25-hydroxyvitamin D(3), a non-calcemic CH(2) homolog of the natural hormone with antiproliferative activity in vitro, was ineffective as an inhibitor of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced induction of ornithine decarboxylase activity in mouse epidermis. However, a hybrid analog incorporating not only the calcemia-ablating 1 beta-hydroxymethyl alteration, but potentiating C,D ring 16-unsaturation and side chain 24,24-fluorination and 26, 27-homologation was found to be as effective as calcitriol. Several non-calcemic 24- or 25-t-butyl sulfones, some containing side chain fluorination but all lacking the 25-hydroxyl group, were also shown to be active in this assay. Three sulfones and the 1 beta-hydroxymethyl hybrid were evaluated as inhibitors of multistage carcinogenesis in mouse skin. Female CD-1 mice were initiated with a single dose of 7,12-dimethylbenz[a]anthracene and then promoted twice weekly for 20 weeks with TPA. Deltanoids were applied topically 30 min before TPA. Unlike calcitriol, none of the atypical deltanoids affected body weight gain in these animals. Minimal effects on urinary calcium excretion were observed following chronic treatment with these analogs. All deltanoids inhibited the incidence and multiplicity of papilloma formation, with the hybrid analog showing the greatest efficacy. With this deltanoid, tumor incidence was significantly reduced by 28% and tumor multiplicity by 63%. These results, coupled with the rich chemical diversity available in side chain sulfur-containing deltanoids, particularly when combined with A ring modifications such as 1 beta-hydroxylalkyl groups, provide important new advances in the fundamental understanding of chemical structure-biological activity relationships as well as more potent and safe vitamin D analogs for cancer chemoprevention and other medicinal uses.

Can exercise therapy improve the outcome of microdiscectomy?

STUDY DESIGN: A prospective randomized controlled trial of exercise therapy in patients who underwent microdiscectomy for prolapsed lumbar intervertebral disc. Results of a pilot study are presented. OBJECTIVE: To determine the effects of a postoperative exercise program on pain, disability, psychological status, and spinal function. SUMMARY OF BACKGROUND DATA: Microdiscectomy is often used successfully to treat prolapsed lumbar intervertebral disc. However, some patients do not have a good outcome and many continue to have low back pain. The reasons for this are unclear but impairment of back muscle function due to months of inactivity before surgery may be a contributing factor. A postoperative exercise program may improve outcome in such patients. METHODS: Twenty patients who underwent lumbar microdiscectomy were randomized into EXERCISE and CONTROL groups. After surgery, all patients received normal postoperative care that included advice from a physiotherapist about exercise and a return to normal activities. Six weeks after surgery, patients in the EXERCISE group undertook a 4-week exercise program that concentrated on improving strength and endurance of the back and abdominal muscles and mobility of the spine and hips. Assessments of spinal function were performed in all patients during the week before surgery and at 6, 10, 26, and 52 weeks after. The assessment included measures of posture, hip and lumbar mobility, back muscle endurance capacity and electromyographic measures of back muscle fatigue. On each occasion, patients completed questionnaires inquiring about pain, disability and psychological status. RESULTS: Surgery improved pain, disability, back muscle endurance capacity and hip and lumbar mobility in both groups of patients. After the exercise program, the EXERCISE group showed further improvements in these measures and also in electromyographic measures of back muscle fatigability. All these improvements were maintained 12 months after surgery. The only further improvement showed by the CONTROL group between 6 and 52 weeks was an increase in back muscle endurance capacity. CONCLUSION: A 4-week postoperative exercise program can improve pain, disability, and spinal function inpatients who undergo microdiscectomy. [Key words: electromyogram median frequency, exercise therapy, intervertebral disc prolapse, microdiscectomy, randomized controlled trial, spinal function.

Antimalarial, antiproliferative, and antitumor activities of artemisinin-derived, chemically robust, trioxane dimers.

Nine C-10 non-acetal derivatives of the natural trioxane artemisinin (1) were prepared as dimers using some novel chemistry. As designed, each dimer was stable chemically. C-10 Olefinic dimers 7 and C-10 saturated dimers 8-13 all showed good to excellent antimalarial and antiproliferative activities in vitro. Dimers 8, 10, and 12 were especially potent and selective at inhibiting growth of some human cancer cell lines in the NCI in vitro 60-cell line assay.

Conceptually new sulfone analogues of the hormone 1alpha, 25-dihydroxyvitamin D(3): synthesis and preliminary biological evaluation.

A conceptually new series of vitamin D(3)-like nonfluorinated and fluorinated 16-ene side chain tert-butyl sulfones 3-7 has been synthesized. Even though these novel C,D-ring side chain analogues of the hormone 1alpha,25-dihydroxyvitamin D(3) (1,1,25D(3)) lack a terminal OH group, thought previously to be essential for high biological activity, they are highly antiproliferative and, in several cases, transcriptionally active in vitro but desirably noncalcemic in vivo. The side chain sulfone group may be binding to the nVDR as a hydrogen-bond acceptor, in contrast to the hydrogen-bond donor function of the 25-OH group of natural 1,25D(3).

Good outcome from surgery for ampullary tumour.

BACKGROUND: Ampulla of Vater tumours are rare but usually resectable. There is debate as to the better surgical approach between the standard radical procedure, which provides adequate resection margins, and local resection, which may carry a lower mortality. This study reports the 16-year experience of a specialist unit with these tumours, and compares our results with that of recently published series. METHOD: A retrospective review of patients admitted with an ampullary tumour to the Hepatobiliary and Pancreatic Surgery Unit, Royal Adelaide Hospital, Adelaide, Australia, between January 1981 and April 1997. RESULTS: Twenty-five patients (13 men, 12 women) of median age 65 years were admitted with an ampullary tumour to the unit during this period. The most common presentation was obstructive jaundice. Multiple endoscopic biopsy was found to be very reliable in distinguishing between benign and malignant tumours. Five patients, all male, had benign neoplasms: three adenomas, one carcinoid and one gangliocytic paraganglioma. Transduodenal local excision was performed in four patients. One patient had a Whipple procedure resulting in the only in-hospital death at 3 months. Twenty patients had adenocarcinoma, of which 13 patients had a pancreaticoduodenectomy, two local excisions, two palliative bypasses, two were unfit for surgery and one declined surgery. The resectability rate was 88%, with no operative mortalities. The 5-year actuarial survival of patients who underwent radical resection was 49%. CONCLUSIONS: Proximal pancreaticoduodenectomy, preferably a pylorus-preserving procedure, is safe and effective in the treatment of ampullary carcinoma, with low operative mortality and good long-term survival. Local resection is only recommended for small benign tumours and for patients who may be unfit for radical surgery.

Costs of breast cancer treatment in the United Kingdom.

Breast cancer is a major source of mortality and morbidity to women in the UK. In this paper we estimate the costs of treating breast cancer using random samples of secondary and primary care records. We estimate the average cost per case of breast cancer to be pound 7247 which gives a total cost of pound 243 million per annum for the whole of the UK.

Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1alpha, 25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation.

Four new hybrid analogues of 1alpha,25-dihydroxyvitamin D3 (1) have been synthesized in a convergent manner by joining A-ring and C, D-ring fragments. Each hybrid analogue, having a noncalcemic 1-hydroxymethyl group and a potentiating 16-ene 24,24-difluorinated C,D-ring side chain, was designed to be lipophilic and inert toward 24-hydroxylase enzyme catabolism. Each hybrid analogue with 1beta, 3alpha-substituent stereochemistry (i.e., analogues 3b and 4b) showed a pharmacologically desirable combination of in vitro high antiproliferative activity in two different cell lines and high transcriptional activity with also low calcemic activity in vivo.

Variations in population health status: results from a United Kingdom national questionnaire survey.

OBJECTIVE: To measure the health of a representative sample of the population of the United Kingdom by using the EuroQoL EQ-5D questionnaire. DESIGN: Stratified random sample representative of the general population aged 18 and over and living in the community. SETTING: United Kingdom. SUBJECTS: 3395 people resident in the United Kingdom. MAIN OUTCOME MEASURES: Average values for mobility, self care, usual activities, pain or discomfort, and anxiety or depression. RESULTS: One in three respondents reported problems with pain or discomfort. There were differences in the perception of health according to the respondent's age, social class, education, housing tenure, economic position, and smoking behaviour. CONCLUSIONS: The EQ-5D questionnaire is a practical way of measuring the health of a population and of detecting differences in subgroups of the population.

Correlating clinical indicators of lower-limb ischaemia with quality of life.

The objectives of the study were to analyse the impact of increasing lower-limb ischaemia upon quality of life and to assess the correlation between clinical indicators of lower-limb ischaemia and such quality. A prospective observational study of a consecutive series of 235 patients (144 men and 91 women; median age 68 (range 41-87) years presenting with varying degrees of lower-limb ischaemia graded according to ISCVS criteria was performed. Data was collected at interview before any intervention. Clinical indicators of lower-limb perfusion included: intermittent claudication and maximum walking distance on standardized treadmill testing; ankle:brachial pressure indices and isotope limb blood flow. Quality of life analysis was performed using the EuroQol (EQ) questionnaire. This is a standardized generic instrument for describing health-related quality of life and consists of a descriptive system of five dimensions, each measured on three levels. Thus, a profile and two single indices of quality of life were derived using different methods. Increasing lower-limb ischaemia results in a statistically significant deterioration in both global quality of life and in all EQ-measured quality of life dimensions (P < 0.01 Kruskal-Wallis, ANOVA). The correlation between clinical indicators and quality of life is statistically significant but not sufficiently close (correlation coefficients < 0.6) to assume that variations in clinical indicators result in reciprocal variations in quality of life. In conclusion, as might be expected, a significant correlation exists between clinical indicators of lower-limb ischaemia and health-related quality of life. However, the low correlation coefficients emphasize how tenuous the association is. Thus, a significant improvement in the clinical indicators of lower-limb ischaemia cannot be assumed to impart a similar benefit on quality of life. The latter concept must therefore be analysed independently.

Predictive value of molecular dosimetry: individual versus group effects of oltipraz on aflatoxin-albumin adducts and risk of liver cancer.

Studies in animals and humans have established serum aflatoxin-albumin adducts as biomarkers of exposure to aflatoxin B1 (AFB1), a food-borne hepatocarcinogen. To assess the utility of measurements of aflatoxin-albumin adducts to predict risk of hepatocellular carcinoma (HCC), 123 male F344 rats were dosed with 20 microg of AFB1 daily for 5 weeks after randomization into three groups: no intervention; delayed-transient (500 ppm of oltipraz, weeks 2 and 3 relative to AFB1); or persistent (500 ppm oltipraz, weeks -1 to 5). Serial blood samples were collected from each animal at weekly intervals throughout aflatoxin B1 exposure and assayed for levels of aflatoxin-albumin by radioimmune assay. Area under the curve (AUC) values for aflatoxin-albumin adducts decreased 20 and 39% in the delayed-transient and persistent oltipraz intervention groups, respectively, as compared to no intervention. Similarly, the total incidence of HCC dropped from 83 to 60% (P = 0.03) and 48% (P < 0.01) in these groups. Tumor multiplicity was also reduced in the two oltipraz intervention groups, whereas time to HCC was increased. Mononuclear cell leukemia, a common neoplasm in F344 rats, was seen in 39% of the control animals, whereas the two oltipraz interventions reduced incidence to 18% (P = 0.05) and 13% (P = 0.01), respectively. Overall, a significant association was seen between biomarker AUC and risk of HCC (P = 0.01). However, when the predictive value of aflatoxin-albumin adducts was assessed within treatment groups, there was no association between AUC and risk of HCC (P = 0.56). Thus, aflatoxin-albumin adducts can be useful for monitoring population-based changes induced by interventions, such as in chemoprevention trials, but have limited utility in identifying individuals destined to develop HCC. As a consequence, the use of this biomarker in quantitative risk assessment should be pursued cautiously.

Trioxane dimers have potent antimalarial, antiproliferative and antitumor activities in vitro.

A series of tetracyclic and tricyclic trioxane dimers has been prepared with ether and ester tethers of varying length and flexibility. Several of these trioxane dimers have been found to have potent and potentially therapeutically valuable antimalarial, antiproliferative, and antitumor activities in vitro.

Quality of life analysis in patients with lower limb ischaemia: suggestions for European standardisation.

INTRODUCTION AND OBJECTIVES: In this era of evidence-based medicine and limited resources we seem obliged, on clinical and economic grounds, to demonstrate that we improve not only patient survival but also the quality of patients' lives. This study aims to determine the impact of increasing lower limb ischaemia on quality of life (QOL) and which of three commonly used generic QOL instruments is the most valid, reliable, and responsive to change in patients with lower limb ischaemia. PATIENTS AND METHODS: Two hundred and thirty-five patients, 144 men and 91 women, median age 68 years (range 41-87 years) were graded according to ISCVS suggested reporting standards, i.e. 16 mild, 116 moderate and 25 severe claudicants; 33 patients had rest pain and 45 tissue loss. Patients completed Short Form 36 (SF36), EuroQol (EQ-5D) and Nottingham Health Profile (NHP) questionnaires at interview. Additional copies of questionnaires were posted to 80 patients prior to attendance. Correlation between the two sets of responses reflects test-retest reliability. Correlation between domains measured by the three instruments reflects convergent and divergent validity. Kruskal Wallis ANOVA detected QOL changes across the whole group. Spearman Rank was used to analyse validity and reliability. Responsiveness was analysed using the Mann-Whitney U-test. RESULTS: Increasing lower limb ischaemia confers significant (p < 0.05) deterioration in: SF36 measured: physical functioning, physical role, pain, general health, vitality, social functioning and mental health. EQ-5D measured: mobility, self-care, usual activities, pain and anxiety/depression. NHP measured: energy, pain, emotional reaction, sleep, social isolation and physical mobility. All three instruments are significantly reliable (rs > 0.7). The validity of SF36 and NHP (rs = 0.68-0.78) is superior to EQ-5D (rs = 0.37-0.7). SF36 & NHP are equally responsive to changes in physical activity and pain. SF36 and EQ-5D are most responsive to changes in social activity. SF36 is most responsive to changes in psychological status. CONCLUSIONS: QOL deteriorates markedly with increasing lower limb ischaemia. The SF36 would appear to be the most appropriate generic QOL analysis tool for these patients. We recommend its widespread adoption throughout Europe, thus providing a standardised tool for reporting generic QOL.

Treatment of a giant haemangioma of the liver with Kasabach-Merritt syndrome by orthotopic liver transplant a case report.

We describe a case of giant cavernous haemangioma of the liver with disseminated intravascular coagulopathy (Kasabach-Merritt syndrome) which was cured by orthotopic liver transplant. A 47 year old man presented with bleeding and tender massive hepatomegaly after tooth extraction. Investigations showed disseminated intravascular coagulopathy and a giant hepatic haemangioma involving both lobes of the liver. Initial treatment failed to resolve the coagulopathy and liver resection was attempted. At laparotomy the tumour was unresectable and the only option for cure was to offer a liver transplantation. The orthotopic liver transplant was performed 20 days after initial laparotomy. Subsequently, all coagulation parameters returned to normal and the patient remains well after 12 months. Orthotopic liver transplant can be considered for giant hepatic haemangioma with Kasabach-Merritt syndrome when resection is necessary and a partial hepatectomy is not technically feasible.