Selection for treatment of patients at high risk of fracture by the short versus long term prediction models - data from the Belgian FRISBEE cohort.

Our imminent model was less sensitive but more selective than FRAX® in the choice of treatment to prevent imminent fractures. This new model decreased NNT by 30%, which could reduce the treatment costs. In the Belgian FRISBEE cohort, the effect of recency further decreased the selectivity of FRAX®. PURPOSE: We analyzed the selection for treatment of patients at high risk of fracture by the Belgian FRISBEE imminent model and the FRAX® tool. METHODS: We identified in the FRISBEE cohort subjects who sustained an incident MOF (mean age 76.5 ± 6.8 years). We calculated their estimated 10-year risk of fracture using FRAX® before and after adjustment for recency and the 2-year probability of fracture using the FRISBEE model. RESULTS: After 6.8 years of follow-up, we validated 480 incident and 54 imminent MOFs. Of the subjects who had an imminent fracture, 94.0% had a fracture risk estimated above 20% by the FRAX® before correction for recency and 98.1% after adjustment, with a specificity of 20.2% and 5.9%, respectively. The sensitivity and specificity of the FRISBEE model at 2 years were 72.2% and 55.4%, respectively, for a threshold of 10%. For these thresholds, 47.3% of the patients were identified at high risk in both models before the correction, and 17.2% of them had an imminent MOF. The adjustment for recency did not change this selection. Before the correction, 34.2% of patients were selected for treatment by FRAX® only, and 18.8% would have had an imminent MOF. This percentage increased to 47% after the adjustment for recency, but only 6% of those would suffer a MOF within 2 years. CONCLUSION: In our Belgian FRISBEE cohort, the imminent model was less sensitive but more selective in the selection of subjects in whom an imminent fracture should be prevented, resulting in a lower NNT. The correction for recency in this elderly population further decreased the selectivity of FRAX®. These data should be validated in additional cohorts before using them in everyday practice.

Risk factors for imminent fractures: a substudy of the FRISBEE cohort.

Multiple factors increase the risk of an imminent fracture, including a recent fracture, older age, osteoporosis, comorbidities, and the fracture site. These findings could be a first step in the development of a model to predict an imminent fracture and select patients most at need of immediate treatment. INTRODUCTION: The risk of a recurrent fragility fracture is maximal during the first 2 years following an incident fracture. In this prospective cohort study, we looked at the incidence of recurrent fractures within 2 years after a first incident fracture and we assessed independent clinical risk factors (CRFs) increasing this imminent fracture risk. METHODS: A total of 3560 postmenopausal women recruited from 2007 to 2013 were surveyed yearly for the occurrence of fragility fractures. We identified patients who sustained a fracture during the first 2 years following a first incident fragility fracture. We quantified the risk of a new fracture and assessed independent CRFs, associated with an imminent fracture at various sites. RESULTS: A recent fracture was a significant CRF for an imminent fracture (OR (95% CI): 3.7 (2.4-5.7) [p < 0.0001]). The incidence of an imminent fracture was higher in subjects above 80 years (p < 0.001). Other CRFs highly predictive in a multivariate analysis were osteoporosis diagnosis (p < 0.01), a central fracture as the index fracture (p < 0.01), and the presence of comorbidities (p < 0.05), with likelihood ratios of 1.9, 1.9, and 2.2, respectively. An imminent fracture was better predicted by a central fracture (p < 0.01) than by a major osteoporotic fracture. The hazard ratio was the highest for a central fracture. CONCLUSION: In patients with a recent fracture, older age, osteoporosis, comorbidities, and fracture site were associated with an imminent fracture risk. These findings could be a first step in the development of a model to predict an imminent fracture and select patients most at need of immediate and most appropriate treatment.

Osteoporosis treatment gap in a prospective cohort of volunteer women.

Despite the availability of efficient drugs to prevent osteoporotic fractures, only a minority of women receives osteoporosis therapy after a fracture. The high treatment gap in our cohort consisted of unselected volunteer patients highlights the urgent need of additional education, especially for the medical profession, regarding the risk-benefit balance of treatment. INTRODUCTION: Despite the availability of efficient drugs to prevent osteoporotic fractures, only a minority of women receives osteoporosis therapy after a fracture, with a treatment gap around 80%. This can have dramatic consequences for patients and the healthcare systems. METHODS: In this study based on longitudinal data from the FRISBEE (Fracture RIsk Brussels Epidemiological Enquiry) cohort of 3560 volunteer women aged 60 to 85 years, we evaluated the 1-year treatment gap after a first major incident fragility fracture. RESULTS: There were 386 first validated fragility fractures, 285 major osteoporotic fractures (MOF) and 101 "other major" fractures. The rate of untreated patients was 85.0% (82.8% for MOF versus 91.0 % for "other major" fracture sites) (p = 0.04), with a lower rate for spine (70.5%) and hip (72.5%) versus shoulder (91.6%) and wrist (94.1%) (p < 0.0001). More specifically, the treatment gap for patients with osteoporosis, defined by a T-score < - 2.5 SD was 74.6% versus 76.5% for patients with osteoporosis defined by the presence of hip, shoulder, or spine fractures, independently of DXA results. When considering age groups, the rate of untreated women was 87.9% for women 60-70 years old, 88.2% between 70 and 80 years and 77.8% above 80 years (p = 0.03), with a greater difference between women who were younger or older than 80 years at inclusion: 88.1% versus 77.8% (p = 0.009). A diagnosis of osteoporosis (p = 0.01) and age (p = 0.03) were the only clinical risk factors (CRFs) significantly associated with treatment initiation. CONCLUSIONS: This study highlights the urgent need of additional education, especially for the medical profession, regarding the risk-benefit balance of treatment.

Rituximab: a benchmark in the development of chemotherapy-free treatment strategies for follicular lymphomas.

Background: With the introduction of the anti-CD20 antibody rituximab, the outcome of patients with follicular lymphoma (FL) has greatly improved over the last two decades. First-line prolonged rituximab monotherapy is effective, achieving long-term remission and prolonged failure-free survival in some patients. Additionally, rituximab has been shown to synergize with chemotherapeutic and novel targeted agents alike with measurable gains in duration of response. As such, rituximab has made its mark in the treatment of FL and remains a valid agent despite the availability of newer monoclonal antibodies. This review summarizes the evolving role of rituximab as the first available anti-CD20 monoclonal antibody, emphasizing its clear activity as a single agent and in combination with chemotherapy or molecular targeted agents, and setting the standard for the development of new anti-CD20 monoclonal antibodies. Conclusion: We provide data that support the ongoing use of rituximab as a therapeutic partner for novel agents in future clinical trials exploring chemotherapy-free alternatives.

[How to avoid overmedicalization of the elderly patient ?] / Comment éviter la surmédicalisation du patient âgé ?

Over-medicalization is a broad concept, which also concerns the elderly patient. It encompasses both over-diagnosis and over-treatment. An increasing awareness of this issue has emerged since 2013, with the first " Preventing Overdiagnosis " conference. Currently, Evidence-Based Medicine does not prevent over-diagnosis. Indeed, the presence of geriatric characteristics such as multiple comorbidities, polypharmacy and frailty can lead to misdiagnosis and to potentially deleterious treatment. Subclinical hypothyroidism and Alzheimer's disease are two examples of pitfalls in the interpretation of biological and para-clinical data that may lead to the administration of useless treatment. Different issues are discussed to identify the causes of over-medicalization and to better prevent it.

La surmédicalisation est un concept large, qui concerne également le patient âgé. Elle englobe à la fois le surdiagnostic et sa conséquence à savoir le surtraitement. Une sensibilisation à ce sujet a émergé depuis 2013, date du premier congrès " Preventing Overdiagnosis ". Actuellement, l'Evidence-Based Medicine ne permet pas d'éviter le surdiagnostic chez le patient âgé. En effet, la présence de caracté- ristiques gériatriques telles que les multiples comorbidités, la polymédication et la fragilité peut mener à l'élaboration d'un diagnostic erroné et à l'instauration d'un traitement potentiellement délétère. L'hypothyroïdie subclinique et la maladie d'Alzheimer sont deux exemples de pièges potentiels à l'interprétation de données biologiques et paracliniques pouvant mener à l'administration d'un traitement futile. Différentes pistes sont abordées pour identifier les causes de la surmédicalisation et mieux la prévenir.

Oncogenic osteomalacia induced by a sinonasal tumour: case report and review.

BACKGROUND: Oncogenic osteomalacia (OOM) is a rare paraneoplastic syndrome characterized by hypophosphatemia and overexpression of a phosphaturic agent, fibroblast growth factor 23 (FGF23). OOM is associated with a variety of mesenchymal tumours referred to as phosphaturic mesenchymal tumours. Head and neck regions are concerned in 5-10% of cases. METHODS AND RESULTS: We report the case of a 42-year-old female with OOM caused by a hemangiopericytoma of the left ethmoid sinus. The period between first symptoms and surgical excision of the lesion was approximately 5 years. We also conducted a PubMed-based search to identify all cases of OOM related to sinonasal tumour. Twenty eight cases in the sinonasal area were reported in the literature. CONCLUSION: OOM is an important diagnosis because resection of the causative tumour results in cure of the disease.

Impact of ribotype 027 on Clostridium difficile infection in a geriatric department.

The purposes of this study were to describe the epidemiology (2001-2009) of Clostridium difficile infections (CDI) in a geriatric department and to compare the clinical data of patients infected with a 027 or non-027 strain. We retrospectively identified all geriatric patients with CDI and analysed the clinical and microbiological data of 133 patients for whom a ribotype was available between March 2003 and December 2009. The incidence of CDI in our geriatric department increased from 0.2 per 100 admissions in 2001 to 8.1 in 2004 and decreased to 1.3 in 2008 before a new rise to 2.1 in 2009. The percentage of ribotype 027 decreased from 2007 but it remained the most prevalent ribotype during the years 2007-2009, with a greater dispersion of ribotypes. The mean age of the patients was 84 years and the median Charlson index was 6.0. Previous use of fluoroquinolones was a significant risk factor for developing a CDI with an 027 strain (p = 0.001). Cure was significantly lower in the 027 group (p = 0.003). The total attributable mortality was 24.1 %. A multiparametric model showed that attributable mortality was influenced by the ribotype 027 (p = 0.037), the severity of clinical symptoms (p = 0.001) and the type of treatment (p = 0.002). Oral vancomycin had a protective effect against mortality. Attention should be paid to elderly patients developing a CDI, especially after the administration of fluoroquinolones. Oral vancomycin could be recommended as the first-line agent not only to protect against recurrence or severe CDI, but to diminish the attributable mortality risk.

Discriminating value of HR-pQCT for fractures in women with similar FRAX scores: A substudy of the FRISBEE cohort.

Areal bone mineral density (aBMD) has a low sensitivity to identify women at high fracture risk. The FRAX algorithm, by combining several clinical risk factors, might improve fracture prediction compared to aBMD alone. Several micro-architectural and biomechanical parameters which can be measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) are associated with fracture risk. HR-pQCT in combination or not with finite element analysis (FEA) may be used to improve bone strength prediction. Our aim was to assess whether HR-pQCT measurements (densities, cortical and trabecular microarchitecture, biomechanical proprieties assessed by FEA) had an added value in predicting fractures in a subgroup of women belonging to the Belgian FRISBEE cohort. One hundred nineteen women who sustained a fracture (aged 60 to 85 years) during the initial follow-up of our cohort had a radius and tibia examination by HR-pQCT and were compared with controls matched for their FRAX score at baseline. We found that low distal radius total (OR = 1.41 [1.07-1.86] per SD, p < 0.05) and trabecular densities (OR = 1.45 [1.10-1.90], p < 0.01), trabecular number (OR = 1.32 [1.01-1.72], p < 0.05), intra individual distribution of separation (OR = 0.73 [0.54-0.99], p < 0.05) as several FEA parameters were significantly associated with fractures. At the distal tibia, impaired cortical density (OR = 1.32 [1.03-1.70] per SD, p < 0.05) and thickness (OR = 1.29 [1.01-1.63], p < 0.05) and apparent modulus (OR = 1.30 [1.01-1.66], p < 0.05) were significantly correlated with fractures. A low ultra distal radial aBMD (UDR) measured at the time of HR-pQCT was significantly associated with fractures (OR = 1.67 [1.22-2.28], p < 0.01). Women from both groups were followed further after the realization of the HR-pQCT and 46 new fractures were registered. In this second part of the study, low UDR aBMD (OR = 1.66 [1.18-2.35], p < 0.01), total (OR = 1.48 [1.08-2.03], p < 0.05), cortical (OR = 1.40 [1.04-1.87], p < 0.05) and trabecular (OR = 1.37 [1.01-1.85], p < 0.05) densities or apparent modulus (OR = 1.49 [1.07-2.05], p < 0.05) at the radius were associated with a significant increase of fracture risk. At the tibia, only the cortical density was significantly associated with the fracture risk (OR = 1.34 [1.02-2.76], p < 0.05). These results confirm the interest of HR-pQCT measurements for the evaluation of fracture risk, also in women matched for their baseline FRAX score. They also highlight that UDR aBMD contains pertinent information.

What is the validity of self-reported fractures?

We assessed the validity of self-reported fractures, over a median follow-up period of 6.2 years, in a well characterized population-based cohort of 3560 postmenopausal women, aged 60-85 years, from the Fracture Risk Brussels Epidemiological Enquiry (FRISBEE) study. Incident low-traumatic (falls from a standing height or less) or non-traumatic fractures, including peripheral fractures, were registered during each annual follow-up telephone interview. A self-reported fracture was considered as a true positive if it was validated by written reliable medical reports (radiographs, CT scans or surgical report). False positives fractures were considered to be those for which the radiology report indicated that there was no fracture at the reported site. Among self-reported fractures, false positive rates were 14.4% for all fractures. The rate of false positives of 11.2% (n = 48/429) was not negligible for the four classical major osteoporotic fractures (MOFs: hip, clinical spine, forearm or shoulder fractures). In terms of fracture site, we found the lowest false positive rate (4.4%) at the hip, and the highest (16.8%) at the spine, with the proximal humerus and the wrist in between, at about 10% each. The global rates of false positives were 12.5% (n = 22/176) for other major fractures and 22.3% (n = 49/220) for minor fractures. Younger subjects, individuals with fractures at sites other than the hip, with a lower education level, or with a higher BMI were more likely to report false positive fractures. Our data indicate that the inaccuracy of self-reported fractures is clinically relevant for several major fractures, which could influence any fracture risk prediction model.

[Evaluation of vitamin D deficiency in hospitalized patients in Brussels]. / Evaluation de la carence en vitamine D chez des patients hospitalisés a Bruxelles.

Blood levels of 25 hydroxyvitamin D (25(OH) vit D) were measured in 332 patients (192 women, mean age 69.1 +/- 17.8 SD and 140 men, 61.9 +/- 18) hospitalized in C.H.U. Brugmann for acute diseases without any link with vitamin D supply and/or metabolism. More than 60% of this population presented with serum concentrations below the lower limit of normal (12 ng/ml) whereas than less than 5% reached 30 ng/ml, a level generally recommended to avoid vitamin D insufficiency. The inverse relationship between blood levels of 25(OH) vit D and parathyroid hormone reinforced the opinion that 30 ng/ml is the minimum to reach to avoid secondary hyperparathyroidism. Young patients are nor at a lesser risk of vitamin D deficiency than the older patients, women showed a lesser deficiency than men. Factors likely to have contributed to vitamin D deficiency are a low social status and dark skin. In countries without abundant sun exposure, such as Belgium, systematic administration of vitamin D supplement is recommended, in particular in subjects at risk of deficiency, during autumn and winter, including all ages of life.

Does the Prediction Accuracy of Osteoporotic Fractures by BMD and Clinical Risk Factors Vary With Fracture Site?

Several clinical risk factors (CRFs) have been shown to predict the risk of fragility fractures independently of BMD, but their accuracy in the prediction of a particular fracture site has not been extensively studied. In this study based on longitudinal data from the FRISBEE cohort (Fracture Risk Brussels Epidemiological Enquiry), we evaluated if CRFs are specific for sites of incident osteoporotic fractures during follow-up. We recruited 3560 postmenopausal women, aged 60 to 85 years, from 2007 to 2013, and surveyed yearly for the occurrence of fragility fractures during 6.2 years (median). We analyzed the association between CRFs included in the FRAX (fracture risk assessment tool) model or additional CRFs (falls, sedentary lifestyle, early untreated menopause, diabetes, use of selective serotonin reuptake inhibitors or proton pump inhibitors) and the first incident validated major osteoporotic fracture (MOF; n = 362; vertebra, hip, shoulder, and wrist) or other major fractures (n = 74; ankle, pelvis/sacrum, elbow, knee, long bones). Uni- and multivariate analyses using the Cox proportional hazards model were used. For MOFs considered together, the risk of fracture was highly associated in uni- and multivariate analyses (p<0.01) with osteoporosis (T-score < -2.5), prior fracture, age, BMD (assessed by DXA), and fall history (HR 2.34, 1.82,1.71, 1.38, and 1.32, respectively). For each site analyzed separately, prior OF, age, smoking, and total hip BMD remained independent predictors for hip fractures (HR 5.72, 3.98, 3.10, 2.32, and 1.92, respectively); osteoporosis, age, prior OF, glucocorticoids, and spine BMD for vertebral fracture (HR 2.08, 1.87, 1.78, 1.76, and 1.45, respectively); osteoporosis, prior OF, and femoral neck BMD (HR 1.83, 1.60, and 1.56, respectively) for wrist fracture; osteoporosis, prior OF, and spine BMD (HR 2.48, 1.78, and 1.31, respectively) for shoulder fracture; prior OF and diabetes (HR 2.62 and 2.03) for other major fractures. Thus, a prior fracture and BMD were the best predictors of fracture risk at any site. Other CRFs have a weaker predictive value, which is a function of the site of a future fracture. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Risk factors for meticillin resistance and outcome of Staphylococcus aureus bloodstream infection in a Belgian university hospital.

The aim of this study was to identify institution-specific risk factors for meticillin resistance in Staphylococcus aureus bloodstream infection (BSI) and to evaluate the impact of meticillin resistance on mortality. A total of 154 episodes of S. aureus BSI were identified between 1 January 2002 and 31 December 2004: 66 meticillin-resistant S. aureus (MRSA) BSI and 88 meticillin-susceptible S. aureus (MSSA) BSI. Seventy-eight episodes (51%) were considered to be community-acquired and 76 (49%) as nosocomial. Risk factors associated with MRSA BSI included not living at home (P=0.001), prior antibiotic exposure (P=0.002), insulin-requiring diabetes (P=0.028) and nosocomial BSI (P=0.031), especially more than 12.5 days after admission. There was an association between BSI-related mortality and the following variables: septic shock (P<0.001), endocarditis (P=0.002) and MRSA BSI (P=0.021). In conclusion, S. aureus BSI is a serious condition, especially when septic shock or endocarditis occurs, and is aggravated by meticillin resistance. We advise glycopeptides as empirical therapy for patients not arriving from home, those exposed to antibiotics, and those with insulin-requiring diabetes and/or nosocomial BSI.

Low back pain as presenting manifestation of giant cell arteritis associated to abdominal aortitis.

Giant cell arteritis (GCA) is the most common vasculitis in Western countries in individuals over the age of 50. The diagnosis is relatively straightforward when typical features, such as headache, jaw claudication or other ischemic complications are present. Although atypical presentations of GCA have been described, herein we report for first time low back pain as the presenting manifestation of this vasculitis. We also emphasize the importance of considering the use of positron emission tomography (PET) in the evaluation of GCA patients presenting without "overt" cranial ischemic manifestations.

Distribution of clinical risk factors for fracture in a Brussels cohort of postmenopausal women: The FRISBEE study and comparison with other major cohort studies.

OBJECTIVES: The estimation of fracture risk using clinical risk factors (CRFs) is of primary concern in osteoporosis management, but only some risk factors have been thoroughly evaluated and incorporated in predictive models. We have launched a large prospective study, the 'Fracture Risk Brussels Epidemiological Enquiry' (FRISBEE), to develop a new predictive model for osteoporotic fractures. The aims of this report are to describe the methodology of the FRISBEE study and to compare the distribution of CRFs in our cohort with those reported in other large studies. STUDY DESIGN: FRISBEE is a new study that prospectively evaluates a cohort of 3560 post-menopausal women (aged 60-85 years) followed yearly for the occurrence of fragility fractures. Multiple validated CRFs, densitometry (DXA) values and intake of medication were systematically registered at baseline. The distribution of the FRISBEE CRFs has been compared with the distributions of CRFs in the cohorts used to develop the FRAX® model as well as in more recent cohorts. For these recent cohorts, we focused on CRFs not included in FRAX®. RESULTS: The most frequently encountered CRFs used in FRAX® were a prior fragility fracture (27.1%) and a parental history of hip fracture (13.4%). The prevalence of some CRFs not integrated in FRAX® was relatively high, such as the use of proton pump inhibitors (20.8%) and a history of fall(s) (19.7%). The prevalence of many CRFs was quite variable between cohorts; for example, the prevalence of 'personal prior fragility fracture' ranged from 9% to 51%. CONCLUSION: We found considerable heterogeneity in the prevalence of CRFs between cohort studies. The impact of these differences on the predictive value of a particular CRF is unknown. We will construct a predictive model calibrated to the Belgian population. More importantly, the FRISBEE study should allow us to determine the predictive value of newly recognized CRFs in addition to the FRAX® algorithm to reliably estimate fracture risk.

Hemophagocytic syndrome associated with extracerebral toxoplasmosis in an HIV-infected patient.

Hemophagocytic syndrome (HPS) is a clinical entity that combines non-specific clinical and biological features. The diagnosis is usually confirmed by a bone marrow examination. HPS may be primary or secondary to a malignancy or to an infectious or autoimmune disease. Since it was first described, various agents have been implicated, including viruses, bacteria, and parasites. In HIV patients, many cases occur with lymphoma or with a variety of opportunistic infections due to CMV, HHV8, Pneumocystis carinii, Mycobacterium tuberculosis, MAC, toxoplasmosis, and even pneumococcus. We report here a case of an AIDS patient presenting a HPS secondary to an extracerebral form of systemic toxoplasmosis that was only revealed by specific PCR in tissue other than the CNS.

Effect of omega-3 fatty acids on growth of a rat mammary tumor.

The effect of administering marine oil that was rich in omega-3 fatty acids on tumor growth was studied in female inbred F344 rats that received transplants of R3230AC mammary adenocarcinoma. Four groups of rats were maintained on a normal rat chow diet containing 5% fat, and marine oil supplementation was started 1 week prior to transplantation of the tumors. The marine oil provided 17, 33, and 67 mg of 5, 8, 11, 14, 17-eicosapentaenoic acid (EPA) and 16, 32, and 64 mg 4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA) a day. A significant reduction in weight (g) and volume (cm3) of the rat R3230AC mammary tumor was observed after 4 weeks of treatment. EPA (20:5 omega-3) and DHA (22:6 omega-3) were found in choline phospholipid fractions of mammary tumors from rats given marine oil. Both tumor content and synthesis in vitro of prostaglandins of two series were inhibited in the marine oil-treated groups. These data indicated that the mechanism underlying inhibition of mammary tumorigenesis may be linked, in part, to the inhibitory effect of both EPA and DHA on arachidonic acid metabolism.

Effect of flurbiprofen and 16,16-dimethyl-prostaglandin E2 on gastrointestinal tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats. I. Squamous epithelium and mesenchymal tissue.

The effect of exogenous synthetic prostaglandins and the inhibition of endogenous prostaglandin synthesis on gastrointestinal tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] was studied in female Wistar rats (100 g). Animals were divided into 6 groups: Group I was treated with MNNG alone (No. = 43); group II was treated with MNNG after application of the cyclo-oxygenase inhibitor flurbiprofen (No. = 44); group III was treated with MNNG after oral administration of 16,16-dimethyl-prostaglandin E2 (16,16-dm-PGE2; No. = 43); group IV received flurbiprofen alone (No. = 15); group V was treated with 16,16-dm-PGE2 alone (No. = 11). Animals in group VI served as controls (No. = 15). All drugs were administered orally. Hyperkeratosis and hyperplasia of the forestomach developed by 10 days after the first treatment with the carcinogen. Later, benign papillomas and dysplastic lesions were noted. Progressive ingrowth of squamous epithelium from the forestomach ridge into the glandular stomach started as early as day 13 and was more frequent in animals treated with a combination of MNNG plus flurbiprofen (P less than .001). The first squamous cell carcinomas of the forestomach were detected on day 51. Their incidence was 38, 60, and 42% in groups I, II, and III, respectively. This difference was not statistically significant. The incidence of mesenchymal tumors (leiomyosarcoma) in the stomach and duodenum was higher following treatment with MNNG plus flurbiprofen as compared to the incidence following treatment with MNNG alone or in combination with 16,16-dm-PGE2 (P less than .005). No malignant tumors developed in the gastrointestinal tracts of animals treated with flurbiprofen or 16,16-dm-PGE2 alone or in controls. The higher incidence of gastric and duodenal leiomyosarcomas after treatment with flurbiprofen suggests that reduction of prostaglandin synthesis favored the development of MNNG-induced cancer in mesenchymal tissues of the upper gastrointestinal tract.

Dietary fat and mammary cancer. II. Modulation of serum and tumor lipid composition and tumor prostaglandins by different dietary fats: association with tumor incidence patterns.

For investigation of the role of linoleic acid (LA) and its biologically significant metabolites in mammary tumor promotion by dietary fat, a detailed study of the fatty acid group composition of serum lipids, tumor neutral lipids, tumor phospholipids, and tumor prostaglandins (PG's) was conducted in female inbred F344 rats initiated with N-nitrosomethylurea (CAS: 684-93-5) and fed diets containing various types and amounts of fat. The oils, safflower [23%, high fat (HF); 5%, low fat], corn (23%, 5%), olive (23%, 5%), and coconut (23%) varied widely with respect to their LA content and their polyunsaturate:monounsaturate:saturate ratios (9:1:1, 4.6:2.6:1, 0.6:5.9:1, and 0.008:0.05:1, respectively, for safflower, corn, olive, and coconut oils). A modified hexane-based technique was used for extraction of serum and tumor lipids. Total tumor lipids ranged from a low of 5 to a high of 228 mg/g (wet wt) with no differences found among the 7 dietary groups. The phospholipid content of the tumors ranged from 27 to 47% of total tumor lipid, again with no differences seen among dietary groups. Total serum lipids varied from a low of 3.77 mg/ml (safflower oil, 23%) to a high of 6.11 mg/ml (coconut oil, 23%), and an overall inverse trend was observed between total serum lipids and tumor incidence for the 4 HF diet groups. Serum cholesterol levels were significantly depressed in the HF safflower oil and corn oil groups compared to those in all other dietary groups and, in general, varied inversely with respect to mammary tumor incidence. Serum and tumor neutral fatty acid profiles closely reflected those of the diet, while tumor phospholipids appeared more resistant to diet-induced changes. Olive oil-fed animals exhibited high levels of oleic acid in both serum and tumor lipids. The levels of the major metabolite of LA, arachidonic acid (AA), in tumor phospholipids were highly variable and did not equate with dietary or serum LA levels. A positive association was found among dietary LA, tumor PGE2, and mammary tumor incidence among the 4 HF groups; however, no association was found between tumor AA levels and either tumor PGE2 levels or mammary tumor incidence. The results of this study suggest that dietary LA may exert its effects on mammary tumor promotion by virtue of its role as a PG precursor; but the precise steps in this sequence and possible competitive interactions between essential fatty acids, monoenes, and saturates and the PG-synthesizing system remain to be determined.

Effect of flurbiprofen and 16,16-dimethyl prostaglandin E2 on gastrointestinal tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats: glandular epithelium of stomach and duodenum.

The effect of an exogenous synthetic prostaglandin analogue, 16,16-dimethyl prostaglandin E2 (16,16-dm-PGE2), as well as the effect of endogenous prostaglandin synthesis inhibition by a cyclooxygenase inhibitor, flurbiprofen, on chemically induced gastric carcinogenesis has been investigated in rats. Carcinogenesis was induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; CAS:70-25-7). Animals were divided into six groups: Group I, treatment with MNNG alone; Group II, treatment with 16,16-dm-PGE2 plus MNNG; Group III, treatment with flurbiprofen plus MNNG; Group IV, treatment with 16,16-dm-PGE2 alone; Group V, treatment with flurbiprofen alone; and Group VI, controls. Treatment with high doses of MNNG resulted in rapid development of malignant tumors originating from the glandular epithelium of the stomach and duodenum in animals of all groups receiving the carcinogen. The first gastric adenocarcinoma infiltrating the muscularis proper was detected after 139 days in an animal treated with a combination of MNNG and flurbiprofen. The incidence of infiltrating adenocarcinoma and the incidence of all neoplastic lesions of the glandular stomach were both significantly higher in animals treated with a combination of MNNG and flurbiprofen compared with treatment by MNNG alone or in combination with 16,16-dm-PGE2 (P less than 0.05 and P less than 0.001). The difference in tumor incidence between the last two groups was not significant. The first duodenal adenocarcinoma was detected on Day 114 in another animal of the group treated with MNNG plus flurbiprofen. When compared with the group treated with MNNG plus 16,16-dm-PGE2, significantly more animals developed duodenal adenocarcinoma when treated with MNNG plus flurbiprofen (P less than 0.005) or with MNNG alone (P less than 0.05). Results of this study indicate that inhibition of endogenous prostaglandin synthesis favors development of adenocarcinoma in the glandular stomach of rats. Vice versa, the addition of an exogenous prostaglandin analogue inhibits the development of duodenal adenocarcinoma. This protective effect of prostaglandins may be due to an increase of the thickness of the mucus gel covering the glandular epithelium, thereby preventing access of carcinogen to the mucosa.