Studies in the diagnosis of breast disease (author's transl)]

The relative diagnostic accuracy of clinical examination, mammography, thermography and ultrasound was investigated in a comparative study. Mammography proved to be the most accurate diagnostic method, followed by clinical examination, thermography and ultrasound. Whereas in cases of advanced cancer (T2 to T4 tumour diameter greater than 2 cm) the correct diagnosis was made most reliably by clinical examination, mammography was superior to all other procedures in T1 tumours and in impalpable tumours. In our opinion thermography and ultrasound should be excluded for routine use or as a screening test because of the high false negative results. It is, however, noteworthy, that small intraparenchymal cysts can be detected and localized by ultrasound in a very high percentage of cases.     

Preoperative irradiation affects functional results after surgery for rectal cancer

PURPOSE: The Swedish Rectal Cancer Trial has unequivocally demonstrated that preoperative high-dose (5 × 5 Gy) radiotherapy reduces local failure rates and improves overall survival. This will have an impact on the primary treatment of rectal cancer. This study investigates the effect of preoperative high-dose radiotherapy on long-term bowel function in patients treated with anterior resection. METHODS: A questionnaire was answered by 92 percent (203/220) of patients who were included in the Swedish Rectal Cancer Trial and who were alive after a minimum of five years. Thirty-two patients were excluded, mainly because of postoperative stomas and dementia, which left 171 for analysis. RESULTS: Median bowel frequency per week was 20 in the irradiated group (n=84) and 10 in the surgery-alone group (n=87;P<0.001). Incontinence for loose stools (P<0.001), urgency (P<0.001), and emptying difficulties (P<0.05) were all more common after irradiation. Sensory functions such as discrimination between gas and stool and ability to safely release flatus did not, however, differ between groups. Thirty percent of the irradiated group stated that they had an impaired social life because of bowel dysfunction, compared with 10 percent of the surgery-alone group (P<0.01). CONCLUSIONS: The study indicates that high-dose radiotherapy influences long-term bowel function, thus emphasizing the need for finding predictive factors for local recurrence to exclude patients with a very high probability for cure with surgery alone and to use optimized radiation techniques.Supported by the Swedish Cancer Society (Grant 1921-B97-15XCC).Read at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 26, 1997.     

Role of the innate immune system in host defence against bacterial infections: focus on the Toll-like receptors

The innate immunity plays a critical role in host protection against pathogens and it relies amongst others on pattern recognition receptors such as the Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domains proteins (NOD-like receptors, NLRs) to alert the immune system of the presence of invading bacteria. Since their recent discovery less than a decade ago, both TLRs and NLRs have been shown to be crucial in host protection against microbial infections but also in homeostasis of the colonizing microflora. They recognize specific microbial ligands and with the use of distinct adaptor molecules, they activate different signalling pathways that in turns trigger subsequent inflammatory and immune responses that allows a immediate response towards bacterial infections and the initiation of the long-lasting adaptive immunity. In this review, we will focus on the role of the TLRs against bacterial infections in humans in contrast to mice that have been used extensively in experimental models of infections and discuss their role in controlling normal flora or nonpathogenic bacteria. We also highlight how bacteria can evade recognition by TLRs.     

Mental health problems and healthcare contacts in an urban and a rural area. Comparisons of two Swedish counties

Mental health problems are common in the general population. The aim of this study was to investigate differences in frequencies of self-reported psychiatric symptoms, harmful alcohol use and healthcare contacts, in an urban and a rural area in Sweden. Two samples of 10,441 (urban site) and 3538 (rural site) subjects, aged 20-64, responded to a questionnaire, covering demographic characteristics and self-report psychiatric instruments as well as contact with healthcare during the past 12 months. Psychiatric symptoms and symptoms of substance abuse were reported by 17% of the urban women compared with 13% of the rural women, and by 20% of the urban men compared with 15% of the rural men. This difference is mainly due to an uneven age distribution in the two populations and remains statistically significant only in the oldest age group (50-64 years). Symptoms of anxiety and depression occurred with similar frequencies in both samples. Harmful alcohol use was reported by 3.6% of the urban women, 1.5% of rural women, 11.8% of urban men and 8.6% of rural men. The urban sample had more often been in contact with medical services, 77% vs. 52%. Symptoms of anxiety and depression were equally common in the two samples. Harmful use of alcohol was more common in the urban sample, especially among women. Most obvious was the stronger inclination to seek help in the urban sample.     

Recurrent superantigen exposure in vivo leads to highly suppressive CD4+CD25+ and CD4+CD25‐ T cells with anergic and suppressive genetic signatures

Staphylococcal enterotoxin B (SEB) activates T cells via non‐canonical signalling through the T cell receptor and is an established model for T cell unresponsiveness in vivo. In this study, we sought to characterize the suppressive qualities of SEB‐exposed CD4⁺ T cells and correlate this with genetic signatures of anergy and suppression. SEB‐exposed CD25⁺ and CD25^‐Vβ8⁺CD4⁺ T cells expressed forkhead box P3 (FoxP3) at levels comparable to naive CD25⁺ T regulatory cells and were enriched after exposure in vivo. Gene related to anergy in lymphocytes (GRAIL), an anergy‐related E3 ubiquitin ligase, was up‐regulated in the SEB‐exposed CD25⁺ and CD25^‐FoxP3⁺Vβ8⁺CD4⁺ T cells and FoxP3^‐CD25^‐Vβ8⁺CD4⁺ T cells, suggesting that GRAIL may be important for dominant and recessive tolerance. The SEB‐exposed FoxP3⁺GRAIL⁺ T cells were highly suppressive and non‐proliferative independent of CD25 expression level and via a glucocorticoid‐induced tumour necrosis factor R‐related protein‐independent mechanism, whereas naive T regulatory cells were non‐suppressive and partially proliferative with SEB activation in vitro. Lastly, adoptive transfer of conventional T cells revealed that induction of FoxP3⁺ regulatory cells is not operational in this model system. These data provide a novel paradigm for chronic non‐canonical T cell receptor engagement leading to highly suppressive FoxP3⁺GRAIL⁺CD4⁺ T cells.     

The NQO1*2/*2 polymorphism is associated with poor overall survival in patients following resection of stages II and IIIa non-small cell lung cancer

NAD(P)H:quinone oxidoreductase 1 (NQO1), is a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones into hydroquinones. A polymorphism (NQO1*2) alters enzymatic activity of NQO1 resulting in diminished NQO1 activity. Malignancies with NQO1*2 may be resistant to radiation and chemotherapy with resulting poorer survival. NQO1 allele was evaluated in subjects enrolled in ECOG 3590, a randomized comparison of radiation (RT) vs radiation and chemotherapy with cisplatin/etoposide (RCT) in patients with completely resected stages II and IIIa NSCLC. Overall survival was estimated using the Kaplan-Meier method and compared via the log-rank test. Cox models were used to assess the impact of covariates on outcomes. Among 152 patients with assessable samples, 24 (16%) had NQO1*2. Median follow-up was 139 months. The presence of NQO1*2/*2 was associated with decreased overall survival (OS) (median in the heterozygote/wild-type group 42.3 vs. 33.5 months in the variant group, p=0.04). In a multivariable Cox model, variant NQO1 (HR = 1.58, p = 0.05), age <60 (HR = 0.67, p = 0.04), PS 1 (HR = 1.47, p = 0.05), cardiovascular disease (HR = 1.93, p = 0.003) and alkaline phosphatase <100 mg/ml (HR = 0.59, p = 0.005) were all significant predictors of OS. NQO1*2/*2 may be an independent predictor of poor overall survival in individuals with resected stages II and IIIa NSCLC. Although the basis for the NQO1 association with decreased survival requires additional evaluation, NQO1 may represent a biomarker for guiding individualized therapy.     

Effect of tecarfarin,a novel vitamin K epoxide reductase inhibitor,on coagulation in beagle dogs

Background and purpose:

Tecarfarin (ATI-5923) is a novel vitamin K epoxide reductase inhibitor that is metabolized by esterase (mainly human carboxylesterase 2) to a single major metabolite, ATI-5900, in rats, dogs and humans. Tecarfarin is not significantly metabolized by CYP450 enzymes. The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs.

Experimental approach:

Effects on coagulation were assessed by measuring the activity levels of Factor VII and Factor X and thromboplastin-induced coagulation times, reported as prothrombin time (PT).

Key results:

Continuous intravenous infusions and oral administration of tecarfarin and warfarin caused a dose-dependent decrease in activity of Factor VII and Factor X, and associated increase in PT. Intravenous fresh frozen canine plasma or subcutaneous vitamin K₁ treatment reversed the anticoagulant effects of orally administered tecarfarin. Consistent with the inhibitory effects of amiodarone on CYP2C9, co-administration of amiodarone significantly increased the anticoagulation effect of warfarin and plasma warfarin concentrations. In contrast, amiodarone had no effect on the anticoagulation induced by tecarfarin or tecarfarin plasma concentrations in this model.

Conclusions and implications:

Overall, the data presented herein indicate that tecarfarin, via a vitamin K-dependent mechanism, causes changes in key parameters of haemostasis in beagle dogs that are consistent with effective anticoagulation. Compared to warfarin it has a decreased potential to interact metabolically with drugs that inhibit CYP450 enzymes and, therefore, may offer an improved safety profile for patients.