Time-dependent risk of developing distant metastasis in breast cancer patients according to treatment, age and tumour characteristics.

BACKGROUND: Metastatic breast cancer is a severe condition without curative treatment. How relative and absolute risk of distant metastasis varies over time since diagnosis, as a function of treatment, age and tumour characteristics, has not been studied in detail. METHODS: A total of 9514 women under the age of 75 when diagnosed with breast cancer in Stockholm and Gotland regions during 1990-2006 were followed up for metastasis (mean follow-up=5.7 years). Time-dependent development of distant metastasis was analysed using flexible parametric survival models and presented as hazard ratio (HR) and cumulative risk. RESULTS: A total of 995 (10.4%) patients developed distant metastasis; the most common sites were skeleton (32.5%) and multiple sites (28.3%). Women younger than 50 years at diagnosis, with lymph node-positive, oestrogen receptor (ER)-negative, >20 mm tumours and treated only locally, had the highest risk of distant metastasis (0-5 years' cumulative risk =0.55; 95% confidence interval (CI): 0.47-0.64). Women older than 50 years at diagnosis, with ER-positive, lymph node-negative and ≤20-mm tumours, had the same and lowest cumulative risk of developing metastasis 0-5 and 5-10 years (cumulative risk=0.03; 95% CI: 0.02-0.04). In the period of 5-10 years after diagnosis, women with ER-positive, lymph node-positive and >20-mm tumours were at highest risk of distant recurrence. Women with ER-negative tumours showed a decline in risk during this period. CONCLUSION: Our data show no support for discontinuation at 5 years of clinical follow-up in breast cancer patients and suggest further investigation on differential clinical follow-up for different subgroups of patients.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Less correspondence between expectations before and cosmetic results after risk-reducing mastectomy in women who are mutation carriers: a prospective study.

PURPOSE: The primary aim was to describe satisfaction with the cosmetic results six months and one year after risk-reducing mastectomy (RRM) with immediate breast reconstruction. Another aim was to ascertain associations between ratings on "correspondence between the overall results and expectations before RRM" and age, mutation carrier status, salpingo-oophorectomy (SOE) before RRM, body image, and with sexual pleasure and discomfort. METHODS: 91/100 women who underwent RRM between 1997 and 2005 were included. Assessments were made six and twelve months after RRM with questionnaires regarding satisfaction with the cosmetic results, sexuality (SAQ), and body image (BIS). RESULTS: At both assessment points, >70% of the women considered the overall results of RRM to correspond to their expectations. Over 80% were satisfied with the size of their breasts, but 49% indicated at the one-year assessment that at least one breast was too hard and 73% indicated that they had no or only minor sensitivity in the breasts. In the univariate analyses, associations between "correspondence between the overall results and expectations before RRM" and mutation carrier status (p = 0.039) and SOE (p = 0.025) were found, but only mutation carrier status remained in the multivariate analysis (0.037). CONCLUSION: The majority of the women reported that the results of RRM corresponded to their expectations, with lower levels of correspondence in mutation carriers than in non-carriers. Overall satisfaction with the cosmetic result was high, but a majority of the women were unsatisfied with the softness of the reconstructed breasts. These results can be useful when informing patients about RRM.

Musculoskeletal symptoms and perceived work strain among reindeer herders in Sweden.

BACKGROUND: There is a shortage of knowledge on the extent of musculoskeletal symptoms in reindeer husbandry. AIMS: To investigate the prevalence and relative risk for musculoskeletal symptoms and perceived psychosocial work strain among reindeer herders. METHODS: The prevalence of self-reported musculoskeletal symptoms during the last week and last year, respectively, were obtained from male reindeer herders (n=74) of northern Sweden. Prevalence ratios (PRs) were calculated using two reference groups-women of reindeer-herding families (n=53) and men in blue-collar occupations (n=194). Comparisons were made of perceived job strain between the study and reference groups. Associations between job strain factors and the occurrence of musculoskeletal symptoms from different body regions were analysed with regression statistics. RESULTS: The PRs for musculoskeletal symptoms from the hand/wrist (PR 3.48, 95% CI 1.86-6.50) and lower back (PR 1.44, 95% CI 1.06-1.95) were significantly higher among the reindeer herders in comparison with men working with other blue-collar occupations. The reindeer herders reported significantly higher work demands and decision latitude compared with both reference groups (P<0.05). Significant associations were observed between demands and prevalence of symptoms from the lower back (OR 1.42, 95% CI 1.01-2.01) and from at least one body region (OR 1.58, 95% CI 1.07-2.32). CONCLUSIONS: The relative risk for musculoskeletal symptoms, particularly from the hands/wrists and lower back, was high among reindeer herders. It is suggested that musculoskeletal symptoms constitute a considerable health problem in modern reindeer husbandry, which calls for implementation of preventive measures addressing psychosocial, physical and socio-economic risk factors.

Individuals with an increased risk of colorectal cancer: perceived benefits and psychological aspects of surveillance by means of regular colonoscopies.

PURPOSE: To evaluate the psychological consequences of genetic counseling followed by a surveillance program using colonoscopy among individuals with increased risk of colorectal cancer. PATIENTS AND METHODS: Two hundred sixty-five individuals, participating in a surveillance program with colonoscopy, were mailed a survey questionnaire that assessed their experience of the surveillance program and their perception of the risk of colorectal cancer. The Hospital Anxiety and Depression scale and the Swedish Short Form-36 Health Survey was also included. RESULTS: Two hundred forty individuals completed the questionnaire and were divided into the following risk groups: risk group 1, an individual with a mutation in hMLH1 or hMSH2 and a lifetime colorectal cancer risk of 80% (n = 28); risk group 2, a lifetime colorectal cancer risk of 40% (n = 129); and risk group 3, a lifetime colorectal cancer risk of 20% (n = 83). Among all individuals, the mean for perceived benefit was 8.0, and the perception of discomfort was 3.3 on the visual analog scale (1-10). In risk group 1, 61% underestimated personal risks as being 40% or less. Approximately 50% of the subjects in risk groups 2 and 3 either under- or overestimated their lifetime risk. According to the Swedish Short Form-36 Health Survey and the Hospital Anxiety and Depression scale, the study sample resembled the reference population. CONCLUSION: A majority of the study sample understood why they were under surveillance, and regular colonoscopies were well-tolerated. The wide range of risk perception as well as low-risk perception in mutation positive subjects is acceptable, as long as these individuals adhere to surveillance programs and do not demonstrate increased levels of anxiety or depression.

Risk factors for cardiovascular diseases among Swedish Sami--a controlled cohort study.

OBJECTIVE: To investigate the occurrence of clinical, psychosocial and behavioural risk factors for cardiovascular diseases (CVD) among reindeer herding (RS) and non-reindeer herding Sami (NRS). STUDY DESIGN: A retrospective cohort study, comparing risk factors behind CVD between Sami and non-Sami, RS and NRS, and Sami men and women. METHODS: A cohort of 611 Swedish Sami (276 men and 335 women) was constructed from national population registers. A twice as large control cohort of non-Sami was created, matched by age, gender and area of residence. Information on risk factors was obtained from a database containing clinical and psychosocial-behavioural data from a regional CVD preventive programme for the period 1990-2001. RESULTS: The Sami and the non-Sami showed similar risk factor patterns. The main differences were related to working conditions and lifestyle factors of the RS. The RS men had lower blood pressure, were more physically active and had higher job demand and decision latitude. The RS women showed more negative scores on the indices of the job strain model. CONCLUSIONS: Previously reported differences in CVD mortality between Sami and non-Sami, and Sami men and women, can only partly be explained by different exposure to the psychosocial and behaviour risk factors investigated in this study.

Prevalence and incidence of hyperplastic polyps and adenomas in familial colorectal cancer: correlation between the two types of colon polyps.

BACKGROUND AND AIMS: Colorectal adenomas are recognised as precursors of colorectal carcinomas. The significance of hyperplastic (metaplastic) colorectal polyps is unknown. The relationship between hyperplastic polyps and adenomas, and the prevalence and incidence of these lesions were evaluated in individuals predisposed to familial colorectal cancer. METHODS: A total of 299 individuals participating in our surveillance programme during 1990-2000 were retrospectively evaluated. Subjects were classified into three groups: hereditary non-polyposis syndrome (HNPCC) (n=108), hereditary colorectal cancer (HCRC) (n=127), and individuals with empirical risk estimates-two close relatives (TCR) (n=64). Findings from 780 colonoscopies were evaluated regarding prevalence and incidence of hyperplastic polyps and adenomas. Correlations between hyperplastic polyps and adenomas were calculated by Pearson correlation. RESULTS: In total, 292 hyperplastic polyps and 186 adenomas were observed in 98 and 90 individuals, respectively. A positive correlation was found between the numbers of hyperplastic polyps and adenomas (r=0.40; p<0.001). Correlations between adenomas and hyperplastic polyps were similar in the three groups. The risk of detecting new hyperplastic polyps (odds ratio 5.41) or adenomas (OR 2.56) increased significantly when there was a positive finding at first colonoscopy. CONCLUSION: Hyperplastic polyps as well as adenomas may identify individuals with a high risk of colorectal cancer. This information is important when these individuals are selected and included in tailored surveillance programmes.

Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer.

BACKGROUND AND AIMS: Polypectomy in the colon has been shown to prevent colorectal cancer in both the general population and in familial colorectal cancer. Individuals with a family history of colorectal cancer have an increased risk of the disease. Over a period of 10 years, 304 subjects at risk were included in ongoing surveillance with regular colonoscopies. To compile the medical findings and experience generated during this period, a retrospective cross sectional study was performed. SUBJECTS: Subjects were classified into three family groups: families with hereditary non-polyposis colorectal cancer (HNPCC); families with hereditary colorectal cancer (HCC, non-Lynch syndrome); and a third group of families with only empirical risk estimates based on a family history of two close relatives (TCR) with colorectal cancer. METHODS: The risk population was studied with regard to age at onset, prevalence, number, cancer risk, size, dysplasia, and distribution of adenomas. A comparison was made within the family groups and with a reference group representing the general population. RESULTS: In total, 195 adenomas and six cancers were detected among 85 individuals. The relative risk of having an adenoma in the whole risk population compared with the general population was 2.6. Subjects from TCR families had most adenomas and HNPCC subjects had the least. A shift from proximal adenomas to distal carcinomas in families with HCC and TCR suggested a higher cancer risk in distal adenomas in these syndromes. HNPCC families showed a younger age at onset and adenomas with a higher degree of dysplasia. In HNPCC, there was a similar localisation of adenomas and carcinomas, suggesting a high risk of cancer in all adenomas. CONCLUSIONS: There was clear overrepresentation of adenomas in all three family types compared with the reference population. In HNPCC, we found earlier onset of adenomas and faster progression to cancer. Families with HCC, and even more so TCR subjects, had a later onset and lower risk of cancer from proximal adenomas. Based on these results, surveillance protocols in Sweden have been revised.

The importance of glucose for the Escherichia coli mediated citrate depletion in synthetic and human urine.

OBJECTIVE: Escherichia coli has previously been shown to reduce urine citrate and influence urine pH. In this study the influence of glucose on the E. coli mediated citrate decrease has been investigated. MATERIAL AND METHODS: In synthetic urine, a glucose concentration of > or = 1 mmol/l was a prerequisite for bacteria to grow and lower citrate. At glucose concentrations > or = 5 mmol/l an E. coli mediated pH decrease correlated to urine glucose was observed. RESULTS: In human urine, variations in urine glucose influenced the citrate decrease and addition of glucose accelerated the E. coli mediated citrate decrease, which in certain urines could be very pronounced. CONCLUSIONS: Citrate has a pronounced effect on the activity product of calcium oxalate and calcium phosphate and the E. coli mediated decrease in urine citrate may be involved in the formation of urinary tract stones and catheter encrustations.

Conjugate chemistry and cellular processing of EGF-dextran.

Conjugates with specific binding to the epidermal growth factor receptor, EGFR, of interest for radionuclide based imaging and therapy were prepared using mouse epidermal growth factor, mEGF, and dextran. In one type of conjugate, mEGF was coupled to dextran by reductive amination in which the free amino group on the mEGF N-terminal reacted with the aldehyde group on the reductive end of dextran. The end-end coupled conjugate could be further activated by the cyanopyridinium agent CDAP, thereby introducing tyrosines to the dextran part. In the other type of conjugate, the cyanylating procedure using CDAP was applied, first to activate dextran and then allowing for the amino terminus of mEGF to randomly attach to the dextran. In the latter case, radionuclide-labelled tyrosines or glycines could be added in the same conjugation step. All types of mEGF-dextran conjugates had EGFR-specific binding since the binding could be displaced by an excess of non-radioactive mEGF. The conjugates were to a large extent internalized in the test cells and the associated radioactivity was retained intracellularly for different times depending on both the type of cells and conjugate applied. Different intracellular 'traffic routes' for the radionuclides are discussed as well as applications for both imaging and therapy.

Concrement formation and urease-induced crystallization in urine from patients with continent ileal reservoirs.

OBJECTIVES: To study the relationship between urinary tract infection, urine composition and concrement formation in patients with continent ileal reservoirs for urinary diversion. PATIENTS AND METHODS: The study comprised 27 patients (seven men and 20 women, mean age 47 years, range 23-76) with continent ileal reservoirs who were followed for a mean of 67 months (range 13-146) by annual reservoiroscopy, intravenous urography and urine culture; at the final follow-up, a sample of their morning urine was analysed for a range of compounds and the number and size of any particles present or produced in response to incubation with urease. RESULTS: The presence of urease-producing bacteria was associated with the formation of concrement. However, a few patients in whom an infection with urease-producing organisms was not detected also formed concrement. Urine from those patients forming stones tended to have a high calcium and a low citrate concentration. After incubation with urease, significantly more and larger particles were formed in the urine from stone formers. There was a strong correlation (r = 0.8) between urinary calcium content and urinary pH when the urease-induced precipitation commenced, and between urinary calcium and the size and volume of the crystals developed (r = 0.9) after 4 h of incubation. CONCLUSIONS: There are many factors which might influence the formation of concrement, e.g. outflow conditions, the presence of staples or infection in the reservoir, and the composition of the urine is also important. It thus appears appropriate to determine if measures to reduce urinary calcium and increase urinary citrate can decrease the episodes of stone formation in those patients with continent ileal reservoirs for urinary diversion who frequently form stones.

Impact of Escherichia coli on urine citrate and urease-induced crystallization.

Escherichia coli (E. coli) is usually not a urease producer. It is, however, often cultured in urinary phosphate containing calculi including ammonium magnesium phosphate stones. This suggests the possibility that E. coli might be involved in stone forming process. The effect of E. coli on urine citrate and urease-induced crystallization in human urine has been studied in vitro. E. coli was found to strongly reduce urine citrate (after 48 hours). In the E. coli inoculated samples, the urease-induced crystallization was increased. There was a strong correlation, r = 0.8, between the citrate decrease and the increase in calcium precipitation. The results indicate that E. coli and the reduced urine citrate influences urease-induced crystallization in vitro.

Unique ability of the Proteus mirabilis capsule to enhance mineral growth in infectious urinary calculi.

Struvite (MgNH4PO4.6H2O) calculi are a common complication of Proteus mirabilis urinary tract infections. Although urease is a major virulence factor in calculus formation, the polysaccharide capsule (CPS) of this organism also enhances struvite crystallization and growth in vitro (L. Clapham, R. J. C. McLean, J. C. Nickel, J. Downey, and J. W. Costerton, J. Crystal Growth 104:475-484, 1990). We obtained purified CPS, of known structure and varying anionic character, from P. mirabilis ATCC 49565 and several other organisms. Artificial urine was added to CPS, and the pH was elevated from 5.8 to 8.5 by the addition of urease or titration with 0.25 M NH4OH to induce struvite crystallization. Crystallization was measured by particle counting (Coulter counter), and the morphology (crystal habit) was examined by phase-contrast microscopy. In the presence of partially anionic P. mirabilis CPS, struvite formation occurred at a lower pH than in the absence of CPS or in the presence of other neutral, partially anionic, or anionic CPS. At pH 7.5 to 8.0, significantly more struvite crystals formed in the presence of P. mirabilis CPS than under other experimental conditions. With the exception of one polymer (curdlan) which did not bind Mg2+, enhancement of struvite formation by CPS polymers was inversely proportional to their Mg2+ binding ability. We speculate that the structure and partial anionic nature of P. mirabilis CPS enable it to enhance struvite formation by weakly concentrating Mg2+ ions during struvite crystal formation. This illustrates a new virulence aspect of bacterial CPS during infection.

Long-term studies of urease-induced crystallization in human urine.

Urine samples were inoculated with viable Proteus mirabilis or purified Jack bean urease. The subsequent pH increase and crystallization were followed for 2 weeks. Particle formation was detected much earlier and at a lower pH in urines inoculated with Proteus, in which a higher end pH was also reached. The crystal configuration in bacteria and urease inoculated samples was different. Crystal aggregation was also much more pronounced in the Proteus mirabilis inoculated samples. The total precipitation was markedly increased in the Proteus mirabilis inoculated samples. The presence of live Proteus mirabilis thus has a profound influence on urease-induced crystallization in human urine. Despite the formation of rather large crystal aggregates in the Proteus-inoculated urines, no firm aggregates of a "prestone" type were observed.

Influence of Escherichia coli on urease-induced crystallisation in human urine.

Urease was added to urines inoculated with Escherichia coli 24 hours earlier and to control urines not inoculated with E. coli. The inoculation did not change the concentration of the measured urine components. The urease-induced ammonium ion production and pH increase was reduced in E. coli-inoculated urines compared to control urines. This suggests that E. coli can inhibit urease. The precipitation of both phosphate and magnesium on glass rods inserted in the urine was reduced with 40-50% in the E. coli-inoculated urines. The results demonstrate that E. coli can influence urease-induced crystallisation.

The influence of pH and urine composition on urease enzymatic activity in human urine.

It is reasonable to assume that the rate of pH increase in urine induced by urease-producing microorganisms is one of the factors which determine whether crystallisation with subsequent stone formation will occur or not. To evaluate how the time needed to increase urine pH varies between different urine samples and how it depends on urine composition, a standardised amount of urease was added to different human urine samples. The incubations were performed in a pH-stat. This allowed simultaneous study of how urease enzymatic activity depends on urine pH and how it varies between different urines. The enzymatic activity was found to be negatively correlated to urine pH and to vary between different urines. The rate of the pH increase varied markedly between different urines. Small pH increases depended on the native urine pH and urease enzymatic activity. Higher pH increases up to the levels of phosphate crystallisation depended more on urine phosphate, the major urine buffer. The results presented show that urine composition influences the urease-induced pH increase. This might have clinical implications.

E. coli and urease-induced crystallisation in urine.

The effects of urine preinoculation with E. coli for 20 h on urease activities in urine have been studied in synthetic as well as human urine. The E. coli preinoculation increased pH in both synthetic and human urine. Urease enzymatic activity was enhanced in E. coli-preinoculated synthetic urine. The intraluminal urease-induced precipitation was increased in E. coli-preinoculated synthetic urine. The precipitation on glass rods, which more closely reflects crystal growth and aggregation, was reduced. The process of urease-induced crystallisation thus appears to be influenced by E. coli. In human urine, the effects of E. coli preinoculation were less uniform but a significantly increased urease-induced precipitation after E. coli preinoculation could be reproduced in human urine also.