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Childhood onset Crohn's disease (CD) is considered more aggressive than adult onset disease. Epithelioid cell granulomas in intestinal biopsies are one, non-obligate, criterion of CD. We investigated granulomas as markers of CD severity in children followed to adulthood.Forty-five individuals with childhood onset CD were studied from diagnosis until attainment of final height, with data on disease location, medical and surgical management and with detailed growth data analyses. A blinded review of diagnostic biopsies was also performed.We found granulomas in 22/45 (49%) children at diagnosis, altogether in 28/45 (62%) patients during the disease course (median overall follow-up - 12.3 years, range 9.3-18). Granulomas were found in 9/11 (82%) with upper gastrointestinal involvement (cumulatively 17/20, 85%) (p = 0.017 and p = 0.006, respectively). The time from diagnosis to initiating immune modulating treatment (median 4.5 months, range 0-75) was shorter in the granuloma-positive group (16/22) compared to the granuloma-negative group (18/23) (median 33 months, range 2-105; p = 0.01). The median standard deviation score height at diagnosis and final adult height (both adjusted for target height) did not correlate to findings of granulomas.Epithelioid cell granulomas were associated with a shorter time to initiating immune modulating drugs, as a possible sign of more severe disease, but growth was not affected.

It is not known if verum (real) acupuncture is effective for nausea and vomiting (emesis) during radiotherapy.We randomly treated 215 blinded cancer patients with verum: penetrating 'deqi' creating acupuncture (n = 109) or non-penetrating sham needles (n = 106) two to three times per week. The patients documented emesis daily during the radiotherapy period. Primary end point was the number of patients with at least one episode of nausea.In the verum and the sham acupuncture group, 70% and 62% experienced nausea at least once during the radiotherapy period (relative risk 1.1, 95% CI 0.9-1.4) for a mean number of 10.1 and 8.7 days. Twenty five percent and 28% vomited, and 42% and 37% used antiemetic drugs at least once, respectively. Ninety-five percent in the verum acupuncture group and 96% in the sham acupuncture group believed that the treatment had been effective against nausea. In both groups, 67% experienced positive effects on relaxation, mood, sleep or pain reduction and 89% wished to receive the treatment again.Acupuncture creating deqi is not more effective than sham in radiotherapy-induced nausea, but in this study, nearly all patients in both groups experienced that the treatment was effective for nausea.

Aim: Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disturbance of immunoregulation. HLH comprises primary and acquired forms with different disease severity. A large proportion of deaths occur early into treatment. We investigated association with early death for laboratory and clinical parameters before the start of and 2 weeks into therapy. Methods: A total of 232 children from Scandinavia, Germany or Italy, fulfilling diagnostic criteria and/or with familial disease and/or HLH-causing mutations, receiving HLH treatment 1994–2008 were included. The relation between clinical findings and early pre-transplant death was examined using the Cox proportional hazards model, with a 4-month right-truncation of the outcome. Patients were censored at last follow-up or transplant. Statistically significant predictors were adjusted for sex, age and each other. Results: The following features were significantly associated with adverse outcome: hyperbilirubinaemia (>50 μmol/L; adjusted hazard ratio (aHR) 3.2; 95% confidence interval 1.3–8.1, p = 0.011), hyperferritinaemia (>2000 μg/L; aHR 3.2; 1.2–8.6, p = 0.019), cerebrospinal fluid pleocytosis (>100 × 106/L; aHR 5.1; 1.4–18.5, p = 0.012) at diagnosis, and thrombocytopenia ( 2000 μg/L; aHR 10.6; 1.2–96.4, p = 0.037) 2 weeks into therapy. Non-improvement of fever, anaemia and/or thrombocytopenia also had adverse impact. Conclusion: There seem to be easily available clinical predictors of early mortality in HLH patients, which may help guide treatment decisions.

Aim To investigate the association between couples’ communication before the wife’s death to cancer and the widower’s feelings of guilt and regret after the loss, in a population-based data. Methods Men (n = 907) younger than 80 years and living in Sweden, who had lost their wives due to cancer, were asked 4–5 years after their loss to answer an anonymous postal questionnaire it included questions about the couple’s end-of-life communication during the last 3 months of life and the widower’s feelings of guilt or regret during the first 6 months after the wife’s death. Results During the last 3 months of their wives’ lives, men who had not talked about the impending death with their wives had a higher risk of experiencing feelings of guilt than men who did talk (relative risk (RR) 2.0, 95% confidence interval [CI] 1.2–3.4). Men who were not able to spend as much time as they wished with their wives had an increase in the risk of having feelings of guilt twice that of men who spent time (RR 2.0 95% CI 1.5–2.7). Men who did not talk with their wives about how they could cope practically or emotionally after the death had elevated risks of guilt feelings compared with men who talked (RR 1.8, 95% CI 1.0–3.0; RR 1.7, 95% CI 1.0–2.9, respectively). Men who realised it was too late to discuss the impending death had an increased risk of guilt feelings (RR 4.3, 95% CI 2.9–6.6). Men who thought that not everything had been brought to closure before their wives’ deaths had 3.3 times increased risk of guilt feeling (RR 3.3, 95% CI 1.7–6.4). Conclusions A man who does not have end-of-life discussions with his wife during the last 3 months before her death from cancer may be subject to a significantly greater risk of experiencing feelings of guilt or regret in widowhood than men who did engage in such discussions.

We have investigated whether hematopoietic stem cell transplantation (HSCT) before the death of children with cancer has a long-term effect on the physical and psychological well-being of the parents. A nationwide questionnaire was sent out to all bereaved parents in Sweden who had lost a child due to a malignancy from 1992 to 1997. Self-reported levels of anxiety, depression and quality of life as well as overall psychological and physical well-being in bereaved parents of children who underwent HSCT were compared with bereaved parents whose children did not receive a transplant. Bereaved parents whose children underwent HSCT had, according to a visual digital scale, an increased relative risk (RR) of long-term anxiety (RR 1.5; 95% confidence interval (CI) 1.0-2.1), poor psychological well-being (RR1.3; 95% CI 1.1-1.5), low quality of life (RR 1.4; 95% CI 1.2-1.7) and poor physical health (RR 1.3; 95% CI 1.1-1.5), whereas the State-Trait Anxiety Inventory and 'The Göteborg Quality of Life Instrument' were non-significantly increased (RR 1.3; 95% CI 0.8-2.3 and RR 1.7; 95% CI 0.9-3.3, respectively). The risks of these consequences were further augmented in case of multiple HSCT. We suggest that bereaved parents of children undergoing HSCT may be at greater risk of decreased psychological well-being than other bereaved parents of children with cancer.

Study Type - Preference (prospective cohort) Level of Evidence 4 OBJECTIVES: To describe and compare long-term defecation disturbances in patients who had undergone a cystectomy due to urinary blad ...

OBJECTIVES To determine whether or not an improved hygiene can lessen the incidence of symptomatic urinary tract infections (UTIs) in patients treated by cystectomy for urinary bladder cancer. PATIENTS AND METHODS We attempted to contact during their follow-up all men and women aged 30-80 years who had undergone cystectomy and urinary diversion at seven Swedish hospitals. During a qualitative phase we identified hygienic measures and included them in a study-specific questionnaire. The patients completed the questionnaire at home. Outcome variables were dichotomized and the results presented as relative risks (RR) with 95% confidence interval. RESULTS We received the questionnaire from 452 (92%) of 491 identified patients. The proportion of patients who had a symptomatic UTI in the previous year was 22% for orthotopic neobladder and cutaneous continent reservoir, and 23% for non-continent urostomy diversion. The RR for a UTI was 1.1 (0.5-2.5) for 'never washing hands' before handling with catheters or ostomy material. Patients with diabetes mellitus had a RR of 2.1 (1.4-3.2) for having a symptomatic UTI. CONCLUSIONS We could not confirm lack of hygiene measures as a cause of UTI for men and women who had a cystectomy with urinary diversion. Patients with diabetes mellitus have a greater risk of contracting a UTI.

Anxiety is contagious: symptoms of anxiety in the terminally ill chid affect long-term psychological well-being in bereaved parents

Background: If we can learn how to increase preparedness before the death of a loved one, we can possibly decrease the next-of-kin’s long-term morbidity. Methods: In a population-based study, 691 of 907 (76%) men in Sweden who lost a wife to cancer 4–5 years earlier answered an anonymous questionnaire about their preparedness at the time of their wife’s death as well as potential predictors for preparedness. Results: A final logistic regression model indicates following predictors for preparedness, among others: the length of the widower’s intellectual awareness time before his wife’s death [relative risk (RR) 4.1, confidence interval (CI) 2.7– 6.1], the widower could take in the information that his wife’s disease could not be cured (RR 3.5, CI 2.3–5.2), the couple had arranged their economical affairs (RR 1.5, CI 1.3–1.7), the wife had stayed at a palliative care unit during her last months of life (RR 1.2, CI 1.1–1.4) and health care personnel supported the husband to participate in his wife’s care (RR 1.6, CI 1.3–2.1). Conclusions: We identified several care-related factors that may influence the preparedness of men before their wife’s death to cancer. These factors can be considered in future intervention studies aiming at influencing preparedness before the death of a loved one.

To assess whether diagnostic random bladder biopsies and the detection of concomitant carcinoma in situ (CIS) have an impact on the frequency of intravesical bacille Calmette-Guérin (BCG) instillations or radical cystectomy; and whether this affects the cancer-specific survival in patients with pTaG3 or pT1G1-G3 transitional cell carcinoma of the urinary bladder.A population-based cohort of 538 patients with newly diagnosed bladder cancer was prospectively registered in the Stockholm County during 1995 and 1996 and followed for more than 5 years.Random biopsies were recommended in all patients but the decision to take biopsies was made by the treating urologist and hence performed in 326 out of 538 patients (61%), which revealed concomitant CIS in 47 patients(14%). Sixty out of 103 (58%) patients with pTaG3 or pT1G1-G3 tumours, in whom random biopsies were performed, received intravesical BCG compared with five out of 22 patients (23%) where random biopsies were not taken (p = 0.004). Moreover, 23 out of 103 patients (22%) with pTaG3 or pT1G1-G3 tumours in whom random biopsies were performed underwent radical cystectomy compared with none out of 22 patients (0%) without random biopsies (p = 0.013). The Cox proportional hazard ratio for death due to bladder cancer in patients with pTaG3 or pT1G1-G3 tumours among patients not having versus having undergone random biopsies was 2.5 (95% confidence interval 1.1-5.6).Patients diagnosed in Stockholm in 1995 or 1996 with pTaG3 or pT1G1-G3 bladder tumours having undergone random bladder biopsies more frequently underwent BCG treatment and radical cystectomy and had higher cancer-specific survival than patients who did not undergo random biopsies.

Background Quality-of-life outcomes are important in the choice of treatment strategy for men with localized prostate cancer. Objective To evaluate how follow-up time, number of physical symptoms, and presence of androgen deprivation affected quality of life among men randomized to radical prostatectomy or watchful waiting. Design, setting, and participants The study group was composed of all 376 living men included in the Swedish part of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) [1] between January 1, 1989, and February 29, 1996. Quality-of-life data were collected after a mean follow-up time of 4.1 yr. Intervention All patients were randomly assigned to radical prostatectomy or watchful waiting. Forty-five men were androgen deprived. Measurements Data of specific symptoms, symptom-induced stress, sense of well-being, and self-assessed quality of life were obtained by means of a questionnaire. Psychological symptoms were assessed using seven-point visual digital scales. Results and limitations In analyses stratified on the basis of the numbers of physical symptoms, anxiety and depressed mood were less common, and sense of well-being and self-assessed quality of life were better throughout in the radical prostatectomy group than in the watchful waiting group. As the number of physical symptoms increased, all psychological variables became worse and more prominent in the watchful waiting group. After a follow-up time of 6–8 yr, a significant decrease in quality of life ( p =0.03) was seen in the watchful waiting group. Twenty-four percent of androgen-deprived patients assigned to watchful waiting reported high self-assessed quality of life compared with 60% in the radical prostatectomy group. Eighty-eight percent of patients had clinically detected tumors. Conclusions Androgen deprivation negatively affected self-assessed quality of life in men assigned to watchful waiting. The number of physical symptoms was associated with the level of quality of life. Quality of life was lower with longer follow-up time in both groups and was statistically significant in the watchful waiting group ( p =0.03).

To investigate the effects of ileum resection in orthotopic neobladder construction on gastrointestinal function and metabolic control.We included 28 patients who underwent radical cystectomy and construction of an orthotopic neobladder or continent ileal reservoir for bladder cancer. As controls, 10 patients endoscopically treated for non-invasive bladder cancer (TaG2) were enrolled. Gastrointestinal symptoms, enterohepatic bile salt circulation, gastric emptying and gastrointestinal hormones involved in metabolic control were monitored.Of the cystectomy patients, 25% experienced daily diarrhoea and faecal urgency due to bile acid malabsorption, compared to 0% of the controls (p = 0.013). The cystectomy patients experienced faster gastric emptying and had higher levels of peptide YY. Plasma concentrations of insulin, glucagon-like peptide-1 and glucose were unchanged.Using the distal ileum for orthotopic neobladder construction causes bowel disorders in a quarter of cystectomy patients. Diarrhoea and faecal urgency are probably caused by decreased reabsorption of bile and are not due to changes in gastrointestinal hormones. A sizeable proportion of patients develop bile salt-induced diarrhoea, which can be relieved by treatment with cholestyramine.

Parental feelings of guilt can be a serious problem after the death of a child to a malignancy. This study identified predictors of feelings of guilt in parents during the year after a child's death.The Swedish Cause of Death Register and Swedish Cancer Register were used to identify all parents in Sweden who had a child who died of a malignancy between 1992-1997.Among parents not reporting recent depression, those who were not confident that their child would immediately receive help from the staff in the hospital while he or she was sick with a malignancy (compared to those who felt partly or entirely sure, relative risk [RR] 4.0; 95% confidence interval [CI] 2.1-7.6), were at increased risk for reporting daily or weekly feelings of guilt in the year after the child's death. Parents who perceived that the staff in the pediatric cancer ward were incompetent were at increased risk (compared to parents reporting partial or total competence, RR 3.7; 95% CI 1.6-8.6). Compared to parents reporting that their children had moderate or much access, those who felt their children had little or no access to pain relief, dietary advice, anxiety relief, and relief of other psychological symptoms beside anxiety were at more than two times greater risk for reporting feelings of guilt.Bereaved parents' perceptions of inadequate health care were associated with subsequent feelings of guilt during the year following their child's death due to a malignancy.

Purpose Palliative care is an important part of cancer treatment. However, little is known about how care-related factors affect bereaved intimates in a long-term perspective. We conducted a population-based, nationwide study addressing this issue, focusing on potential care-related stressors in parents losing a child to cancer. Methods In 2001, we attempted to contact all parents in Sweden who had lost a child to cancer in 1992 to 1997. The parents were asked, through an anonymous postal questionnaire, about their experience of the care given and to what extent these experiences still affect them today. Results Information was supplied by 449 (80%) of 561 eligible parents. Among 196 parents of children whose pain could not be relieved, 111 (57%) were still affected by it 4 to 9 years after bereavement. Among 138 parents reporting that the child had a difficult moment of death, 78 (57%) were still affected by it at follow-up. The probability of parents reporting that their child had a difficult moment of death was increased (relative risk = 1.4; 95% CI, 1.0 to 1.8) if staff were not present at the moment of death. Ten percent of the parents (25 of 251 parents) were not satisfied with the care given during the last month at a pediatric hematology/oncology center; the corresponding figure for care at other hospitals was 20% (33 of 168 parents; P = .0163). Conclusion Physical pain and the moment of death are two important issues to address in end-of-life care of children with cancer in trying to reduce long-term distress in bereaved parents.

Background. Some consider the loss of a child as the most stressful life event. When the death is caused by a malignancy, the parents are commonly exposed not only to their own loss, but also to the protracted physical and emotional suffering of the child. We investigated parental risk of anxiety and depression 4–9 years after the loss of a child owing to a malignancy.Method. In 2001, we attempted to contact all parents in Sweden who had lost a child due to a malignancy during 1992–1997. We used an anonymous postal questionnaire and utilized a control group of non-bereaved parents with a living child.Results. Participation among bereaved parents was 449/561 (80%); among non-bereaved 457/659 (69%). We found an increased risk of anxiety (relative risk 1·5, 95% confidence interval 1·1–1·9) and depression (relative risk 1·4, 95% confidence interval 1·1–1·7) among bereaved parents compared with non-bereaved. The risk of anxiety and depression was higher in the period 4–6 years after bereavement than in the 7–9 years period, during which the average excess risks approached zero. Psychological distress was overall higher among bereaved mothers and loss of a child aged 9 years or older implied an increased risk, particularly for fathers.Conclusions. Psychological morbidity in bereaved parents decreases to levels similar to those among non-bereaved parents 7–9 years after the loss. Bereaved mothers and parents who lose a child 9 years or older have on average an excess risk for long-term psychological distress.

To evaluate how an increasing burden of symptoms influences well-being, anxiety and depression at different intervals after a radical cystectomy with urostomy for bladder cancer, as this therapy can induce long-term distressful symptoms.Patients with bladder cancer undergoing radical cystectomy in Stockholm between 1969 and 1995 were matched with 434 controls from the normal population; all 404 patients operated on between 1985 and 1995 at three other hospitals in Sweden were invited to enter the study. The final analysis included 306 patients and 310 controls, all assessed for symptoms and well-being.A low or moderate level of well-being was reported by 35% of the patients having none or one of the symptoms studied, by 39% with two symptoms, by 45% with three symptoms and by 66% of those with four or more symptoms. The values, irrespective of symptom burden, were 45% after 2-5 years of follow-up, 58% after 6-10 years and 38% at10 years after surgery. The total symptom burden also influenced the risk of anxiety and depression. Symptom prevalence remained largely unaffected by the duration of follow-up, except for defecation urgency.The number of long-term symptoms after radical surgery with a urostomy for urinary bladder cancer affects the risk of anxiety, depression and low or moderate well-being.

Point mutations and single nucleotide polymorphisms (SNPs) in the CDKN2A gene in bladder cancer patients have been resolved only to a limited extent. The exact frequency of mutations remains uncertain and reports on SNPs are lacking. In this population-based study we investigated mutations and polymorphisms in the CDKN2A gene in bladder cancer patients from all hospitals within the Stockholm County. Mutations were determined in 4 exons of the CDKN2A gene in tumor-tissues from 172 bladder cancer patients and 2 single nucleotide polymorphisms in the 3′ UTR of the CDKN2A gene were studied in 309 cases. Missense mutations were identified in only 4 of 172 (2.3%) cases, including 1 in the germ-line. Frequencies of the 500 CG and 540 CT polymorphisms in the 3′ UTR of the CDKN2A in bladder cancer cases were not statistically significantly different compared to an ethnically matched control population. The tumor-specific survival was significantly shorter in patients with either the 500 CG or 540 CT polymorphism than those with wild-type CDKN2A gene (P = 0.02). Our results corroborate the earlier findings that single base mutation is not the prime mode of inactivation of the CDKN2A gene in bladder cancer. Further, the results indicate, a role for the 3′ UTR polymorphisms in the CDKN2A gene in tumor invasiveness. © 2002 Wiley-Liss, Inc.

The expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) mRNA was determined in 194 subjects with newly detected bladder neoplasms, selected from a larger population-based series. An association was found between uPA and uPAR expression (n = 172; Spearman rs = 0.60, p < 0.001). Both uPA and uPAR mRNA levels were higher in muscle invasive (T2+) tumors than in noninvasive mucosal tumors (Ta) or those invading submucosa (T1). The relative hazard ratios (RHRs) for cancer-specific death associated with elevated expression (95% CI), adjusted for age and gender in a Cox proportional hazard model, were 1.8 (1.0–3.3) for uPA (upper quartile cut-line), 2.2 (1.3–4.0) for uPAR (median quartile cut-line) and 2.5 (1.3–4.9) for uPA + uPAR. An RHR for metastatic disease of 4.0 (1.6–9.9) was observed for uPAR. Restricting the analyses to T2+ tumors, the corresponding figures were: 2.1 (1.1–3.9) for uPA, 1.6 (0.8–3.3) for uPAR and 2.5 (1.1–5.6) for both. We conclude that expression of uPA and uPAR is associated with the clinical behaviour of bladder neoplasms, possibly providing means for refined staging of muscle invasive tumors and target proteins for novel therapies. © 2002 Wiley-Liss, Inc.

Mutations in genes for perforin-dependent lymphocyte cytotoxicity are associated with haemophagocytic lymphohistiocytosis, a rare disease of severe hyperinflammation that typically becomes evident in early childhood. It has been suggested that individuals with hypomorphic biallelic mutations in genes associated with haemophagocytic lymphohistiocytosis are at increased risk of developing haematological malignancies. We aimed to assess whether relatives of patients with primary haemophagocytic lymphohistiocytosis (ie, heterozygous carriers of these mutated genes) were more likely to develop cancer.In this retrospective cohort study, we used a multigeneration registry to identify relatives (parents and grandparents) of 79 Swedish children (15 years) with primary haemophagocytic lymphohistiocytosis diagnosed between 1971 and 2011. For each relative, we randomly selected eight matched individuals from the Swedish total population registry, stratified for sex, birth year, and birth region. Relatives and matched controls were cross-linked with the Swedish Cancer Registry to establish cancer incidence rate. We then calculated the incidence rate ratio between first-degree and second-degree relatives and the matched controls. Additionally, we assessed natural-killer-cell-mediated cytotoxicity in a subgroup of first-degree relatives using standard 4 h (51)Cr assay and flow cytometry quantification of the upregulation of surface CD107a.We identified 346 first-degree and second-degree relatives from 67 families (67 mothers, 66 fathers, 106 grandmothers, and 107 grandfathers) and 2768 matched controls. Median follow-up was 49 years, range 0-54 years. By death or last follow-up (Dec 31, 2012), first-degree relatives had a significantly increased incidence rate of malignancies than did controls (incidence rate per 1000 person-years 2.78 [95% CI 1.42-4.15] vs 1.56 [1.16-1.95]; incidence rate ratio 1.79 [95% CI 1.06-3.03]; p=0.030). Mothers had a particularly increased risk (incidence rate per 1000 person-years 4.43 [95% CI 1.99-6.87] vs 1.60 [1.08-2.11]; incidence rate ratio 2.78 [95% CI 1.48-5.21]; p=0.0014), whereas no difference was found between fathers and controls (1.24 [0.00-2.51] vs 1.52 [0.89-2.15]; 0.82 [0.29-2.29]; p=0.70) or between grandparents and controls (7.24 [5.44-9.04] vs 6.36 [5.70-7.03]; 1.14 [0.88-1.48]; p=0.33). Functional analysis of heterozygous carriers of mutations associated with haemophagocytic lymphohistiocytosis could not show significantly reduced lymphocyte cytotoxicity.Heterozygous mutations in genes associated with haemophagocytic lymphohistiocytosis might be a new risk factor for cancer. The increased risk of cancer might imply haploinsufficiency of cytotoxic lymphocyte-mediated immunosurveillance of cancer in carriers of these mutations. Our findings might support intensified screening for malignancies in relatives of patients with haemophagocytic lymphohistiocytosis.Swedish Children's Cancer Foundation, Swedish Research Council, Histiocytosis Association, Swedish Cancer Society, Swedish Cancer and Allergy Foundation, Mary Béve Foundation, Karolinska Institutet Research Foundation, Stockholm County Council (ALF-project).

We studied the advice mothers with stillbirths were given concerning a suitable time to become pregnant. A questionnaire was sent in 2001 to mothers with a stillbirth at one of five hospitals in the Stockholm region in Sweden. At three months follow-up, 33 mothers participated and at 12 months 31. The advices varied from waiting one to 12 months. Eleven mothers were advised to trust their own feelings of readiness and six were advised to wait until they had dealt with their grief before becoming pregnant. At one year post-loss, most of the mothers felt that a suitable time for a subsequent pregnancy was as soon as the mother herself wanted. Mothers whose baby had died in utero were given radically different kinds of advice concerning a suitable time for a subsequent pregnancy. The best advice seems to be that the mother should wait until she, herself, feels ready.

Actions by health professionals and the atmosphere surrounding the birth of a stillborn baby may determine the nature of the mother's contact with her baby. A questionnaire studied mothers' feelings when holding their stillborn baby. A total of 33 mothers of stillborn babies born after 22 weeks completed the questionnaire three months after the birth. All mothers saw their baby. Before meeting the baby, 23 women had feelings of being afraid. Thirty-one mothers held their baby. When holding their baby all mothers felt tenderness and grief, 29 warmth and 25 prides. Fifteen mothers at the same time felt insecure when holding the baby, 12 had feelings of discomfort and 11 feelings of fear. A hypothesis for future investigations is that the more that a mother can be prepared for what is to come after birth, the better the chance that feelings of fear or discomfort can be diminished.

Background: It is not known whether or not delivering acupuncture triggers mechanisms cited as placebo and if acupuncture or sham reduces radiotherapy-induced emesis more than standard care. Methodology/Principal Findings: Cancer patients receiving radiotherapy over abdominal/pelvic regions were randomized to verum (penetrating) acupuncture (n = 109; 99 provided data) in the alleged antiemetic acupuncture point PC6 or sham acupuncture (n = 106; 101 provided data) performed with a telescopic non-penetrating needle at a sham point 2-3 times/week during the whole radiotherapy period. The acupuncture cohort was compared to a reference cohort receiving standard care (n = 62; 62 provided data). The occurrence of emesis in each group was compared after a mean dose of 27 Gray. Nausea and vomiting were experienced during the preceding week by 37 and 8% in the verum acupuncture group, 38 and 7% in the sham acupuncture group and 63 and 15% in the standard care group, respectively. The lower occurrence of nausea in the acupuncture cohort (verum and sham) compared to patients receiving standard care (37% versus 63%, relative risk (RR) 0.6, 95 % confidence interval (CI) 0.5-0.8) was also true after adjustment for potential confounding factors for nausea (RR 0.8, CI 0.6 to 0.9). Nausea intensity was lower in the acupuncture cohort (78% no nausea, 13% a little, 8% moderate, 1% much) compared to the standard care cohort (52% no nausea, 32% a little, 15% moderate, 2% much) (p = 0.002). The acupuncture cohort expected antiemetic effects from their treatment (95%). Patients who expected nausea had increased risk for nausea compared to patients who expected low risk for nausea (RR 1.6; Cl 1.2-2.4). Conclusions/Significance: Patients treated with verum or sham acupuncture experienced less nausea and vomiting compared to patients receiving standard care, possibly through a general care effect or due to the high level of patient expectancy. Original Publication:Anna Enblom, Mats Lekander, Mats Hammar, Anna Johnsson, Erik Onelov, Martin Ingvar, Gunnar Steineck and Sussanne Börjeson, Getting the Grip on Nonspecific Treatment Effects: Emesis in Patients Randomized to Acupuncture or Sham Compared to Patients Receiving Standard Care, 2011, PLOS ONE, (6), 3, .http://dx.doi.org/10.1371/journal.pone.0014766Licensee: Public Library of Science (PLoS)http://www.plos.org/

• To describe and compare long-term defecation disturbances in patients who had undergone a cystectomy due to urinary bladder cancer with non-continent urostomies, continent reservoirs and orthotopic neobladder urinary diversions.• During their follow-up we attempted to contact all men and women aged 30-80 years who had undergone cystectomy and urinary diversion at seven Swedish hospitals. • During a qualitative phase we identified defecation disturbances as a distressful symptom and included this item in a study-specific questionnaire together with free-hand comments. The patients completed the questionnaire at home. • Outcome variables were dichotomized and the results are presented as relative risks with 95% confidence interval.• The questionnaire was returned from 452 (92%) of 491 identified patients. Up to 30% reported problems with the physiological emptying process of stool (bowel movement, sensory rectal function, awareness of need for defecation, motoric rectal and anal function, straining ability). • A sense of decreased straining capacity was reported by 20% of the men and women with non-continent urostomy and 14% and 8% of those with continent reservoirs and orthotopic neobladders, respectively.• Of the cystectomized individuals 30% reported problems with the physiological emptying process of stool (bowel movement, sensory rectal function, awareness of need for defecation, motoric rectal and anal function, straining ability). • Those wanting to improve the situation for bladder cancer survivors may consider communicating before surgery the possibility of stool-emptying problems, and asking about them after surgery.

We studied the relation between unrelieved symptoms in terminally ill children and the psychological well-being in the bereaved parents 4-9 years after their loss.We contacted parents in Sweden who had lost a child to a malignancy 1992-1997. The parents were asked to assess symptoms affecting their child's well-being during his or her last month of life, and their own current psychological well-being.Altogether 449/561 (80%) eligible parents supplied information on 19 specific symptoms that may occur in children with a malignancy and how each of these symptoms had affected their child's well-being during his or her last month of life (not applicable, none, low, moderate, or severe). These results were linked to questions concerning the parents' self-assessed mental health. Parents of children who were affected by disturbed sleep also had increased risk to develop these symptoms; RR 2.0 [1.4-2.9] for depression, 1.8 [1.3-2.5] for anxiety, 1.5 [1.2-1.8] for decreased psychological well-being, and 1.5 [1.3-1.9] for decreased quality of life.Bereaved parents whose children were affected by anxiety or disturbed sleep due to anxiety or pain had an increased risk of long-term psychological morbidity. Reducing psychological complications in seriously ill children may also improve the psychological well-being in bereaved parents.

Purpose: To assess parents’ ability to absorb information that their child’s cancer was incurable and to identify factors associated with parents’ ability to absorb this information. Patients and Methods: An anonymous mail-in questionnaire study was performed as a population-based investigation in Sweden between August and October of 2001. 449 parents who lost a child to cancer 4–9 years earlier (response rate 80%) completed the survey. 191 (43%) of the bereaved parents were fathers and 251 (56%) were mothers. Results: Sixty percent of parents (n = 258) reported that they were able to absorb the information that their child’s illness was incurable. Parents were better able to absorb this information when the information was given in an appropriate manner (RR 1.6; CI 1.3–2.0), when they shared their problems with others during the child’s illness course (RR 1.4; CI 1.1–1.8) and when they had no history of depression (RR 1.3; CI 1.0–1.8). Parents who reported that they were able to absorb the information were more likely to have expressed their farewells to the child in their desired manner (RR 1.3; CI 1.0–1.5). Conclusions: Parents who received information that their child’s illness was incurable in an appropriate manner are more likely to absorb that information. Whether or not parents are able to absorb the information that their child’s cancer is incurable has implications in terms of preparation for the child’s impending death.

Aim To investigate if a cancer patient’s unrelieved symptoms during the last 3 months of life increase the risk of long-term psychological morbidity in the surviving widower. Methods Men (n = 907) younger than 80 years and living in Sweden, who had lost their wives due to cancer, were asked 4–5 years after their loss to answer an anonymous postal questionnaire that included questions about their current psychological morbidity and their wives’ unrelieved symptoms during the last 3 months of life. Results If the wife suffered unrelieved anxiety or pain during the last 3 months of her life, then the widowers had a higher risk of sleep-related problems 4–5 years after the loss. When the wife had suffered from anxiety, the relative risks (RR) for the widowers’ sleep-related problems were: difficulty falling asleep (RR 1.7, 95% CI 1.0–3.0) and waking up at night with anxiety (RR 4.9, 95% CI 1.5–15.7). When the wife had unrelieved pain, the widowers years later had an increased risk of difficulty falling asleep at night (RR 1.8, 95% CI 1.0–3.3). Conclusions The unrelieved patients’ end-of-life problems increase the risk of widowers’ long-term mental suffering. Efficient and effective diagnoses and treatment of pain and anxiety in terminally ill cancer patients are critical for both patients and their surviving widowers.

PurposeTo assess unresolved parental grief, the associated long-term impact on mental and physical health, and health service use.Patients and MethodsThis anonymous, mail-in questionnaire study was performed as a population-based investigation in Sweden between August 2001 and October 2001. Four hundred forty-nine parents who lost a child as a result of cancer 4 to 9 years earlier completed the survey (response rate, 80%). One hundred ninety-one (43%) of the bereaved parents were fathers, and 251 (56%) were mothers. Bereaved parents were asked whether or not, and to what extent, they had worked through their grief. They were also asked about their physical and psychological well-being. For outcomes of interest, we report relative risk (RR) with 95% CIs as well as unadjusted odds ratios and adjusted odds ratios.ResultsParents with unresolved grief reported significantly worsening psychological health (fathers: RR, 3.6; 95% CI, 2.0 to 6.4; mothers: RR, 2.9; 95% CI, 1.9 to 4.4) and physical health (fathers: RR, 2.8; 95% CI, 1.8 to 4.4; mothers: RR, 2.3; 95% CI, 1.6 to 3.3) compared with those who had worked through their grief. Fathers with unresolved grief also displayed a significantly higher risk of sleep difficulties (RR, 6.7; 95% CI, 2.5 to 17.8). Mothers, however, reported increased visits with physicians during the previous 5 years (RR, 1.7; 95% CI, 1.1 to 2.6) as well as a greater likelihood of taking sick leave when they had not worked through their grief (RR, 2.1; 95% CI, 1.2 to 3.5).ConclusionParents who have not worked through their grief are at increased risk of long-term mental and physical morbidity, increased health service use, and increased sick leave.

Feelings of guilt are common after bereavement. We investigated whether feelings of guilt after the loss of a husband to cancer are associated with the health care provided at the time close to and at the moment of death.The study population consisted of 506 widows of men who died of prostate cancer in 1995 or of urinary bladder cancer in 1995 or 1996 at the ages 45-74 years. We collected information on the received health care at the time of the husband's death from the widows, through a postal questionnaire.Widows who perceived that their husbands did not get enough pain relief had an increased relative risk of 1.7 (95% CI 1.1-2.8), for guilt feelings, compared to widows who felt that their husbands had adequate pain relief. If a widow considered her husband being exposed to less satisfactory care or treatment, she had an almost two-fold increased relative risk, 1.9 (95% CI 1.2-3.1), for guilt feelings after the husband's death, compared to a widow who thought that satisfactory care or treatment was provided.Feelings of guilt after bereavement may occur in response to the perception of inadequate health care during the last months and at the actual moment of death of the significant other.

Purpose It is still uncertain whether or not parents can ever come to terms with the loss of a child and whether professional or social support facilitate the long-term grief process. Methods A Swedish population-based study, which sent an anonymous, mail-in questionnaire to parents who had lost a child to a malignancy 4 to 9 years earlier, gained the participation of 449 (80%) of 561 parents. Parents were asked whether, and to what extent, they had worked through their grief. Questions were also asked regarding those who provided parents with support. We examined candidate factors to determine their associations with greater likelihood of working through parental grief. Results Overall, most parents (74%) stated that they had worked through their grief “a lot” or “completely” at the time of the follow-up. Parents who had shared their problems with others during the child's illness (fathers: relative risk [RR], 3.0; 95% CI, 1.8 to 5.0; mothers: RR 1.9; 95% CI, 1.2 to 2.8) and who had access to psychological support during the last month of their child's life (fathers: RR 1.4; 95% CI, 1.0 to 1.8; mothers: RR 1.3; 95% CI, 1.1 to 1.6) were more likely to have worked through their grief. In cases where health care staff offered parents counseling during the child's last month, the parents were more likely to have worked through their grief (fathers: RR 1.5; 95% CI, 1.2 to 1.8; mothers; RR 1.2; 95% CI, 1.1 to 1.4). Conclusion Most parents eventually work through the grief associated with losing a child to cancer. In the long term, sharing the emotional burden with others facilitates the grieving process.

We investigated the feasibility of using single-item visual-digital scales for measuring anxiety and depression for research purposes within the oncology and palliative care setting. Data were retrieved from five nationwide postal questionnaires comprising 3030 individuals (response rate 76%): cancer patients, widows/parents who had lost their husband/child to cancer and population controls. All questionnaires contained the Center for Epidemiological Studies Depression scale (CES-D) and Spielberger's State-Trait Anxiety Inventory (STAI-T) as well as seven-point Visual-Digital Scales (VDS) assessing anxiety and depression. Each stepwise increased score on the VDS-depression provided a statistically significant increase in the mean score on CES-D (Spearman's r=0.582). The VDS-anxiety correlated with mean scores on STAI-T (Spearman's r=0.493), however, not all stepwise increased scores on the VDS-anxiety gave a statistically significant increase on the STAI-T. Positive- and negative predictive values were 51% and 91% for VDS-depression and 64% and 80% for VDS-anxiety. Missing data for STAI-T were 7% and 9% for CES-D; the corresponding figures were 2% for the VDS-depression and 3% for VDS-anxiety. With low attrition and agreement with psychometric scales, the Visual-Digital Scales are a feasible alternative for research in the oncology setting. However, the high negative predictive value and the low positive predictive value suggest that the visual- digital scales mainly detect the absence of the symptoms.

Summary Background We aimed to study care-related determinants of when parents gain awareness of their child's impending death to cancer, and whether the duration of this awareness affects the parents' long-term morbidity. Methods Between August 2001 and October 2001, 449 of 561 (80%) parents who had lost a child due to any malignancy in Sweden between Jan 1, 1992, and Dec 31, 1997 (identified on the Swedish Causes of Death Register), answered a 365-item postal questionnaire designed to ascertain when, before the child's actual death, they had become intellectually and emotionally aware of the child's impending death (awareness time). The primary endpoints were intellectual awareness time (defined as time between intellectual realisation that a disease is fatal and the actual time of death) and emotional awareness time (defined as time between emotional realisation that a disease is fatal and the actual time of death). Parents' awareness of less than 24 h was referred to as a short awareness time. Findings 436 parents answered the question about intellectual awareness and 433 parents answered the question about emotional awareness. 112 parents (26%) reported a short intellectual awareness time and 195 parents (45%) reported a short emotional awareness time. The risk of having short intellectual awareness time was increased if parents had absence of information on their child's fatal condition (mothers relative risk [RR] 3·6 [95% CI 2·3–5·5]; fathers 2·9 [1·8–4·5]) and if curative treatment was used towards the end of life (mothers 4·1 [2·6–6·5]; fathers 2·7 [1·7–4·2]). The risk of short emotional awareness time was increased if parents had absence of information indicating the child would die (mothers 1·5 [1·1–2·0]; fathers 1·8 [1·3–2·5]) and absence of talks about death with the other parent (mothers 1·5 [1·1–2·0]; fathers 1·7 [1·2–2·2]). Compared with fathers who had longer emotional awareness time, fathers with short emotional awareness time had an increased risk of depression (adjusted RR 1·8 [1·0–3·3]) and absence from employment due to sick leave or early retirement (RR 8·5 [1·1–67·8]) at follow-up. This difference was not noted for mothers. Interpretation Health-care professionals can influence parents' intellectual and emotional awareness of a child's impending death due to cancer. Short emotional awareness increases the risk of long-term depression in bereaved fathers.

The 9p21 locus is a major target in the pathogenesis of human urinary bladder cancer. This locus harbours the CDKN2A/ARF tumour suppressor gene, which encodes two cell-cycle regulatory proteins: p16INK4a and p14ARF. We studied how homozygous deletions and multiple duplications at this locus affect prognosis and survival in patients with bladder cancer.Real-time quantitative polymerase chain reaction (QPCR), based on simultaneous amplification of ARF and a reference gene, glyceraldehyde-3-phosphate dehydrogenase, was used to measure homozygous deletions and multiple duplications in a population-based material consisting of 478 patients with urinary bladder cancer. Results from real-time QPCR were compared with clinico-pathological parameters and survival curves were generated using the Kaplan-Meier method.Real-time QPCR analysis showed 71 (15%) homozygous deletions and 8 (2%) multiple duplications. We were unable to find any association between either stage or grade and urinary neoplasms with homozygous deletions. However, although there were only a limited number of patients with multiple duplications, 7/8 of them had highly malignant tumours (G2b-G4 oror = T1; p = 0.02).Urinary bladder cancers constitute a spectrum of neoplasms with varying clinical manifestations. We were unable to establish a prognostic relevance for patients with tumours harbouring homozygous deletions at the CDKN2A/ARF locus. However, our data did indicate that patients with multiple duplications at the CDKN2A/ARF locus had poor survival. This suggests that multiple duplications, in combination with other genetic changes, have cooperative effects which have a negative outcome on urinary bladder cancer prognosis.

In this population-based study, we found that parents who are aware that their child will die from a malignancy are more likely to care for their child at home during the child’s last month of life compared to parents who are not aware. End-of-life home care was comparable to hospital care for satisfactory pain relief, access to pain relief and access to medications for other physical symptoms. Using an anonymous postal questionnaire, we obtained information from 449 parents in Sweden who had lost a child due to a malignancy between 1992 and 1997, 4 to 9 years before participating in our study. The prevalence of dying at home and being cared for at home during the last month of life was 23.7% when parents realized intellectually more than 1 month in advance that the child would die (versus 12% who did not), 28.7% for parents who sensed that the child was aware of his or her imminent death (versus 7.8% who did not sense this) and 21.9% for those who received information that the child’s illness was incurable (versus 9.4% who did not receive the information). Prevalence of children’s unrelieved pain was 11.6% for those receiving home care and 15.3% for those receiving care outside the home.

OBJECTIVE To evaluate whether the single nucleotide polymorphism (SNP), Asp1104His (G3507C), in the XPG gene affects malignant phenotypes of nonmuscle-invasive urinary bladder neoplasms (NIBN), by investigating associations between the SNP and clinicopathological variables in patients with NIBN. PATIENTS AND METHODS The 233 patients constituted newly diagnosed cases of primary NIBN in the Stockholm area. The Asp1104His polymorphism in the XPG gene was genotyped using a polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS The GC + CC genotypes were more frequent in stage pT1 tumours at initial diagnosis than pTa (odds ratio 1.9, 95% confidence interval 1.0–3.5, P = 0.048). The difference was larger in the young group (4.6, 1.9–11.8, P = 0.001). In the young group, the GC + CC genotypes were significantly more frequent in high-grade than in low-grade tumours (3.1, 1.5–6.8, P = 0.004) whereas in the older group the genotypes were less frequent in high-grade tumours (0.3, 0.1–0.7, P = 0.007). The XPG genotypes were not associated with tumour recurrence, stage progression or survival. CONCLUSION These results suggest that the SNP in the XPG gene might be related to tumour invasiveness in NIBN.

Objectives A patient with newly diagnosed localized prostate cancer can choose from an array of therapies. A patient's willingness to trade life for freedom from therapy-induced long-term symptoms is poorly investigated. Methods In October 2002, we attempted to collect information from the 591 men who had been diagnosed and registered with prostate cancer in 1999 in Stockholm County. In a postal questionnaire, men were asked to balance absence or presence of certain therapy-induced long-term symptoms against varying lengths of survival gain as a consequence of the therapy. Results Information was provided by 511 (86%) of the 591 men. A large majority of the men participating in this study ended up in one of two extreme categories: either they accepted the therapy-induced symptom to gain survival or they did not. For fecal leakage, 78% of the men chose one of two extreme categories compared with 74% for urinary leakage, 71% for tender enlarged breasts, 73% for erectile dysfunction, and 78% for restricted diet. Thirty-seven percent of the men in the study were willing to accept fecal leakage if there was only the slightest chance to gain survival, comparing percentages for urinary leakage, tender enlarged breasts, restricted diet, and erectile dysfunction and were 48%, 53%, 55%, and 64%, respectively. Conclusion Willingness to accept therapy-induced long-term symptoms to avoid a shortened survival due to prostate cancer varies dramatically among men with localized prostate cancer and a large majority of men are in one of two extreme categories. Among symptoms, long-term fecal leakage was the one fewest men were willing to accept to gain survival.

BACKGROUND One of the questions faced by the parents of a child who is terminally ill with a malignant disease is whether or not they should talk about death with their child. METHODS In 2001, we attempted to contact all parents in Sweden who had lost a child to cancer between 1992 and 1997. Among 561 eligible parents, 449 answered a questionnaire, and 429 stated whether or not they had talked about death with their child. RESULTS None of the 147 parents who talked with their child about death regretted it. In contrast, 69 of 258 parents (27 percent) who did not talk with their child about death regretted not having done so. Parents who sensed that their child was aware of his or her imminent death were more likely to regret not having talked about it (47 percent, as compared with 13 percent of parents who did not sense this awareness in their child; relative risk, 3.7; 95 percent confidence interval, 2.3 to 6.0). The same variable was related to having talked about death (50 percent vs. 13 percent; relative risk, 3.8; 95 percent confidence interval, 2.6 to 5.6), as was being religious (42 percent vs. 25 percent; relative risk, 1.7; 95 percent confidence interval, 1.2 to 2.3). The child's age was related to both having talked about death and the parents' regretting not having talked about it. CONCLUSIONS Parents who sense that their child is aware of his or her imminent death more often later regret not having talked with their child than do parents who do not sense this awareness in their child; overall, no parent in this cohort later regretted having talked with his or her child about death.

To describe in detail the diagnosis and clinical course of an unselected population-based cohort of patients with newly diagnosed bladder neoplasms.A total of 538 patients registered in the Stockholm region with newly diagnosed primary bladder neoplasms (transitional cell carcinomas) in 1995 and 1996 were followed for at least 5 years. All hospitals and urology units in the region participated in the study. Treatment and follow-up were performed according to a standard-of-care programme. Routine pathological reports were used. Original case records were scrutinized on location in 2001. In addition, a tumour bank of freshly frozen tumour tissue was established.The calculated 5-year cancer-specific survival rate for the 538 patients in the cohort was 78%. No patient (0/29) with TaG1 tumours showed progression or died of bladder cancer. Only 2/187 patients (1%) with stage Ta and grade 2A or 2B tumours died of bladder cancer. In contrast, after 5 years of follow-up, patients with TaG3 and T1G2B tumours had disease-specific death rates of 20% and 27%, respectively. The result of the first cystoscopy examination after the initial resection of non-invasive tumours was of prognostic value. Recurrent disease was present in 62% (248/402) of all patients with Ta and T1 tumours at diagnosis and patients with T1 tumours had recurrences earlier than those with Ta tumours. Moreover, 32% (35/110) of the patients who presented with T1 tumours at diagnosis progressed to muscle-invasive disease during the follow-up period. The overall prognosis for patients presenting with muscle-invasive tumours (T2+) was dismal, with 69% (80/116) of the patients dying of the disease.We analysed a population-based cohort of patients with urinary bladder neoplasms in order to establish a clearly defined and unselected clinical series, with the main aims of comparing and evaluating the clinical utility of new molecular biology techniques. In the present series, TaG1 tumours behaved benignly. The disease-specific mortality rate was low for initial TaG2 tumours, intermediate for initial TaG3 and T1 tumours and high for initial T2+ tumours.

The influence of specific symptoms on emotions and social activities in the individual patient varies. Little is known about this variation in urinary bladder cancer survivors (in other words, about the relative importance of sources of symptom-induced distress).We attempted to enroll 404 surgical patients treated with cystectomy and a conduit or reservoir in four Swedish towns (Stockholm, Orebro, Jönköping, Linköping), 101 surgical patients treated with cystectomy and orthotopic neobladder at the Herlev Hospital in Copenhagen, Denmark, and 71 patients treated with radical radiotherapy for bladder cancer, as well as 581 men and women controls in Stockholm and Copenhagen. An anonymous postal questionnaire was used to collect the information.A total of 503 out of 576 (87%) treated patients and 422 out of 581 (73%) controls participated but 59 patients were excluded. The primary source of self-assessed distress among cystectomised patients was compromised sexual function; reduced intercourse frequency caused great distress in 19% of the conduit patients, 20% of the reservoir patients and 19% of the bladder substitute patients. The primary source of self-assessed distress in patients treated with radical radiotherapy was symptoms from the bowel; 17% reported great distress due to diarrhoea, 16% due to abdominal pain, 14% due to defecation urgency and 14% due to faecal leakage. The highest proportion of subjects being distressed was 93% (substantial: 43%, moderate: 29% and little: 21%) for treated upper or lower urinary retention (indwelling catheter or nephrostomy).The distress caused by a specific symptom varies considerably and the prevalence of symptoms causing great distress differs between treatments in bladder cancer survivors. It is possible that patient care and clinical research can be made more effective by focusing on important sources of symptom-induced distress.

Objective: To investigate whether the previously reported association between IL-1α mRNA levels and survival in urinary bladder cancer remains in an extended patient material and to search a mechanism behind a possible antitumoral activity of IL-1α. Patients and Methods: IL-1α mRNA levels were determined in 164 tumors with quantitative TaqMan PCR. Results: A large variation was found in mRNA levels of IL-1α. We found, by immunohistochemistry, that IL-1α is expressed by tumor rather than stromal cells. In a univariate Cox proportional hazards model, low levels (median split) of IL-1α mRNA were associated with a relative hazard ratio (RHR) of 1.7 (95% CI: 1.0–2.9) for cancer-specific death ( n =157); a restriction to muscle invasive tumors ( n =63) resulted in an RHR of 1.8 (0.9–3.3). In bivariate analyses, adjustment for age, stage and grade respectively, decreased the RHR and the association between IL-1α expression and cancer-specific survival was not statistically significant. Which factors to regard as confounders remains unclear. Conclusions: Low levels of IL-1α mRNA expression are associated with an increased risk for cancer-specific death in the investigated material. However, confounding is an issue and to determine whether or not the observed association is causal, we need a defined mechanism and data from other studies.

Point mutations and single nucleotide polymorphisms (SNPs) in the CDKN2A gene in bladder cancer patients have been resolved only to a limited extent. The exact frequency of mutations remains uncertain and reports on SNPs are lacking. In this population-based study we investigated mutations and polymorphisms in the CDKN2A gene in bladder cancer patients from all hospitals within the Stockholm County. Mutations were determined in 4 exons of the CDKN2A gene in tumor-tissues from 172 bladder cancer patients and 2 single nucleotide polymorphisms in the 3' UTR of the CDKN2A gene were studied in 309 cases. Missense mutations were identified in only 4 of 172 (2.3%) cases, including 1 in the germ-line. Frequencies of the 500 C--G and 540 C--T polymorphisms in the 3' UTR of the CDKN2A in bladder cancer cases were not statistically significantly different compared to an ethnically matched control population. The tumor-specific survival was significantly shorter in patients with either the 500 C--G or 540 C--T polymorphism than those with wild-type CDKN2A gene (P = 0.02). Our results corroborate the earlier findings that single base mutation is not the prime mode of inactivation of the CDKN2A gene in bladder cancer. Further, the results indicate, a role for the 3' UTR polymorphisms in the CDKN2A gene in tumor invasiveness.

The expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) mRNA was determined in 194 subjects with newly detected bladder neoplasms, selected from a larger population-based series. An association was found between uPA and uPAR expression (n = 172; Spearman r(s) = 0.60, p0.001). Both uPA and uPAR mRNA levels were higher in muscle invasive (T2+) tumors than in noninvasive mucosal tumors (Ta) or those invading submucosa (T1). The relative hazard ratios (RHRs) for cancer-specific death associated with elevated expression (95% CI), adjusted for age and gender in a Cox proportional hazard model, were 1.8 (1.0-3.3) for uPA (upper quartile cut-line), 2.2 (1.3-4.0) for uPAR (median quartile cut-line) and 2.5 (1.3-4.9) for uPA + uPAR. An RHR for metastatic disease of 4.0 (1.6-9.9) was observed for uPAR. Restricting the analyses to T2+ tumors, the corresponding figures were: 2.1 (1.1-3.9) for uPA, 1.6 (0.8-3.3) for uPAR and 2.5 (1.1-5.6) for both. We conclude that expression of uPA and uPAR is associated with the clinical behaviour of bladder neoplasms, possibly providing means for refined staging of muscle invasive tumors and target proteins for novel therapies.