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  • 1.
    Adolfsson, Per I.
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Ahlstrand, Christer
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Hultgren, Sitti
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Svensson, Samuel P. S.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Characterization of EDG receptor expression and proliferative response in cultured human BPH smooth muscle cellsManuscript (preprint) (Other academic)
    Abstract [en]

    The endogenous phospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are both known to generate a Vvide variety of effects in various cell systems by the endothelial differentiation gene (Edg) receptor family, including 7 different G-protein coupled Edg receptors.

    In this study, expression of LPA- and SlP Edg receptors was examined, and so was the effect with respect to proliferation on cultured BPH smooth muscle cells smc. Mmeover, theresponse on cAMP levels was examined. Finally, a potential link between activation of the MAP kinase cascade and the LPA stimulated proliferation was investigated.

    First, the RT-PCR analysis of the Edg receptors in BPH smc, demonstrated a heterogeneous expression including all receptors except the Edg6 subtype. Further, in contrast to LPA, the mitogen effect of SIP, demonstrated a concentration-dependent biphasic response, including stimulation below 1μM, whereas inhibition was obtained at higher concentrations. Forskolin induced a rapid and transient cAMP response in LPA stimulated cells, with a peak-value after 3 minutes. After 15 minutes the cAMP level had retmned to base-line level. However a gradual increase to 15% of maximum value was obtained after additional 30 minutes, and thereafter a gradual reduction was observed. The mentioned antiproliferative response generated by SIP could not be conelated to an intracellular cAMP increase. Finally, when the LPA treated smc was co-incubated with the MAPK kinase inhibitor PD98059 (10 μM) the mitogen response was eliminated.

    The cAIVIP increase, which was induced by forskolin, corresponds with mentioned antiproliferative effect whereas a similar con-elation was not obtained regarding SIP. The intracellular signal mechanisms triggered by LPA and S1P in BPH smc remain to be further investigated.

  • 2.
    Eriksson, Per
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Renal disease in primary Sjögren's syndrome1996Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Primary Sjögren's syndrome (SS) is characterised by inflammation in the lacrimal and salivary glands. The kidneys may be involved, e.g. tubulointerstitial nephritis (TIN) and distal renal tubular acidosis (dRTA). dRTA is often associated with hypocitraturia, and both represent risk factors for the development of urolithiasis. The present investigations were undertaken to evaluate renal tubular function (including -dRTA), glomerular filtration rate (GFR), renal histopathology and mechanisms of stone formation, as well as the serum IgG subclass pattern in patients with SS. Furthermore, patients presenting with urolithiasis and dRTA in absence of sicca symptoms, as well as patients with urolithiasis andhypocitraturia, were studied with respect to autoantibodies and clinical features of SS.

    Renal tubular dysfunction, such as dRTA; impaired urine concentrating ability; hypocitraturia; and decreased tubular reabsorption of phosphate (1RP%), was conunonly detected in the SS-patients. Tubular proteinuria (al-microglobulin) and tubular enzymuria (NAG) were primarily associated with decreased GFR.

    GFR, investigated with 5Icr-EDTA plasma clearance, was below the reference limit in 33% of SS-patients. An inverse correlation was found between GFR and the extent of tubulointerstitial nephritis (adjusted CTIN score). Decreased GFR was mostly due to TIN, although urolithiasis and upper urinary tract infections may have contributed in some patients.

    TIN was demonstrated in most biopsied patients with SS, and the histopathological picture was characterised by mainly focal interstitial inflanunation, tubular atrophy, interstitial fibrosis and a varying extent of glomerular sclerosis.

    Fourty-one percent of the SS-patients had formed at least one stone, and calcium phosphate was the main constituent in most stones. All stone formers had dRTA, and most of them had hypocitraturia. Urinary calcium and urate excretion was also significantly higher than in non-stone formers.

    The SS-patients often had low serum levels of IgG2, despite high levels of total IgG. Low levels of IgG2 were sometimes associated with infections. A high IgG lngG2 ratio indicated autoimmune disease.

    Of 10 patients presenting with urolithiasis and dRTA, anti-SS-A antibodies were detected in eight. Subjective sicca symptoms subsequently developed l-48 years after the presentation of urolithiasis, and objective signs of SS were found in 7 patients.

    In a large population of hypocitraturic stone formers, ANA and anti-SS-A antibodies were commonly detected in the women but not in the men. Four of 14 evaluated hypocitraturic women with anti-SS-A antibodies or ANA, fulfilled the criteria for SS.

    In conclusion, the present investigations show that 24-hour urinary excretion of citrate is a valuable tool for detection of renal disease in SS, slightly-moderately decreased GFR is not unusual in SS-patients with. renal disease, the "adjusted CTIN score" can be a useful tool for quantifying the extent of tu'bulointerstitial nephritis, and the urine composition in stone formers with SS is similar to that of other dRT A-patients.

    The possibility of a Sjögren-related renal disease charcterised by urolithiasis and/or dRTA and antibodies to SS-A, regardless of whether subjective sicca symptoms are present or not, is hypothesised.

  • 3.
    Fjellstedt, Erik
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Clinical and genetic studies on patients with cystinuria2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cystinuria is a genetic disorder with autosomal recessive inheritance. It is caused by a defective proximal tubular reabsorbtion of cystine and the dibasic amino acids. The low urinary solubility of cystine causes a life-long stone disease, contributing to about 1% of all urinary stones in adults. Treatment is based on high fluid intake and the use of sulfhydryl compounds such as tiopronin and D-penicillamine to decrease the urinary concentration of cystine, and alkalinization of the urine to increase the urinary solubility of cystine. Reduction of sodium intake is also a favoured regimen because of eo-transportation of sodium and cystine in the proximal tubules. Advancements in molecular genetics have led to the identification of two genes associated with cystinuria (SLC3A1 and SLC7A9). These genes cannot, however, explain all cases of cystinuria.

    Investigation of SLC3A1 in 53 Swedish patients with cystinuria revealed 12 novel mutations, and the allelic frequency of the most common mutation (M467T) was shown to be 0.5% in a normal population. (Paper I). Studies of SLC7A9 revealed three novel and one previously known mutation. One patient had novel mutations in both alleles, one patient showed a novel mutation in one of the alleles and one patient showed a previously known mutation in SLC7A9 and two in SLC3A1, leaving 14 patients in whom cystinuria was not explained by genetic observations (Paper m. In order to relate these genetic findings to excretion of cystine in the urine, 33 patients treated with sulfhydryl compounds were studied (Paper III). Ten of these patients showed either mutation in one of the SLC3A1 alleles (8) or a complete lack of mutations in both genes (2). These 10 patients showed a significantly higher urinary excretion of total cystine compared to 23 patients in whom both SLC3A1 alleles were mutated (p < 0.01). The same was true for the 8 patients with only one SLC3A1 allele mutated (p < 0.05). These findings support the existence of yet unknown genes involved in the regulation of urinary cystine excretion, the basis of cystine stone formation. Treatment is primarily aimed at the prevention of such stones and should be guided by the urinary cystine concentration, trying to avoid supersaturation. In order to improve patient surveillance in terms of urinary supersaturation with cystine a procedure was introduced comprising one daytime and one night urine sample during the 24-hour period (Paper IV). Twenty-six patients were followed over a 3.5 year period using this strategy. It was found that 47% of cystine supersaturation episodes (> 1200 µmol/L) would have evaded detection by analysis carried out in 24-hour urine collections. Furthermore, a significant decrease in the frequency of renal stone episodes (p < 0.05) and active stone removals (p < 0.01) was found when compared to a previous, equivalent period during which 24-hour urine collections were used. The period guided by divided urine samples was also characterized by a significant decrease in free cystine concentrations (p < 0.01) and a significant increase in urinary volumes (p < 0.05). In the tiopronin-treated patients, there was a significant increase in the tiopronin dose and a subsequent decrease in urinary cystine excretion (p < 0.05). The use of cystine analysis in divided urine samples thus made a higher degree of individual treatment possible. The effects of sodium bicarbonate and potassium citrate were compared in 14 cystinuric patients (Paper V). Potassium citrate has been the favoured agent, as it does not contain sodium, but there have been no reports in which potassium citrate has been compared to sodium bicarbonate in the treatment of patients with cystinuria. Sodium bicarbonate was effective in alkalizing the urine, but caused a significantly increased urinary sodium excretion (p < 0.01). A significant correlation was found between urinary sodium and cystine excretion in tiopronin treated patients (p < 0.001). Potassium citrate was shown to produce a significant increase in urinary pH. Potassium citrate was associated with a significant increase in plasma potassium (p < 0.05), but no case of severe hyperkalemia was found. Potassium citrate could thus be recommended for urinary alkalinization in cystinuric patients without severe renal impairment.

    List of papers
    1. Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients
    Open this publication in new window or tab >>Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients
    Show others...
    2001 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 18, no 6, p. 516-525Article in journal (Refereed) Published
    Abstract [en]

    Cystinuria is an autosomal recessive disorder that affects luminal transport of cystine and dibasic amino acids in the kidneys and the small intestine. Three subtypes of cystinuria can be defined biochemically, and the classical form (type I) has been associated with mutations in the amino acid transporter gene SLC3A1. The mutations detected in SLC3A1 tend to be population specific and have not been previously investigated in Sweden. We have screened the entire coding sequence and the intron/exon boundaries of the SLC3A1 gene in 53 cystinuria patients by means of single strand conformation polymorphism (SSCP) and DNA sequencing. We identified 12 novel mutations (a 2 bp deletion, one splice site mutation, and 10 missense mutations) and detected another three mutations that were previously reported. Five polymorphisms were also identified, four of which were formerly described. The most frequent mutation in this study was the previously reported M467T and it was also detected in the normal population with an allelic frequency of 0.5%. Thirty-seven patients were homozygous for mutations in the SLC3A1 gene and another seven were heterozygous which implies that other genes may be involved in cystinuria. Future investigation of the non-type I cystinuria gene SLC7A9 may complement our results but recent studies also suggest the presence of other potential disease genes.

    Keywords
    cystinuria, CSNU, CNSU1, CNSU3, SLC3A1, SLC7A9, transporter, amino acid
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12855 (URN)10.1002/humu.1228 (DOI)
    Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2017-12-14Bibliographically approved
    2. Mutation analysis of SLC7A9 in cystinuria patients in Sweden
    Open this publication in new window or tab >>Mutation analysis of SLC7A9 in cystinuria patients in Sweden
    Show others...
    2003 (English)In: Genetic Testing, ISSN 1090-6576, E-ISSN 1557-7473, Vol. 7, no 1, p. 13-20Article in journal (Refereed) Published
    Abstract [en]

    Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas non-type I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12856 (URN)10.1089/109065703321560886 (DOI)
    Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2017-12-14Bibliographically approved
    3. Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds
    Open this publication in new window or tab >>Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds
    Show others...
    2003 (English)In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 31, no 6, p. 417-425Article in journal (Refereed) Published
    Abstract [en]

    Advances in molecular genetics have brought a deeper understanding of cystinuria. This autosomal recessive disease, which is caused by a defective tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine, results in a lifelong risk of renal stone formation because of the low solubility of cystine in urine. Mutations detected within the two genes known to be associated with cystinuria, SLC3A1 (related to type I) and SLC7A9 (related to non-type I), cannot, however, in all cases explain the disease. Inasmuch as a high urinary concentration of cystine is the basis of stone formation in these patients, our aim was to measure urinary total cystine, arginine, lysine and ornithine, in patients currently lacking a full genetic explanation for their disease. Thirty-three patients with cystinuria who were on long-term treatment with tiopronin or D-penicillamine were divided into two groups. Group 1 comprised eight patients who carried mutation in one of the SLC3A1 alleles and two patients who completely lacked mutations both in the SLC3A1 and the SLC7A9 genes, that is genetic findings discordant with the increased urinary excretion of cystine and the dibasic amino acids in these patients. Group 2 comprised 23 patients homozygous for mutations within SLC3A1, that is genetic findings in accordance with the excretion pattern of classic type I cystinuria. When the two groups were compared, Group 1 had a significantly higher total urinary excretion of cystine (p<0.01) as well as of arginine, lysine and ornithine (p<0.05) than Group 2. Also, when the two patients without mutations were excluded from the calculations, there still was a significant difference in the urinary excretion of total cystine (p<0.05). This suggests that the two patients without any detected mutations in the two known cystine transport genes also contributed to the difference. These unexpected findings indicate that an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.

    Keywords
    Cystinuria, Urinary cystine, Amino acid transport, SLC3A1, SLC7A9, Inherited disease
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12857 (URN)10.1007/s00240-003-0366-6 (DOI)
    Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2017-12-14Bibliographically approved
    4. Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria
    Open this publication in new window or tab >>Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria
    Show others...
    2001 (English)In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 29, no 5, p. 303-310Article in journal (Refereed) Published
    Abstract [en]

    Based on previous observations of the diurnal variation of urinary cystine excretion, the use of separate day and night urine collections was proposed. To improve the medical treatment of patients with cystinuria, this strategy was performed to guide the fluid intake and the administration of SH compounds (tiopronin, D-penicillamine,and MESNA).Twenty-six patients (19 treated with SH compounds and seven with alkalinization and hydration only) were followed during two 3.5-year periods. During Period 1, 24-h urine was collected and during Period 2, separate day and night urine was collected.There were 56 episodes of high urinary cystine supersaturation (>1,200 µmol/l) during Period 2, 47% of which would have evaded detection with 24-h urine analysis. In comparison with Period 1, the urinary cystine concentration was lower (P<0.05), and the urinary volume was higher (P<0.05) during Period 2. Patients treated with tiopronin had reduced cystine excretion (P<0.05) and at the end of Period 2, an increased dose of tiopronin, reflecting a more aggressive treatment. Furthermore, a reduced number of stone episodes and need of active stone removal (P<0.05) was noted in the whole group of patients. Analyses of separate day and night urine samples can be used advantageously to reveal episodes of high supersaturation with cystine not detected in 24-h urine samples. Such a procedure might be useful for optimizing the treatment of patients with cystinuria.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24985 (URN)10.1007/s002400100201 (DOI)9400 (Local ID)9400 (Archive number)9400 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    5. A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria
    Open this publication in new window or tab >>A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria
    2001 (English)In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 29, no 5, p. 295-302Article in journal (Refereed) Published
    Abstract [en]

    For many years, urine alkalinization has been one of the cornerstones in the treatment of homozygous cystinuria. Because of the relationship found between the excretion of urinary sodium and cystine, potassium citrate has emerged as the preferred sodium-free alkalizing agent. To evaluate the usefulness of potassium citrate for urine alkalization in cystinuric patients, sodium bicarbonate and potassium citrate were compared in 14 patients (10 on tiopronin treatment and four without treatment with sulfhydryl compounds). The study started with 1 week without the use of any alkalizing agents (Period 0) followed by 2 weeks with sodium bicarbonate (Period 1) and 2 weeks with potassium citrate (Period 2). Urinary pH, volume, excretion of sodium, potassium, citrate and free cystine, as well as the plasma potassium concentration, were recorded. Potassium citrate was shown to be effective as an alkalizing agent and, in this respect, not significantly different from sodium bicarbonate. Even though a normal diet was used, a significant increase in urinary sodium excretion was observed with sodium bicarbonate (Period 1). Urinary potassium and citrate excretion increased with potassium citrate (Period 2). A significant correlation was found between urinary sodium and cystine in the tiopronin-treated patients. No significant differences in cystine excretion were recorded in Periods 0, 1 and 2. Plasma potassium was significantly higher during Period 2, but only one patient developed a mild hyperkalemia (5.0 mmol/l). The use of potassium citrate for urine alkalization in homozygous cystinuria is effective and can be recommended in the absence of severe renal impairment.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24984 (URN)10.1007/s002400100200 (DOI)9397 (Local ID)9397 (Archive number)9397 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
  • 4.
    Fjellstedt, Erik
    et al.
    Department of Nephrology and Transplantation, Malmö University Hospital, Malmö, Sweden.
    Denneberg, Torsten
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Jeppsson, Jan-Olof
    Departmant of Clinical Chemistry, Malmö University Hospital, Malmö, Sweden.
    Christensson, Anders
    Department of Nephrology and Transplantation, Malmö University Hospital, Malmö, Sweden.
    Tiselius, Hans-Göran
    Department of Urology, Huddinge University Hospital, Stockholm, Sweden.
    Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria2001In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 29, no 5, p. 303-310Article in journal (Refereed)
    Abstract [en]

    Based on previous observations of the diurnal variation of urinary cystine excretion, the use of separate day and night urine collections was proposed. To improve the medical treatment of patients with cystinuria, this strategy was performed to guide the fluid intake and the administration of SH compounds (tiopronin, D-penicillamine,and MESNA).Twenty-six patients (19 treated with SH compounds and seven with alkalinization and hydration only) were followed during two 3.5-year periods. During Period 1, 24-h urine was collected and during Period 2, separate day and night urine was collected.There were 56 episodes of high urinary cystine supersaturation (>1,200 µmol/l) during Period 2, 47% of which would have evaded detection with 24-h urine analysis. In comparison with Period 1, the urinary cystine concentration was lower (P<0.05), and the urinary volume was higher (P<0.05) during Period 2. Patients treated with tiopronin had reduced cystine excretion (P<0.05) and at the end of Period 2, an increased dose of tiopronin, reflecting a more aggressive treatment. Furthermore, a reduced number of stone episodes and need of active stone removal (P<0.05) was noted in the whole group of patients. Analyses of separate day and night urine samples can be used advantageously to reveal episodes of high supersaturation with cystine not detected in 24-h urine samples. Such a procedure might be useful for optimizing the treatment of patients with cystinuria.

  • 5.
    Fjellstedt, Erik
    et al.
    Department of Nephrology and Transplantation, Malmö University Hospital, Malmö, Sweden.
    Denneberg, Torsten
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Jeppsson, Jan-Olof
    Department of Clinical Chemistry, Malmö University Hospital, Malmö, Sweden.
    Tiselius, Hans-Göran
    University Hospital Malmö and Department of Urology, Huddinge University Hospital, Stockholm, Sweden.
    A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria2001In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 29, no 5, p. 295-302Article in journal (Refereed)
    Abstract [en]

    For many years, urine alkalinization has been one of the cornerstones in the treatment of homozygous cystinuria. Because of the relationship found between the excretion of urinary sodium and cystine, potassium citrate has emerged as the preferred sodium-free alkalizing agent. To evaluate the usefulness of potassium citrate for urine alkalization in cystinuric patients, sodium bicarbonate and potassium citrate were compared in 14 patients (10 on tiopronin treatment and four without treatment with sulfhydryl compounds). The study started with 1 week without the use of any alkalizing agents (Period 0) followed by 2 weeks with sodium bicarbonate (Period 1) and 2 weeks with potassium citrate (Period 2). Urinary pH, volume, excretion of sodium, potassium, citrate and free cystine, as well as the plasma potassium concentration, were recorded. Potassium citrate was shown to be effective as an alkalizing agent and, in this respect, not significantly different from sodium bicarbonate. Even though a normal diet was used, a significant increase in urinary sodium excretion was observed with sodium bicarbonate (Period 1). Urinary potassium and citrate excretion increased with potassium citrate (Period 2). A significant correlation was found between urinary sodium and cystine in the tiopronin-treated patients. No significant differences in cystine excretion were recorded in Periods 0, 1 and 2. Plasma potassium was significantly higher during Period 2, but only one patient developed a mild hyperkalemia (5.0 mmol/l). The use of potassium citrate for urine alkalization in homozygous cystinuria is effective and can be recommended in the absence of severe renal impairment.

  • 6.
    Fjellstedt, Erik
    et al.
    Department of Nephrology and Transplantation, Malmö University Hospital, Malmö, Sweden.
    Harnevik, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jeppsson, Jan-Olof
    Department of Clinical Chemistry, Malmö University Hospital, Malmö, Sweden.
    Tiselius, Hans-Göran
    Department of Urology, Huddinge University Hospital and Centre for Surgical Sciences, Karolinska Institutet, Stockholm, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Denneberg, Torsten
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds2003In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 31, no 6, p. 417-425Article in journal (Refereed)
    Abstract [en]

    Advances in molecular genetics have brought a deeper understanding of cystinuria. This autosomal recessive disease, which is caused by a defective tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine, results in a lifelong risk of renal stone formation because of the low solubility of cystine in urine. Mutations detected within the two genes known to be associated with cystinuria, SLC3A1 (related to type I) and SLC7A9 (related to non-type I), cannot, however, in all cases explain the disease. Inasmuch as a high urinary concentration of cystine is the basis of stone formation in these patients, our aim was to measure urinary total cystine, arginine, lysine and ornithine, in patients currently lacking a full genetic explanation for their disease. Thirty-three patients with cystinuria who were on long-term treatment with tiopronin or D-penicillamine were divided into two groups. Group 1 comprised eight patients who carried mutation in one of the SLC3A1 alleles and two patients who completely lacked mutations both in the SLC3A1 and the SLC7A9 genes, that is genetic findings discordant with the increased urinary excretion of cystine and the dibasic amino acids in these patients. Group 2 comprised 23 patients homozygous for mutations within SLC3A1, that is genetic findings in accordance with the excretion pattern of classic type I cystinuria. When the two groups were compared, Group 1 had a significantly higher total urinary excretion of cystine (p<0.01) as well as of arginine, lysine and ornithine (p<0.05) than Group 2. Also, when the two patients without mutations were excluded from the calculations, there still was a significant difference in the urinary excretion of total cystine (p<0.05). This suggests that the two patients without any detected mutations in the two known cystine transport genes also contributed to the difference. These unexpected findings indicate that an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.

  • 7.
    Harnevik, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fjellstedt, Erik
    Department of Nephrology and Transplantation, Malmö University Hospital, Malmö, Sweden.
    Molbæk, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Denneberg, Torsten
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Mutation analysis of SLC7A9 in cystinuria patients in Sweden2003In: Genetic Testing, ISSN 1090-6576, E-ISSN 1557-7473, Vol. 7, no 1, p. 13-20Article in journal (Refereed)
    Abstract [en]

    Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas non-type I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria.

  • 8.
    Harnevik, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fjellstedt, Erik
    Department of Internal Medicine, Motala Hospital, Motala, Sweden.
    Molbæk, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Tiselius, Hans-Göran
    Department of Urology, University Hospital, Huddinge, Sweden.
    Denneberg, Torsten
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients2001In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 18, no 6, p. 516-525Article in journal (Refereed)
    Abstract [en]

    Cystinuria is an autosomal recessive disorder that affects luminal transport of cystine and dibasic amino acids in the kidneys and the small intestine. Three subtypes of cystinuria can be defined biochemically, and the classical form (type I) has been associated with mutations in the amino acid transporter gene SLC3A1. The mutations detected in SLC3A1 tend to be population specific and have not been previously investigated in Sweden. We have screened the entire coding sequence and the intron/exon boundaries of the SLC3A1 gene in 53 cystinuria patients by means of single strand conformation polymorphism (SSCP) and DNA sequencing. We identified 12 novel mutations (a 2 bp deletion, one splice site mutation, and 10 missense mutations) and detected another three mutations that were previously reported. Five polymorphisms were also identified, four of which were formerly described. The most frequent mutation in this study was the previously reported M467T and it was also detected in the normal population with an allelic frequency of 0.5%. Thirty-seven patients were homozygous for mutations in the SLC3A1 gene and another seven were heterozygous which implies that other genes may be involved in cystinuria. Future investigation of the non-type I cystinuria gene SLC7A9 may complement our results but recent studies also suggest the presence of other potential disease genes.

  • 9. Hedlund, Per Olov
    et al.
    Ala-Opas, Martti
    Brekkan, Einar
    Damber, Jan Erik
    Damber, Lena
    Hagerman, Inger
    Haukaas, Svein
    Henriksson, Peter
    Iversen, Peter
    Pousette, Åke
    Rasmussen, Finn
    Salo, Jaakko
    Vaage, Sigmund
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer2002In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 36, p. 405-413Article in journal (Refereed)
  • 10. Helgesen, F
    et al.
    Andersson, S-O
    Gustavsson, O
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Gobén, B
    Carnock, S
    Carlsson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment.
    Holmberg, L
    Johansson, J-E
    Follow-up prostate cancer patients by on-demand contacts with a specialist nurse.2000In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 34, p. 55-61Article in journal (Refereed)
  • 11. Henningsohn, L
    et al.
    Wijkström, H
    Pedersen, J
    Ahlstrand, Christer
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Aus, G
    Bergmark, K
    Onelöv, E
    Steineck, G
    Time after surgery, symptoms and well-being in survivors of urinary bladder cancer2003In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 91, no 4, p. 325-330Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: 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 AND METHODS: 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. RESULTS: 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% at > 10 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. CONCLUSIONS: 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.

  • 12. Hofner, C
    et al.
    DeRiejke, Claes
    Folkestad, Bengt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Speakman, MJ
    Tamsulosin 0,4 mg once daily: effect on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.1999In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 36, p. 335-341Article in journal (Refereed)
  • 13. Holmberg, Lars
    et al.
    Bill-Axelson, Anna
    Helgesen, Fred
    Salo, Jaakko
    Folmerz, Per
    Häggman, Michael
    Andersson, Swen-Olof
    Spångberg, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Busch, Christer
    Nordling, Steg
    Palmgren, Juni
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Norlén, Bo Johan
    A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer2002In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 347, no 11, p. 781-789Article in journal (Refereed)
    Abstract [en]

    Background: Radical prostatectomy is widely used in the treatment of early prostate cancer. The possible survival benefit of this treatment, however, is unclear. We conducted a randomized trial to address this question. Methods: From October 1989 through February 1999, 695 men with newly diagnosed prostate cancer in International Union against Cancer clinical stage T1b, T1c, or T2 were randomly assigned to watchful waiting or radical prostatectomy. We achieved complete follow-up through the year 2000 with blinded evaluation of causes of death. The primary end point was death due to prostate cancer, and the secondary end points were overall mortality, metastasis-free survival, and local progression. Results: During a median of 6.2 years of follow-up, 62 men in the watchful-waiting group and 53 in the radical-prostatectomy group died (P=0.31). Death due to prostate cancer occurred in 31 of 348 of those assigned to watchful waiting (8.9 percent) and in 16 of 347 of those assigned to radical prostatectomy (4.6 percent) (relative hazard, 0.50, 95 percent confidence interval, 0.27 to 0.91, P=0.02). Death due to other causes occurred in 31 of 348 men in the watchful-waiting group (8.9 percent) and in 37 of 347 men in the radical-prostatectomy group (10.6 percent). The men assigned to surgery had a lower relative risk of distant metastases than the men assigned to watchful waiting (relative hazard, 0.63, 95 percent confidence interval, 0.41 to 0.96). Conclusions: In this randomized trial, radical prostatectomy significantly reduced disease-specific mortality, but there was no significant difference between surgery and watchful waiting in terms of overall survival. Copyright ⌐ 2002 Massachusetts Medical Society.

  • 14. Hoppe, A
    et al.
    Denneberg, Torsten
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Cystinuria in the dog: Clinical studies during 14 years of medical treatment2001In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 15, no 4, p. 361-367Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to summarize 14 years of clinical experience with medical treatment of 88 cystinuric dogs. Of special interest was evaluation of recurrence rate of cystine uroliths and adverse effects during long-term tiopronin treatment. Twenty-six different breeds were recognized, and the most common breeds were Dachshunds, Tibetan Spaniels, and Basset Hounds. In 76 of 88 treated dogs (86%), re-formation of cystine uroliths was prevented. Recurrence rate of cystine uroliths changed from 7 months before to 18 months during tiopronin treatment. On 28 occasions, bladder stones were found, and in about 60% of the dogs, the uroliths dissolved. Quantitative measurement of the urinary excretion of cystine showed a significantly (P < .03) higher excretion of cystine in dogs with recurrent urolith formation than in dogs with only 1 urolith episode. Another finding was a significant (P = .02) decrease in urinary cystine excretion in older (>5 years) than in younger (<5 years) dogs. Adverse effects were found in 11 dogs, and the most severe signs were aggressiveness and myopathy. All signs disappeared when tiopronin treatment was stopped. In conclusion, this study emphasizes the importance of an individual strategy for lifelong treatment of cystinuria. In addition to increasing water intake, chemical modification of the cysteine molecule into a more soluble form by means of tiopronin is useful. In dogs with re-formed cystine uroliths, dissolution may be induced by increasing the tiopronin dosage to 40 mg/kg body weight per day. In dogs with a low urolith recurrence rate and low urinary cystine excretion, the tiopronin dosage may be decreased or treatment discontinued.

  • 15.
    Højgaard, Inge
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Crystallisation of calcium phosphate and calcium oxalate in solutions simulating the composition at different levels of the nephron1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Calcium oxalate (CaOx) is the most common constituent of urinary calcium stones, but in many such stones calcium phosphate (CaP) is also present and often located in the centre. From these observations it has been assumed that CaP is important in the process that leads to the development of a calcium stone and furthermore that the initial steps in this crystallisation take place in the nephron. The present investigation was undertaken to assess the risk of crystallisation of calcium salts at different nephron levels.

    Calculation of the ion-activity products of CaOx and different CaP salts Wlder solution conditions corresponding to those at various nephron levels, disclosed that the saturation with CaP was relatively higher than that of CaOx in the proximal tubule (PT), as well as in the proximal (DTp) and distal parts (DTd) of the distal tubule. Supersaturation concentrations necessary for the formation of CaOx crystals were recorded only in solutions with a composition corresponding to that in the collecting duct (CD).

    With an increased calcium concentration CaP was the crystal phase that most easily formed under solution conditions that corresponded to those at nephron levels above the CD. The relative risk of crystallisation of CaP was greatest in DTd~Urine. In CD-solutions CaOx was the preferred crystal type. Precipitation of CaOx in the lower part of CD and in final urine might be the result either of a primary nucleation of CaOx in the presence of a sufficiently high CaOx supersaturation or of a heterogeneous nucleation induced by CaP crystals formed at higher nephron levels.

    The nucleation of CaP and CaOx accomplished by reduction of volume of DTd- and CD- urine was apparently promoted by the urinary macromolecules in dialysed urine (dU). These macromolecules also inhibited the aggregation of CaP in solutions with a composition similar to that of urine in the distal tubule (DTd) and might counteract stone formation by inhibiting the growth and aggregation of both CaOx and CaP crystals during their passage through the CD. Furthermore, citrate had a direct inhibitory effect on the aggregation of CaP in DTd-solutions, an inhibitory effect that was additive to that of dU at concentrations of citrate above 0.5 mmol/L.

    The result~ obtained in these experimental studies support the hypothesis that CaP is the primary nucleus in mixed calcium stones. The process starts with the formation of CaP at a nephron level above the CD, possibly in DTd. A heterogeneous nucleation of CaOx is subsequently induced by dissolution of retained CaP crystals in the acid urine in the CD. The heterogeneous nucleation is probably accomplished by an increased local CaOx supersaturation that occurs at the CaP crystal surface as a result of this dissolution.

  • 16.
    Jahnson, Staffan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Karlsson, Mats
    Tumor mapping of regional immunostaining for p21, p53 and mdm2 in locally advanced bladder carcinoma.2000In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 89, p. 619-629Article in journal (Refereed)
  • 17.
    Jendle-Bengten, Cecilia
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Tiselius, Hans-Göran
    Long-term follow-up of stone formers treated with a low dose of sodium potassium citrate2000In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 34, no 1, p. 36-41Article in journal (Refereed)
    Abstract [en]

    We evaluated the clinical efficacy of long-term preventive treatment with a single evening dose of alkaline citrate. Information was collected from the files of 52 recurrent stone formers prescribed a daily intake of 3.75-5 g of sodium potassium citrate (SPC, 14-18 mmol of citrate). The annual and cumulative rates of stone formation and the rate of recurrence were compared before and during the treatment. A comparison was also made between the patients with (Group R) and without (Group NR) recurrent stone formation during treatment in terms of urine composition and previous history of the disease. For all patients who started the treatment, the number of stones was smaller during treatment (period t(T)) than during a period of the same length immediately before treatment (period t(B)), but greater than the number formed during a corresponding period immediately after the diagnosis (period t(A)). Via questionnaire we found low treatment compliance, with only 62% of the patients reporting consistent taking of their medication (Group T). The patients in Group T had a smaller cumulated number of stones during period t(T) than that during periods t(A) and t(B), but the Kaplan-Meier curve of the fraction of patients remaining stone-free during treatment was almost identical to that recorded in 446 recurrent stone formers without medical treatment. No significant differences were recorded in terms of relevant pretreatment urinary risk factors between Groups T(R) and T(NR), but numerically higher values of calcium oxalate (CaOx) supersaturation and calcium/citrate quotients were observed in Group T(R). When 9 patients with a daily intake of SPC and a citrate excretion below 2.5 mmol/day were compared with 16 hypocitraturic patients only given drinking advice, the cumulated percentages of patients without recurrent stone formation in the 2 groups after 3 years were 44% and 48%, respectively. Although the number of patients in this study was small, our results indicate poor long-term protection from recurrent calcium stone formation when a single evening dose of only 3.75-5 g of SPC was taken. The rate of stone formation was apparently slightly reduced, but the fraction of patients free of recurrence was no different from that in patients without medical treatment.

  • 18.
    Kalman, D
    et al.
    Kir klin ViN.
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    The role of arterial embolization in renal cell carcinoma.1999In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 33, p. 162-170Article in journal (Refereed)
  • 19.
    Köhler, C
    et al.
    Urol Vin.
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Mikroskopisk hematuri hos vuxna - ett diagnostiskt dilemma.1999In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 96, p. 4911-4916Article in journal (Other (popular science, discussion, etc.))
  • 20. Larsson, Caroline
    et al.
    Carlsson, Pether
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Test med vallmofrön ger vägledning vid svårdiagnostiserad vesikoenteral fistel2002In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 99, p. 3703-3705Article in journal (Other academic)
  • 21. Li, C
    et al.
    Grönberg, H
    Matsuyama, H
    Weber, G
    Nordenskjöld, M
    Naito, K
    Bergh, A
    Bergerheim, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Damber, JE
    Larsson, C
    Ekman, P
    Difference between Swedish and Japanese men in the association between AR CAG repeats and prostate cancer suggesting a susceptibility-modifying locus overlapping the androgen receptor gene2003In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 11, p. 529-533Article in journal (Refereed)
  • 22.
    Lidman, Disa
    et al.
    Linköping University, Department of Biomedicine and Surgery, Plastic Surgery, Hand Surgery and Burns. Linköping University, Faculty of Health Sciences.
    Danielsson, Pär
    Linköping University, Department of Biomedicine and Surgery, Plastic Surgery, Hand Surgery and Burns. Linköping University, Faculty of Health Sciences.
    Abdiu, Avni
    Linköping University, Department of Biomedicine and Surgery, Plastic Surgery, Hand Surgery and Burns. Linköping University, Faculty of Health Sciences.
    Fåhraeus, Bengt
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    The functional result two years after a microsurgical penile replantation1999In: Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery, ISSN 2000-656X, E-ISSN 2000-6764, Vol. 33, no 3, p. 325-328Article in journal (Refereed)
    Abstract [en]

    We describe the technique of microsurgical penile replantation and a case followed up after two years. The patient was a young man with decompensated schizophrenia who emasculated himself with a kitchen knife. A particularly good functional result was achieved including restoration of sensation in the penile shaft and in the glans, and return of erectile capacity.

  • 23. Matsuyama, H
    et al.
    Pan, Y
    Oba, K
    Yoshihiro, S
    Matsuda, K
    Hägarth, L
    Kudren, D
    Naito, K
    Bergerheim, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Ekman, P
    The role of chromosome 8p22 deletion for predicting disease progression and pathological staging in prostate cancer2003In: Aktuelle Urologie, ISSN 0001-7868, E-ISSN 1438-8820, Vol. 34, p. 247-249Article in journal (Refereed)
  • 24. Matsuyama, Hideyasu
    et al.
    Pan, Yi
    Yoshihiro, Satoru
    Kudren, David
    Naito, Katsusuke
    Bergerheim, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Ekman, Peter
    Clinical significance of chromosome 8p, 10q, and 16q deletions in prostate cancer2003In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 54, p. 103-111Article in journal (Refereed)
  • 25.
    Pedersen, Knud V.
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Localized carcinoma of the prostate: Aspects on screening, staging, and surgical treatment1993Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The management of localized carcinoma of the prostate is controversial.Opinions vary about whether screening is appropriate for this particular cancer, about the accuracy of pretreatment staging of the primary tumour, and about the value of potentially curable treatment such as radical prostatectomy.

    In the present study screening was assessed from an organizational,medical, economical, and psychological view. 1 494 men were selected from a population of 9 026 men aged 50-69 years and allocated at random to a screening programme for prostate cancer by digital rectal examination. There were two screening rounds, that in 1987 being conducted by an urologist and a general practitioner, and that in 1990 by a general practitioner only. The remaining 7 532 men served as a control group. 78% accepted the invitation to the first screening round, and 70% to the second. In the study group 17.4 prostate cancers were diagnosed per 1 000 men, and in the control group 8.6 per 1 000 men. The screening cost of the programme was 18 000 SEK per detected cancer, and 25 700 SEK per detected cancer treated by a potentially curative method. The long term consequences were analysed using a decision analysis model, and compared with 2 other alternatives for early detection. Inter observer variation in the digital assessment by urologist and general practitioner was analysed. Contrary to the general belief that digital rectal examination is highly subjective, we found good conformity between the observations of the two categories of examiner.

    In 29 patients the predictive value of fine-needle aspiration biopsy was compared with the histological findings in whole organ sections of radical prostatectomy specimens. The preoperative cytological examination predicted correctly the grade of malignancy in the whole organ sections in 59% of the cases. No overestimation of the grade occurred.

    Transrectal ultrasonography was used to predict the category of the primary tumour in 59 patients, and ultrasonically guided biopsies were added in 35. Histopathological examination of the whole organ sections was compared with the ultrasonic findings in 49 cases. The accuracy of staging improved with increasing experience.

    To investigate the role of radical prostatectomy a series of 182 patients was reviewed. The pathological staging was based on whole organ sections. In 109 (60%) cases the tumour was confined to the prostate or the specimen. The Gleason score was significantly higher in patients with involvement of the surgical margin or the seminal vesicles. Urinary continence was regained in 79%, but only 19% were potent after operation. In 131 patients who underwent radical prostatectomy the quality of life was studied by questionnaires. In the long term only distress due to loss of erection persisted, but the overall wellbeing after 18 months was better than before operation.

    CONCLUSION.

    Screening for carcinoma of the prostate by digital rectal examination can be organized with a high population acceptance and at reasonable cost per detected cancer. The introduction of general screening would call for a moderate expansion of available resources. The impact of screening on mortality remains uncertain. Fine-needle aspiration biopsy predict the grade of malignancy in most cases. Transrectal ultrasonography in combination with ultrasonically guided biopsy can facilitate the choice of treatment. The complication rate after radical prostatectomy is low, and assessment of quality of life complements knowledge concerning the clinical outcome of radical prostatectomy.

  • 26.
    Sandblom, Gabriel
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Diagnosis, management, quality of life, and long-term survival in prostate cancer patients: A study based on national, regional, and local cancer registry data in Sweden2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prostate cancer is a common disease with considerable variaton in clinical behaviour and therapeutic responsiveness. Uncertainty surrounds almost all aspects of prostate cancer management and it has been difficult to conduct proper randomised controlled trials required for reliable evidence-based decision-making. Although randomised controlled trials are under way and may eventually provide unbiased data on the efficacy of the management of prostate cancer in selected patient groups under optimal circumstances, population-based studies are necessary to evaluate variations in incidence and the effectiveness of management as practised in the community at large.

    This study uses three prospectively assembled population-based cohorts and one cross-sectional group of men with prostate cancer:

    1. a local register of all men with prostate cancer in the Central District of Östergotland 1974-1986 (n=813)

    2. the South-East Region Prostate Cancer Register 1987-1996 (n=6782)

    3. the National Prostate Cancer Register 1996-1997 (n=8328)

    4. A cross-sectional group of all men with prostate cancer residing in Östergotland 1999 comprising patients from cohorts 1 and 2 (n=1442)

    The incidence of prostate cancer in the South-East Region increased from 613 in 1987 to 780 in 1993 and then slowly declined. The age-adjusted incidence varied from 89/100 000 to 169/100 000 between the different counties included in the National Prostate Cancer Register 1996. In counties where a large percentage of the tumours were detected when still localised, the incidence was higher and the men younger at diagnosis (both p<0.05). In the age interval 50-59 years of age the median PSA was 13 ng/ml, whereas it was 35 ng/ml in those younger than 50. This difference was significant (p<0.05) and is probably explained by larger total tumour volume among men in the youngest age group. For men with well to moderately differentiated tumours and PSA < 20 ng/ml the risk for regional and distant metastases was below 10%. Between 1987 and 1996 the proportion of men treated with radical prostatectomy in the South-East Region decreased from 11% to 2.5%. During the same period the percentage of patients receiving GnRH-analogues increased from 3.9% to 37.8% while the percentage of patients treated with orchiectomy decreased from 40.0% to 12.8%. For patients treated with radiotherapy the median PSA was 16.7 ng/ml, for those who underwent radical prostatectomy 9.3 ng/ml, for patients receiving GnRH-analogues 61 ng/ml and for those treated with bilateral orchiectomy it was 88 ng/ml. All differences in PSA levels between the treatment groups were significant (p<0.05), indicating that there is a selection process with men having less advanced cancer receiving GnRH-analogues and men with more advanced cancer undergoing bilateral orchiectomy, and similarly a selection of men with smaller tumours being treated with radical prostatectomy rather than radiotherapy. Of the men answering the questionnaire sent to all prostate cancer patients residing in Ostergotland 1999 42% had perceived pain during the previous week and 26% stated their quality of life to be 50% or less on a visual analogue scale. A high health-care availability rating and short time since diagnosis were found to significantly predict lower rating of pain on average (p<0.05). Pain on average was found to be a significant predictive factor for decreased quality of life together with high age, low healthcare availability rating and palliative treatment (p<0.05). Age ≥ 70 years, advanced stage and poor differentiation were risk factors associated with increased risk for prostate cancer death in Östergotland Central District Cohort (p<0.05). The survival curve followed a continuous exponential course throughout the period of observation.

    The geographical as well as temporal variations in incidence are probably explained by differences in diagnostic activity, which also affects the age at diagnosis and distribution of stages. There are also large disparities in management within the country, which reflects the lack of evidence supporting one treatment in favour of another. How diagnostic activity and different local habits in management affect outcome in the long run is still unknown, but the results of our study regarding quality of life and survival may be used as a basis for management decision-making. Patients with localised tumours have a favourable prognosis, even without initial treatment. When deciding on therapy, however, the grade of malignancy should be taken into account as it has a great influence on disease-specific survival. For men with well to moderately differentiated tumours and PSA < 20 ng/ml, further investigation to exclude distant and regional metastases is unnecessary.

    List of papers
    1. Prostate Cancer Registration in Four Swedish Regions 1996: Differences in Incidence, Age Structure and Management
    Open this publication in new window or tab >>Prostate Cancer Registration in Four Swedish Regions 1996: Differences in Incidence, Age Structure and Management
    Show others...
    1999 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 33, no 5, p. 306-311Article in journal (Refereed) Published
    Abstract [en]

    Introduction: In 1996 registration of prostate cancer in four of the six Swedish regions was started to facilitate evaluation of geographical variations in incidence and treatment.

    Material and methods: For all cases of prostate cancer, personal identification number, tumour stage, tumour grade and primary treatment were registered.

    Results: In the four regions covered by the register, 3541 cases of prostate cancer were registered. Altogether there were 5795 cases of prostate cancer diagnosed in Sweden the same year. The age-standardized incidence varied from 89/100 000 to 169/100 000 among counties. The proportion of localized tumours correlated positively to the incidence (p &lt; 0.05) and negatively to mean age at diagnosis (p &lt; 0.01). There was also a significant positive correlation between the proportion of localized tumours and the percentage of patients given curative treatment. All registered variables showed large geographical variations, especially concerning percentage of T1c tumours, treatment of localized tumours and choice of palliative treatment.

    Conclusion: Diagnostic activity varied considerably among counties, resulting in large variation in age-standardized incidence. High incidence is associated with a larger proportion of localized tumours, which, in turn, is associated with early age at diagnosis. In counties where a policy of detecting tumours early is practised, curative treatment is also given more often. Treatment of localized tumours and preference for palliative treatment seem to depend on local traditions. The lack of cytological and histopathological standards makes geographical comparisons based on tumour grade impossible.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25344 (URN)10.1080/003655999750017374 (DOI)9786 (Local ID)9786 (Archive number)9786 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    2. Prostate carcinoma trends in three counties in Sweden 1987–1996
    Open this publication in new window or tab >>Prostate carcinoma trends in three counties in Sweden 1987–1996
    2000 (English)In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 88, no 6, p. 1445-1453Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND To detect changes in the incidence rate and management of prostate carcinoma, all cases of the disease diagnosed in the southeast region of Sweden between 1987–1996 were recorded.

    METHODS The register is based on Swedish personal registration numbers, thereby minimizing the number of dropouts. All cases of prostate carcinoma detected in the southeast region have been recorded according to a defined protocol that has been updated successively to match recent views regarding the disease. To ensure a high number of presented cases, the National Cancer Register was checked for missing cases.

    RESULTS Six thousand seven hundred eighty-two cases of prostate carcinoma were registered in the region between 1987–1996. The age-adjusted incidence rate reached a peak in 1993, followed by a slight decrease. The mean age at diagnosis throughout the period was 74.2 years, with a peak age of 74.8 years in 1992. The number of incidental tumors followed the development of the number of transurethral resections of the prostate performed in the region, with a peak in 1991. The percentage of patients receiving gonadotropin-releasing hormone (GnRH) analogues increased from 3.9% to 37.8% whereas the percentage of patients treated with orchiectomy decreased from 40.0% to 12.8% and the percentage of those treated with radical prostatectomy decreased from 11.1% to 2.5%.

    CONCLUSIONS A diminishing pool of latent tumors may explain the decreasing incidence rate and lower age at diagnosis observed after 1993. Orchiectomy is rapidly being superceded by GnRH analogues. In contrast to trends reported in the U.S., the percentage of men with prostate carcinoma undergoing total prostatectomy appears to be declining in Sweden.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24995 (URN)10.1002/(SICI)1097-0142(20000315)88:6<1445::AID-CNCR24>3.0.CO;2-T (DOI)9415 (Local ID)9415 (Archive number)9415 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    3. Prostate-Specific Antigen for Prostate Cancer Staging in a Population-based Register
    Open this publication in new window or tab >>Prostate-Specific Antigen for Prostate Cancer Staging in a Population-based Register
    Show others...
    2002 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 36, no 2, p. 99-105Article in journal (Refereed) Published
    Abstract [en]

    Objective: Previous studies have shown a relationship between serum prostate-specific antigen (PSA) level and prostate tumour volume. Reports based on selected case series have also indicated that serum PSA may be used for staging, although a varying prevalence of metastasizing tumours complicates the interpretation of these studies. In order to determine the accuracy of the serum level of PSA in predicting the presence of metastases we performed a prospective cohort study of a geographically defined population of men with prostate cancer.

    Methods: Serum level of PSA and the results of investigations for regional lymph node and distant metastases were recorded for all 8328 men with prostate cancer registered in the Swedish National Prostate Cancer Register 1996-1997.

    Results: The prevalence of lymph node metastases among men who had undergone lymph node exploration was 4%, 16% and 33% for well, moderately and poorly differentiated tumours. The corresponding prevalence of distant metastases was 12%, 30% and 48%. With serum PSA <20 ng/ml as a cut-off point the negative likelihood ratios for well and moderately differentiated tumours were found to be 0.47 and 0.45 for lymph node metastases and 0.24 and 0.18 for distant metastases, resulting in post-test probabilities >92% for the exclusion of metastases. In men with poorly differentiated tumours, the negative likelihood ratio would need to be even lower to safely exclude disseminated disease.

    Conclusion: For well to moderately differentiated tumours, further investigations to assess the presence of metastases may be omitted with no great risk for understaging if serum PSA <20 ng/ml.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25341 (URN)10.1080/003655902753679373 (DOI)9783 (Local ID)9783 (Archive number)9783 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Prostate-specific Antigen as Surrogate for Characterizing Prostate Cancer Subgroups
    Open this publication in new window or tab >>Prostate-specific Antigen as Surrogate for Characterizing Prostate Cancer Subgroups
    Show others...
    2002 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 36, no 2, p. 106-112Article in journal (Refereed) Published
    Abstract [en]

    Objective: To evaluate how serum prostate-specific antigen (PSA) levels in a population-based cohort of men with prostate cancer vary with age and intensity in the diagnostic activity and to describe the treatment selection processes associated with PSA level.

    Material and Methods: All men in the Swedish National Prostate Cancer Register diagnosed during 1996-1997 were included. In 1996 the register included 19 counties, covering 61% of the Swedish male population, and in 1997 21 counties with 79% of the Swedish male population.

    Results: A total of 8328 men were registered. PSA levels were missing in 341 cases. With increasing PSA there was a shift towards more advanced and poorly differentiated tumours. PSA at diagnosis increased with age, with the exception of patients younger than 50 years who had higher PSA values. The mean logarithm of PSA correlated negatively with the percentage of localized tumours ( p < 0.005) and the age-adjusted incidence ( p < 0.05) in each respective county in 1997. PSA was higher in men receiving radiotherapy compared with those treated with radical prostatectomy as well as in the group treated with bilateral orchiectomy compared with those receiving GnRH-analogues.

    Conclusions: If PSA is used as a surrogate measure of extent of tumour volume in a population of prostate cancer patients, our findings indicate that age distribution and differences in incidence (possibly due to variation in diagnostic activity) should be taken into account. In our cohort there was a selection process, probably in part guided by PSA level, when choosing type of curative or palliative treatment.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25340 (URN)10.1080/003655902753679382 (DOI)9782 (Local ID)9782 (Archive number)9782 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    5. Pain and health-related quality of life in a geographically defined population of men with prostate cancer
    Open this publication in new window or tab >>Pain and health-related quality of life in a geographically defined population of men with prostate cancer
    2001 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 85, no 4, p. 497-503Article in journal (Refereed) Published
    Abstract [en]

    In order to provide baseline data on pain and health-related quality of life, to explore factors predicting pain and reduced quality of life, and to find potentially undertreated cases in men with prostate cancer, we undertook a population-based questionnaire study. The questionnaire, which included the EuroQo1 instrument, the Brief Pain Inventory form and 8 specially designed questions, was sent to all men with prostate cancer in the county of ╓sterg÷tland, Sweden. Of the 1442 men included in the study, 1243 responded to the questionnaire. Altogether 42% had perceived pain during the previous week and 26% stated their quality of life to be 50% or lower on a visual analogue scale. A high rating of health care availability and short time since diagnosis were found to significantly predict lower ratings of pain (P < 0.05). Pain was found to be a significant predictive factor for decreased quality of life together with high age, low rating of health care availability and palliative treatment (P < 0.05). In conclusion, assessment and treatment of pain is essential for a good quality of life in men with prostate cancer. The monitoring of prostate cancer patients should be individualized to fit the demands of the groups with the greatest need for support.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25343 (URN)10.1054/bjoc.2001.1965 (DOI)9785 (Local ID)9785 (Archive number)9785 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    6. Long-term survival in a swedish population-based cohort of men with prostate cancer
    Open this publication in new window or tab >>Long-term survival in a swedish population-based cohort of men with prostate cancer
    2000 (English)In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 56, no 3, p. 442-447Article in journal (Refereed) Published
    Abstract [en]

    Objectives. To study the long-term survival of patients with prostate cancer, determine the risk factors for prostate cancer death, and investigate the outcome of initially untreated localized prostate cancer and incidentally detected tumors.

    Methods. The survival of 813 patients in a population-based cohort of patients with prostate cancer in Linköping, Sweden, diagnosed from 1974 to 1986, was analyzed.

    Results. At 10, 15, and 20 years after diagnosis, the prostate cancer-specific survival rate of men with localized, initially untreated, prostate cancer was 85.0% (95% confidence interval [CI], 79.0% to 91.0%), 80.0% (95% CI, 72.5% to 87.5%), and 62.6% (95% CI, 43.0% to 82.2%). Age 70 years or older, advanced stage, and poor differentiation were risk factors associated with an increased risk of prostate cancer death. At 10 years, the prostate cancer-specific survival rate among men with localized tumors treated by expectancy was 90% (95% CI, 84% to 97%) for grade 1 tumors, 74% (95% CI, 60% to 89%) for grade 2 tumors, and 59% (95% CI, 29% to 90%) for grade 3 tumors. For patients with incidentally detected tumors, the grade of malignancy was a more important risk factor than tumor volume.

    Conclusions. Patients with localized tumors have a favorable prognosis, even without initial treatment. However, when deciding on therapy, the grade of malignancy should be taken into account, as it has a great influence on survival. We did not see a tendency toward increased mortality when the patients were followed up for longer than 10 years after diagnosis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24993 (URN)10.1016/S0090-4295(00)00696-8 (DOI)9413 (Local ID)9413 (Archive number)9413 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
  • 27.
    Sandblom, Gabriel
    et al.
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Carlsson, Per
    Linköping University, Department of Behavioural Sciences, Centre for Studies of Humans, Technology and Organization. Linköping University, Faculty of Health Sciences.
    Sigsjö, Peter
    Linköping University, Department of Behavioural Sciences, Centre for Studies of Humans, Technology and Organization. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Pain and health-related quality of life in a geographically defined population of men with prostate cancer2001In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 85, no 4, p. 497-503Article in journal (Refereed)
    Abstract [en]

    In order to provide baseline data on pain and health-related quality of life, to explore factors predicting pain and reduced quality of life, and to find potentially undertreated cases in men with prostate cancer, we undertook a population-based questionnaire study. The questionnaire, which included the EuroQo1 instrument, the Brief Pain Inventory form and 8 specially designed questions, was sent to all men with prostate cancer in the county of ╓sterg÷tland, Sweden. Of the 1442 men included in the study, 1243 responded to the questionnaire. Altogether 42% had perceived pain during the previous week and 26% stated their quality of life to be 50% or lower on a visual analogue scale. A high rating of health care availability and short time since diagnosis were found to significantly predict lower ratings of pain (P < 0.05). Pain was found to be a significant predictive factor for decreased quality of life together with high age, low rating of health care availability and palliative treatment (P < 0.05). In conclusion, assessment and treatment of pain is essential for a good quality of life in men with prostate cancer. The monitoring of prostate cancer patients should be individualized to fit the demands of the groups with the greatest need for support.

  • 28.
    Sandblom, Gabriel
    et al.
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Kerstin
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Prostate carcinoma trends in three counties in Sweden 1987–19962000In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 88, no 6, p. 1445-1453Article in journal (Refereed)
    Abstract [en]

    BACKGROUND To detect changes in the incidence rate and management of prostate carcinoma, all cases of the disease diagnosed in the southeast region of Sweden between 1987–1996 were recorded.

    METHODS The register is based on Swedish personal registration numbers, thereby minimizing the number of dropouts. All cases of prostate carcinoma detected in the southeast region have been recorded according to a defined protocol that has been updated successively to match recent views regarding the disease. To ensure a high number of presented cases, the National Cancer Register was checked for missing cases.

    RESULTS Six thousand seven hundred eighty-two cases of prostate carcinoma were registered in the region between 1987–1996. The age-adjusted incidence rate reached a peak in 1993, followed by a slight decrease. The mean age at diagnosis throughout the period was 74.2 years, with a peak age of 74.8 years in 1992. The number of incidental tumors followed the development of the number of transurethral resections of the prostate performed in the region, with a peak in 1991. The percentage of patients receiving gonadotropin-releasing hormone (GnRH) analogues increased from 3.9% to 37.8% whereas the percentage of patients treated with orchiectomy decreased from 40.0% to 12.8% and the percentage of those treated with radical prostatectomy decreased from 11.1% to 2.5%.

    CONCLUSIONS A diminishing pool of latent tumors may explain the decreasing incidence rate and lower age at diagnosis observed after 1993. Orchiectomy is rapidly being superceded by GnRH analogues. In contrast to trends reported in the U.S., the percentage of men with prostate carcinoma undergoing total prostatectomy appears to be declining in Sweden.

  • 29.
    Sandblom, Gabriel
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Dufmats, Monika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Olsson, Mats
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Validity of a population-based cancer register in Sweden - An assessment of data reproducibility in the South-East Region prostate cancer register2003In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 37, no 2, p. 112-119Article in journal (Refereed)
    Abstract [en]

    Background: With a population-based setting, high coverage and accurately recorded data, the validity of a register is guaranteed. The South-East Region Prostate Cancer relies on the National Cancer Register as a basic source of data, thereby ensuring a high coverage of the corresponding geographic area. To assess the reproducibility of the data recorded a random sample of the cases were reviewed a second time and compared to the original recording. Material and methods: The South-East Region Prostate Cancer Register was started in 1987. In addition to the basic data acquired from the Swedish National Register, it also includes tumour stage, grade, treatment and, since 1992, PSA. In the first stage of quality assessment 10 cases for each of the years 1987-1996 from Link÷ping University Hospital were randomly selected for two independent recodings according to the same protocol as the original registration. In the second step 10 cases each for the same years from the remaining 8 hospitals in the region were selected for a single recoding. Results: No systematic deviations were seen between the two independent recodings from Link÷ping, a single recoding was therefore considered sufficient for assessing the reproducibility of the data from the remaining hospitals in the region. The Kappa values for agreement between the original registration and the single recoding ranged from 0.589 to 0.869. Conclusion: The population-based setting and high coverage guarantees the external validity of the register. The internal validity is ensured by the high reproducibility shown in the present study.

  • 30.
    Sandblom, Gabriel
    et al.
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Long-term survival in a swedish population-based cohort of men with prostate cancer2000In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 56, no 3, p. 442-447Article in journal (Refereed)
    Abstract [en]

    Objectives. To study the long-term survival of patients with prostate cancer, determine the risk factors for prostate cancer death, and investigate the outcome of initially untreated localized prostate cancer and incidentally detected tumors.

    Methods. The survival of 813 patients in a population-based cohort of patients with prostate cancer in Linköping, Sweden, diagnosed from 1974 to 1986, was analyzed.

    Results. At 10, 15, and 20 years after diagnosis, the prostate cancer-specific survival rate of men with localized, initially untreated, prostate cancer was 85.0% (95% confidence interval [CI], 79.0% to 91.0%), 80.0% (95% CI, 72.5% to 87.5%), and 62.6% (95% CI, 43.0% to 82.2%). Age 70 years or older, advanced stage, and poor differentiation were risk factors associated with an increased risk of prostate cancer death. At 10 years, the prostate cancer-specific survival rate among men with localized tumors treated by expectancy was 90% (95% CI, 84% to 97%) for grade 1 tumors, 74% (95% CI, 60% to 89%) for grade 2 tumors, and 59% (95% CI, 29% to 90%) for grade 3 tumors. For patients with incidentally detected tumors, the grade of malignancy was a more important risk factor than tumor volume.

    Conclusions. Patients with localized tumors have a favorable prognosis, even without initial treatment. However, when deciding on therapy, the grade of malignancy should be taken into account, as it has a great influence on survival. We did not see a tendency toward increased mortality when the patients were followed up for longer than 10 years after diagnosis.

  • 31.
    Sandblom, Gabriel
    et al.
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Holmberg, L.
    Oncological Centre, Uppsala University, Sweden.
    Damber, J-E
    Department of Urology, Sahlgrenska Hospital, Gothenburg, Sweden.
    Hugosson, J.
    Department of Urology, Sahlgrenska Hospital, Gothenburg, Sweden.
    Johansson, J-E
    Department of Urology and Centre for Assessment of Medical Technology, Örebro Medical Centre, Sweden.
    Lundgren, R,
    5Department of Surgery/Section of Urology, Helsingborg Hospital, Sweden.
    Mattsson, E.
    Oncological Centre, Uppsala University, Sweden.
    Nilsson, J.
    Oncological Centre, Uppsala University, Sweden.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Prostate-specific Antigen as Surrogate for Characterizing Prostate Cancer Subgroups2002In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 36, no 2, p. 106-112Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate how serum prostate-specific antigen (PSA) levels in a population-based cohort of men with prostate cancer vary with age and intensity in the diagnostic activity and to describe the treatment selection processes associated with PSA level.

    Material and Methods: All men in the Swedish National Prostate Cancer Register diagnosed during 1996-1997 were included. In 1996 the register included 19 counties, covering 61% of the Swedish male population, and in 1997 21 counties with 79% of the Swedish male population.

    Results: A total of 8328 men were registered. PSA levels were missing in 341 cases. With increasing PSA there was a shift towards more advanced and poorly differentiated tumours. PSA at diagnosis increased with age, with the exception of patients younger than 50 years who had higher PSA values. The mean logarithm of PSA correlated negatively with the percentage of localized tumours ( p < 0.005) and the age-adjusted incidence ( p < 0.05) in each respective county in 1997. PSA was higher in men receiving radiotherapy compared with those treated with radical prostatectomy as well as in the group treated with bilateral orchiectomy compared with those receiving GnRH-analogues.

    Conclusions: If PSA is used as a surrogate measure of extent of tumour volume in a population of prostate cancer patients, our findings indicate that age distribution and differences in incidence (possibly due to variation in diagnostic activity) should be taken into account. In our cohort there was a selection process, probably in part guided by PSA level, when choosing type of curative or palliative treatment.

  • 32.
    Sandblom, Gabriel
    et al.
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Holmberg, L.
    Regional Oncological Centre, Uppsala University, Sweden.
    Damber, J-E
    Department of Urology, Sahlgrenska Hospital, Gothenburg, Sweden.
    Hugosson, J.
    Department of Urology, Sahlgrenska Hospital, Gothenburg, Sweden.
    Johansson, J-E
    Department of Urology and Centre for Assessment of Medical Technology, Örebro Medical Centre, Sweden.
    Lundgren, R.
    Department of Surgery/Section of Urology, Helsingborg Hospital, Sweden.
    Mattsson, E.
    Regional Oncological Centre, Uppsala University, Sweden.
    Nilsson, J.
    Regional Oncological Centre, Uppsala University, Sweden.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Prostate-Specific Antigen for Prostate Cancer Staging in a Population-based Register2002In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 36, no 2, p. 99-105Article in journal (Refereed)
    Abstract [en]

    Objective: Previous studies have shown a relationship between serum prostate-specific antigen (PSA) level and prostate tumour volume. Reports based on selected case series have also indicated that serum PSA may be used for staging, although a varying prevalence of metastasizing tumours complicates the interpretation of these studies. In order to determine the accuracy of the serum level of PSA in predicting the presence of metastases we performed a prospective cohort study of a geographically defined population of men with prostate cancer.

    Methods: Serum level of PSA and the results of investigations for regional lymph node and distant metastases were recorded for all 8328 men with prostate cancer registered in the Swedish National Prostate Cancer Register 1996-1997.

    Results: The prevalence of lymph node metastases among men who had undergone lymph node exploration was 4%, 16% and 33% for well, moderately and poorly differentiated tumours. The corresponding prevalence of distant metastases was 12%, 30% and 48%. With serum PSA <20 ng/ml as a cut-off point the negative likelihood ratios for well and moderately differentiated tumours were found to be 0.47 and 0.45 for lymph node metastases and 0.24 and 0.18 for distant metastases, resulting in post-test probabilities >92% for the exclusion of metastases. In men with poorly differentiated tumours, the negative likelihood ratio would need to be even lower to safely exclude disseminated disease.

    Conclusion: For well to moderately differentiated tumours, further investigations to assess the presence of metastases may be omitted with no great risk for understaging if serum PSA <20 ng/ml.

  • 33.
    Sandblom, Gabriel
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Incidence rate and management of prostate carcinoma2001In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 55, no 3, p. 135-143Article in journal (Refereed)
    Abstract [en]

    The age-standardised incidence of prostate cancer varies more than one hundredfold between the areas with the highest and lowest incidences in the world. In certain areas, in particular the Western countries, the incidence has increased rapidly over the last 20 years. There are several environmental and genetic factors which partly explain these variations, although the incidence probably depends most of all on the extent to which small latent tumours are detected. As the clinical significance of small tumours is uncertain, the value of early diagnosis and early aggressive treatment is controversial. Randomised trials addressing this question have been initiated and will hopefully provide more evidence-based data in a decade from now. Small localised tumours are managed by radical surgery or radiation therapy. In elderly men or men unfit for operation or radiation therapy surveillance is often preferred. For advanced or metastatic prostate cancers androgen deprivation has been the mainstay of treatment since the early 1940s. Recently, several new treatment strategies have evolved but have not yet been introduced into clinical routine.

  • 34.
    Sandblom, Gabriel
    et al.
    Department of Surgery, Uppsala Akademiska Hospital, Akademiska Sjukhuset, Uppsala, Sweden.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Löfman, Owe
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Rosell, Johan
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Carlsson, Per
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Clinical consequences of screening for prostate cancer: 15 Years follow-up of a randomised controlled trial in Sweden2004In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 46, no 6, p. 717-723Article in journal (Refereed)
    Abstract [en]

    Objective:

    To test the feasibility of a population-based prostate cancer screening programme in general practice and explore the outcome after a 15-year follow-up period.

    Methods:

    From the total population of men aged 50–69 years in Norrköping (n = 9026) every sixth man (n = 1494) was randomly selected to be screened for prostate cancer every third year over a 12-year period. The remaining 7532 men were treated as controls. In 1987 and 1990 only digital rectal examination (DRE) was performed, in1993 and 1996 DRE was combined with a test for Prostate-Specific Antigen (PSA). TNM categories, grade of malignancy, management and cause of death were recorded in the South-East Region Prostate Cancer Register.

    Results:

    There were 85 (5.7%) cancers detected in the screened group (SG), 42 of these in the interval between screenings, and 292 (3.8%) in the unscreened group (UG). In the SG 48 (56.5%) of the tumours and in the UG 78 (26.7%) were localised at diagnosis (p < 0.001). In the SG 21 (25%) and in the UG 41 (14%) received curative treatment. There was no significant difference in total or prostate cancer-specific survival between the groups.

    Conclusions:

    Although PSA had not been introduced in the clinical practice at the start of the study, we were still able to show that it is possible to perform a long-term population-based randomised controlled study with standardised management and that screening in general practice is an efficient way of detecting prostate cancer whilst it is localised. Complete data on stage, treatment and mortality for both groups was obtained from a validated cancer register, which is a fundamental prerequisite when assessing screening programmes.

  • 35. Schäfer, Werner
    et al.
    Abrams, Paul
    Liao, Limin
    Mattiasson, Anders
    Pesce, Francesco
    Spångberg, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Sterling, Arthur
    Zinner, Norman
    van Kerrebroeck, Philip
    Good urodynamic practices: Uroflowmetry, filling cystometry, and pressure-flow studies2002In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 21, p. 261-274Article in journal (Refereed)
  • 36.
    Sennfält, Karin
    et al.
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Carlsson, Per
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Sandblom, Gabriel
    Department of Surgery, Uppsala Academic Hospital, Sweden.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    The estimated economic value of the welfare loss due to prostate cancer pain in a defined population2004In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 43, no 3, p. 290-296Article in journal (Refereed)
    Abstract [en]

    The aim of the study reported here was to estimate the economic value of the welfare loss due to prostate cancer pain by estimating the extent to which pain affects health-related quality of life among patients with prostate cancer. The material consisted of a point estimate of health status among men with prostate cancer in a well-defined population of 200 000 males. Clinical data concerning the disease at diagnosis (extracted from patients’ records and the Regional Prostate Cancer Registry), and health utility ratings (using EuroQol) were obtained from 1 156 males with prostate cancer. A descriptive model showed that optimal treatment that would reduce pain to zero during the whole episode of disease would add on average 0.85 quality-adjusted life years (QALY) to every man with prostate cancer. Based on an estimate of the willingness to pay for a QALY the economic value of this welfare loss due to prostate cancer pain is in the magnitude of €86 600 000 per year (€19 800 000 per million men in Sweden).

  • 37.
    Sennfält, Karin
    et al.
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Carlsson, Per
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Thorfinn, Johan
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Frisk, Jessica
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Henriksson, Martin
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Clinical and Experimental Medicine, Urology. Linköping University, Faculty of Health Sciences.
    Technological changes in the management of prostate cancer result in increased healthcare costs: a retrospective study in a defined Swedish population2003In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 37, no 3, p. 226-231Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    In two previous studies we calculated direct costs for men with prostate cancer who died in 1984-85 and 1992-93, respectively. We have now performed a third cost analysis to enable a longitudinal cost comparison. The aim was to calculate direct costs for the management of prostate cancer, describe the economic consequences of technological changes over time and estimate total direct costs for prostate cancer in Sweden.

    MATERIAL AND METHODS:

    A total of 204 men in a defined population with a diagnosis of prostate cancer and who died in 1997-98 were included. Data on utilization of health services were extracted from clinical records from time of diagnosis to death from a university hospital and from one county hospital in the county of Ostergötland.

    RESULTS:

    The average direct cost per patient has been nearly stable over time (1984-85: 143 000 SEK; 1992-93: 150 000 SEK; 1997-98: 146 000 SEK). The share of costs for drugs increased from 7% in 1992-93 to 17% in 1997-98. The total direct costs for prostate cancer in Sweden have increased over time (1994-85: 610 MSEK; 1992-93: 860 MSEK; 1997-98: 970 MSEK).

    CONCLUSIONS:

    Two-thirds of the total cost is incurred by inpatient care. The share of the total costs for drugs is increasing due to increased use of gonadotrophin-releasing hormone analogues. Small changes in average direct costs per patient despite greater use of technology are explained by the fact that more prostate cancers are detected at the early stages.

  • 38.
    Sennfält, Karin
    et al.
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Carlsson, Per
    Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Diffusion and Economic Consequences of Health Technologies in Prostate Cancer Care in Sweden, 1991-20022006In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 49, no 6, p. 1028-1034Article in journal (Refereed)
    Abstract [en]

       Objective

    To describe the diffusion of six main health technologies used for management of prostate cancer, to estimate the economic consequences of technological changes, and to explore factors behind the diffusion.

    Methods

    Data describing the diffusion 1991–2002 were obtained from population-based databases. Costs were obtained from Linköping University Hospital and Apoteket AB. Factors affecting the diffusion of the technologies were explored.

    Results

    Utilization of technologies with a curative and/or palliative aim has increased over time, except for surgical castration. PSA-tests are used increasingly. The total cost of the study technologies has increased from 20 million euros in 1991 to 65 million euros in 2002. Classification of radical prostatectomy revealed a profile associated with a slow/limited diffusion, while classification of PSA-tests revealed a profile associated with a rapid/extensive diffusion.

    Conclusions

    Several technological changes in the management of prostate cancer have occurred without proven benefits and have contributed to increased costs. There are other factors, besides scientific evidence, that have an impact on the diffusion. Consequently, activities aimed at facilitating an appropriate diffusion of new technologies are needed. The analytical framework used here may be helpful in identifying technologies that are likely to experience inappropriate diffusion and therefore need particular attention.

  • 39.
    Spetz, Anna-Clara
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Vasomotor symptoms in men and the role of Calcitonin Gene-Related Peptide2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hot flushes is a cotmnon phenomenon in women during the menopausal transition. In men treated with castration because of prostate cancer, hot flushes are probably the most cotmnon and distressing side-effect and are as common in these men as in menopausal women but the course of the flushes is unknown. Flushes also occur in healthy aging men, but the prevalence is unknown. The mechanisms behind hot flushes are not fully understood. They are probably caused by instability in the thermoregulatory centre due to a decrease in sex hotmone concentrations. Calcitonin Gene-Related Peptide (CGRP) and perhaps also Neuropeptide Y (NPY) are probably involved in menopausal hot flushes in women and could also be involved in men following therapeutic castration.

    The aims of this thesis were to compare different methods of castration as regards the occunence and course of hot flushes, and to investigate the prevalence of hot flushes in an unselected population of elderly men. A further aim was to see if CGRP and NPY are involved in hot flushes in men, in the same way as has previously been suggested in women.

    In this thesis two different modalities of castration therapy were compared: 1. castration by means of estrogens (Polyestradiol phosphate) and 2. total androgen blockade (a. bilateral orchiectomy or b. GnRH-analogue combined with oral anti-androgen). A much lower incidence of hot flushes were seen in the first group (1). Flushes induced by castration with estrogen were also milder and tended to disappear with time.

    The prevalence of hot flushes in a male population 55 years of age and above was investigated by means of a questionnaire. Thirty per cent of the men repotted flushes and half of these found the flushes distressing, i.e. every sixth man in the study. There was an association between flushes and a number of symptoms that are often related to low testosterone concentrations in the blood.

    The 24-hour urinaty excretion of CGRP was investigated in 17 men with prostate cancer before and after castration. Thirteen of the 17 men developed hot flushes after castration, but the urinary excretion of CGRP was not significantly altered.

    Blood-samples were taken during hot flushes in 10 men for analysis of CGRP- and NPY-plasma concentrations. CGRP increased in 6 men (we failed to obtain CGRP measurements in the other men due to technical problems). NPY concentrations were below the detection limit for the analysis in all samples.

    In conclusion vasomotor symptoms are common in men subjected to castration therapy. Different castration modalities result in different prevalence of hot flushes, something that should be considered when choosing the method of castration for men with prostate cancer. Hot flushes also occur in normal, aging men. The mechanisms behind hot flushes in men and women may be similar. CGRP may be involved in hot flushes in castrated men.

    In order to be able to develop new treatment regimens for these vasomotor symptoms fmther studies on the mechanisms behind hot flushes should be undertaken, in both castrated and in otherwise healthy elderly men.

    List of papers
    1. Prospective evaluation of hot flashes during treatment with parenteral estrogen or complete androgen ablation for metastatic carcinoma of the prostate
    Open this publication in new window or tab >>Prospective evaluation of hot flashes during treatment with parenteral estrogen or complete androgen ablation for metastatic carcinoma of the prostate
    Show others...
    2001 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 166, no 2, p. 517-520Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    We evaluated the incidence and frequency of, and distress due to hot flashes after castration therapy with polyestradiol phosphate and complete androgen ablation.

    Materials and Methods

    A total of 915 men with metastatic prostate carcinoma enrolled in the Scandinavian Prostatic Cancer Group-5 trial study were randomized to intramuscular injections of 240 mg. Polyestradiol phosphate every 2 weeks for 8 weeks followed by monthly subcutaneous injections or complete androgen ablation, that is bilateral orchiectomy or 3.75 mg. of the gonadotropin-releasing hormone analog triptorelin monthly combined with 250 mg. of the antiandrogen flutamide 3 times daily. The incidence and frequency of, and distress due to hot flashes were recorded at regular intervals using a questionnaire.

    Results

    Of the 915 men 901 were evaluated at a median followup of 18.5 months. The incidence of hot flashes was 30.1% and 74.3% in the polyestradiol phosphate and complete androgen ablation groups, respectively (p <0.001). In the polyestradiol phosphate group the frequency of and distress due to hot flashes were significantly lower than in the androgen ablation group. There was complete relief from hot flashes in 50% of the men on polyestradiol phosphate during followup compared with none on androgen ablation. The incidence of hot flashes did not differ in men with and without tumor progression.

    Conclusions

    Endocrine treatment with polyestradiol phosphate induced fewer and less distressing hot flashes than complete androgen ablation. Flashes also disappeared to a greater extent during polyestradiol phosphate than during androgen ablation. The data in this study enable us to provide thorough individual information to patients on the risk and grade of expected distress and duration of hot flashes during polyestradiol phosphate or complete androgen ablation treatment.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25368 (URN)10.1016/S0022-5347(05)65973-3 (DOI)9811 (Local ID)9811 (Archive number)9811 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    2. Hot flushes in a male population aged 55, 65, and 75 years, living in the community of Linköping, Sweden
    Open this publication in new window or tab >>Hot flushes in a male population aged 55, 65, and 75 years, living in the community of Linköping, Sweden
    2003 (English)In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 10, no 1, p. 81-87Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE:

    Hot flushes are as common in castrated men as in menopausal women. We investigated whether hot flushes exist in a normal aging male population and to what extent.

    DESIGN:

    A questionnaire was sent to all men living in Linköping, Sweden, who were 55, 65, and 75 years old ( = 1,885). The questionnaire asked for demographic data, medical history, mood status, medication, castrational therapy, and smoking, exercise, and alcohol habits, among other items. We asked specifically for current hot flushes unrelated to exercise or a warm environment.

    RESULTS:

    Of the questionnaires received, 1,381 were eligible for evaluation; 33 were analyzed separately because these men had been castrated. Hot flushes of any frequency were reported by 33.1% of noncastrated men, 4.3% reported flushes at least a few times per week, and 1.3% reported daily flushes. Half of the men reporting flushes were also bothered by them, ie, almost every sixth man in total. We found a relation between occurrence of hot flushes and other symptoms thought to be related to low testosterone concentration, such as decreased muscle strength or endurance, decreased enjoyment of life, sadness or grumpiness, and lack of energy ( < 0.05).

    CONCLUSIONS:

    Hot flushes occur in one third of a population of noncastrated older men, approximately half of whom consider flushes as bothersome. Neither the mechanisms nor whether the symptoms would respond to testosterone supplementation is known. Androgen substitution to treat symptoms possibly related to a male climacteric is still controversial. Studies are needed to evaluate the needs for and the effects of androgen treatment on vasomotor symptoms.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26461 (URN)10.1097/00042192-200310010-00013 (DOI)11009 (Local ID)11009 (Archive number)11009 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    3. Urinary excretion of calcitonin gene-related peptide in males with hot flushes after castration for carcinoma of the prostate
    Open this publication in new window or tab >>Urinary excretion of calcitonin gene-related peptide in males with hot flushes after castration for carcinoma of the prostate
    Show others...
    2001 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 35, no 2, p. 92-96Article in journal (Refereed) Published
    Abstract [en]

    Objective: The majority of men who undergo surgical or medical castration due to prostatic carcinoma develop vasomotor symptoms with hot flushes. The mechanisms behind these symptoms are poorly understood. One possible explanation is a release of the vasodilatory peptide calcitonin gene-related peptide (CGRP) from perivascular nerves, which seem to be involved in the mechanisms behind vasomotion and sweating in postmenopausal women. The aim of this report was to investigate whether CGRP is involved in vasomotion in men after castration therapy.

    Material and methods: Twenty-four hour urine excretion of CGRP was analysed in 15 men with prostatic carcinoma, using radioimmunoassay before and 3 months after surgical or medical castration.

    Results: Eleven of the 15 men developed hot flushes during the observation period of 3 months. Twenty-four hour urine excretion of CGRP did not change significantly after castration, either in the group as a whole or in those 11 men who developed hot flushes.

    Conclusions: Even though we did not observe any significant changes in 24-h urine excretion of the potent vasodilator CGRP after castration it is possible that serum levels of CGRP increase during hot flushes, without having an effect on the 24-h urine excretion of the peptide.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25429 (URN)10.1080/003655901750170380 (DOI)9875 (Local ID)9875 (Archive number)9875 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Momentary increase in plasma calcitonin gene-related peptide is involved in hot flashes in men treated with castration for carcinoma of the prostate
    Open this publication in new window or tab >>Momentary increase in plasma calcitonin gene-related peptide is involved in hot flashes in men treated with castration for carcinoma of the prostate
    Show others...
    2001 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 166, no 5, p. 1720-1723Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    In women the vasodilatory neuropeptides calcitonin gene-related peptide and neuropeptide Y seem to be involved in menopausal hot flashes. We assessed whether plasma calcitonin gene-related peptide and neuropeptide Y change during hot flashes in men after castration.

    Materials and Methods

    We evaluated 10 men 61 to 81 years old who underwent castration due to cancer of the prostate and had frequent hot flashes for changes in plasma calcitonin gene-related peptide and neuropeptide Y during 1 day at the outpatient clinic. At least 5 blood samples were obtained between flashes and 4 were obtained during each flash. The samples were analyzed for calcitonin gene-related peptide and neuropeptide Y using radioimmunoassay technique. Hot flashes were objectively recorded by measuring peripheral skin temperature and skin conductance.

    Results

    Plasma calcitonin gene-related peptide increased 46% (95% confidence interval 21 to 71) during flashes in the 6 men in whom it was measurable. This change was statistically significant (p = 0.028). The concentration of neuropeptide Y was below the detection limit. Skin conductance and temperature increased significantly during flashes.

    Conclusions

    Calcitonin gene-related peptide is involved in the mechanisms of hot flashes in men who underwent castration due to prostate carcinoma. Thus, there may be a similar mechanism of hot flashes in women and in men deprived of sex steroids.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25313 (URN)10.1016/S0022-5347(05)65660-1 (DOI)9754 (Local ID)9754 (Archive number)9754 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
  • 40.
    Spetz, Anna-Clara
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Hammar, Mats
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Lindberg, Bengt
    Department of Surgery, Kungälv Hospital, Kungälv, Sweden.
    Spångberg, Anders
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Prospective evaluation of hot flashes during treatment with parenteral estrogen or complete androgen ablation for metastatic carcinoma of the prostate2001In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 166, no 2, p. 517-520Article in journal (Refereed)
    Abstract [en]

    Purpose

    We evaluated the incidence and frequency of, and distress due to hot flashes after castration therapy with polyestradiol phosphate and complete androgen ablation.

    Materials and Methods

    A total of 915 men with metastatic prostate carcinoma enrolled in the Scandinavian Prostatic Cancer Group-5 trial study were randomized to intramuscular injections of 240 mg. Polyestradiol phosphate every 2 weeks for 8 weeks followed by monthly subcutaneous injections or complete androgen ablation, that is bilateral orchiectomy or 3.75 mg. of the gonadotropin-releasing hormone analog triptorelin monthly combined with 250 mg. of the antiandrogen flutamide 3 times daily. The incidence and frequency of, and distress due to hot flashes were recorded at regular intervals using a questionnaire.

    Results

    Of the 915 men 901 were evaluated at a median followup of 18.5 months. The incidence of hot flashes was 30.1% and 74.3% in the polyestradiol phosphate and complete androgen ablation groups, respectively (p <0.001). In the polyestradiol phosphate group the frequency of and distress due to hot flashes were significantly lower than in the androgen ablation group. There was complete relief from hot flashes in 50% of the men on polyestradiol phosphate during followup compared with none on androgen ablation. The incidence of hot flashes did not differ in men with and without tumor progression.

    Conclusions

    Endocrine treatment with polyestradiol phosphate induced fewer and less distressing hot flashes than complete androgen ablation. Flashes also disappeared to a greater extent during polyestradiol phosphate than during androgen ablation. The data in this study enable us to provide thorough individual information to patients on the risk and grade of expected distress and duration of hot flashes during polyestradiol phosphate or complete androgen ablation treatment.

  • 41.
    Spetz, Anna-Clara
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Hammar, Mats
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Pettersson, W
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Hot flushes and prostate cancer: pathogenesis and treatment2002In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 90, p. 476-476Article in journal (Refereed)
  • 42.
    Spetz, Anna-Clara
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Pettersson, Bill
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Thorell, Lars-Håkan
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Hammar, Mats
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Momentary increase in plasma calcitonin gene-related peptide is involved in hot flashes in men treated with castration for carcinoma of the prostate2001In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 166, no 5, p. 1720-1723Article in journal (Refereed)
    Abstract [en]

    Purpose

    In women the vasodilatory neuropeptides calcitonin gene-related peptide and neuropeptide Y seem to be involved in menopausal hot flashes. We assessed whether plasma calcitonin gene-related peptide and neuropeptide Y change during hot flashes in men after castration.

    Materials and Methods

    We evaluated 10 men 61 to 81 years old who underwent castration due to cancer of the prostate and had frequent hot flashes for changes in plasma calcitonin gene-related peptide and neuropeptide Y during 1 day at the outpatient clinic. At least 5 blood samples were obtained between flashes and 4 were obtained during each flash. The samples were analyzed for calcitonin gene-related peptide and neuropeptide Y using radioimmunoassay technique. Hot flashes were objectively recorded by measuring peripheral skin temperature and skin conductance.

    Results

    Plasma calcitonin gene-related peptide increased 46% (95% confidence interval 21 to 71) during flashes in the 6 men in whom it was measurable. This change was statistically significant (p = 0.028). The concentration of neuropeptide Y was below the detection limit. Skin conductance and temperature increased significantly during flashes.

    Conclusions

    Calcitonin gene-related peptide is involved in the mechanisms of hot flashes in men who underwent castration due to prostate carcinoma. Thus, there may be a similar mechanism of hot flashes in women and in men deprived of sex steroids.

  • 43.
    Spetz, Anna-Clara
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology.
    Zetterlund, Eva-Lena
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Hammar, Mats
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Incidence and management of hot flashes in prostate cancer.2003In: The journal of supportive oncology, ISSN 1544-6794, Vol. 1, no 4Article in journal (Other academic)
    Abstract [en]

    Hot flashes are as common in men who have been castrated due to prostate cancer as hot flashes are in women after menopause. The symptom can cause significant discomfort for a considerable length of time. The hot flashes are most likely caused by a reduction in sex-hormone levels, which, in turn, causes an instability in the hypothalamic thermoregulatory center. Calcitonin gene-related peptide is involved in menopausal hot flashes in women and possibly also in castrated men. The mainstays of treatment for castrated men with hot flashes remain estrogens, progesterone, and cyproterone acetate, each of which has different side effects. Other treatments for hot flashes include clonidine and antidepressants and, according to one uncontrolled study, electrostimulated acupuncture. Nonetheless, there is a need for more effective and less toxic treatments. In this review, we will discuss the prevalence, duration, distress, physiology, and treatment options of hot flashes in men subjected to castration therapy due to prostate cancer.

  • 44. Sriplakich, S
    et al.
    Jahnson, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Karlsson, MG
    Epidermal growth factor expression: predictive value for the outcome after cystectomy for bladder cancer?1999In: British Journal of Urology, ISSN 0007-1331, E-ISSN 1365-2176, Vol. 83, p. 498-503Article in journal (Refereed)
  • 45. Stattin, P
    et al.
    Johansson, R
    Damber, JE
    Hellström, M
    Hugosson, J
    Lund, R
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Johansson, JE
    Non-systematic screening for prostate cancer in Sweden2003In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 37, p. 461-465Article in journal (Refereed)
  • 46.
    Teriö, Heikki
    Linköping University, Department of Biomedical Engineering. Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Urodynamic modelling and measurement techniques for assessment of urethral function during micturition1989Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    According to Griffiths' theory of flow through elastic tubes the urinary flow is controlled by an elastic constriction. The mechanical properties of this flow-controlling zone are described by the intrinsic urethral pressure as a function of cross-sectional area given by the pressure/area relation p(A)=pmo + KnAn, where pmo is the minimal urethral opening pressure, A the cross-sectional area and Kn and n are parameters describing the distensibility of this zone. Values of the three parameters were estimated from pressure/flow data measured during micturition. The detrusor pressure was measured with suprapubic catheters connected to external transducers and urinary flow was recorded with a balance-type flowmeter with a rotating disc. The detrusor pressure as a function of the volume flow was described by pdet(Q)= pmo + LmQm, where Q is the volume flow and Lm and m parameters, and this function was fitted to recorded data. Using this model it is possible to describe urethral flow properties in a standardized way and to identify different biomechanical changes that may cause obstruction.

    21 randomly selected elderly men without voiding problems were examined urodynamically and the measured pressure/flow data was analysed according to the described model. 19 of these men had pressure/area relations with a low slope indicating high distensibility of the flow-controlling zone.

    The method has also been used to investigate 28 men with benign prostatic hypertrophy, 23 of whom were also studied postoperatively. Preoperatively the minimal opening pressure was substantially elevated compared to normal, parameter Lm was moderately increased and m usually had a low value. The flow-controlling zone therefore had a somewhat reduced distensibility. Postoperatively, the minimal opening pressure was much reduced and the slope of the pressure/flow relation also was lower. The pressure/area relations had lower slopes and the flow-controlling zone could be distended to larger maximum cross-sectional areas. However, in many cases the curve shape suggested that the distension might have been restricted by fibrosis.

    A new, non-invasive method based on detection of pressure variations from turbulent urethral flow was described. The method was studied in a urethral flow model for different degrees of obstruction and volume flows. The power spectrum for the detected signals showed increasing intensity and increased frequency content for increasing volume flow and degree of obstruction. The mean power frequency, which can be seen as a limit between the low and the high frequency parts of the spectrum, was used to characterize the spectrum. It was found to be related to the degree of obstruction and the volume flow.

  • 47.
    Tiselius, H-G
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Hellgren, E
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Radiology. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology UHL.
    Andersson, A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Borrud-Ohlsson, Ann
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Eriksson, I
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Minimally invasive treatment of infection Staghorn stones with schok wave lithotripsy and chemlysis.1999In: Scand J Urol Nephrol Suppl,1999, 1999, p. 286-290Conference paper (Refereed)
  • 48. Tyrrell, CJ
    et al.
    Altwein, JE
    Klippel, F
    Jurincic-Winkler, C
    Varenhorst, Eberhard
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Urology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Lunglmayr, G
    Boccardo, F
    Holdaway, IM
    Haefliger, J-M
    Jordaan, JP
    Comparison of an LH-RH analogue (Goeserelin acetate, ´Zoladex´) with combined androgen blockade in advanced prostate cancer: Final survival results of an internaitonal multicentre randomized-trial.2000In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 37, p. 205-211Article in journal (Refereed)
  • 49.
    Wyon, Yvonne
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Spetz, Anna-Clara
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Hammar, Mats
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Varenhorst, Eberhard
    Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Faculty of Health Sciences.
    Urinary excretion of calcitonin gene-related peptide in males with hot flushes after castration for carcinoma of the prostate2001In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 35, no 2, p. 92-96Article in journal (Refereed)
    Abstract [en]

    Objective: The majority of men who undergo surgical or medical castration due to prostatic carcinoma develop vasomotor symptoms with hot flushes. The mechanisms behind these symptoms are poorly understood. One possible explanation is a release of the vasodilatory peptide calcitonin gene-related peptide (CGRP) from perivascular nerves, which seem to be involved in the mechanisms behind vasomotion and sweating in postmenopausal women. The aim of this report was to investigate whether CGRP is involved in vasomotion in men after castration therapy.

    Material and methods: Twenty-four hour urine excretion of CGRP was analysed in 15 men with prostatic carcinoma, using radioimmunoassay before and 3 months after surgical or medical castration.

    Results: Eleven of the 15 men developed hot flushes during the observation period of 3 months. Twenty-four hour urine excretion of CGRP did not change significantly after castration, either in the group as a whole or in those 11 men who developed hot flushes.

    Conclusions: Even though we did not observe any significant changes in 24-h urine excretion of the potent vasodilator CGRP after castration it is possible that serum levels of CGRP increase during hot flushes, without having an effect on the 24-h urine excretion of the peptide.

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