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E Holmberg

Publications and source records attributed to E Holmberg.

At least 37 records · Page 2Linked to original sources
PubMed1999

Survival in conventionally treated younger (<60 years) multiple myeloma patients: no improvement during two decades. Nordic Myeloma Study Group (NMSG).

The patient registers of five prospective population based Nordic studies were reviewed for patients <60 yr. A total of 313 patients with symptomatic multiple myeloma were identified. Thirty-nine of them were judged retrospectively to have been ineligible for intensive chemotherapy regimens. The remaining 274 patients were considered appropriate as a historical control group for comparison with patients treated with high-dose chemotherapy and autologous stem cell support. Of these, 32 had been diagnosed during the period 1970-83, 101 during the period 1984-89 and 141 during the period 1990-92. The median age was 54 yr. Six percent were Durie/Salmon stage I, 38% stage II and 56% stage III. Melphalan-prednisone was used for initial therapy in 87%. Median survival for all patients with symptomatic myeloma was found to be 41 months, and for those selected for the control group 44 months, with no noted differences between the aforementioned diagnostic periods. We conclude that the expected median survival is 44 months for myeloma patients <60 yr who may be considered for high-dose therapy protocols. New developments in chemotherapy and supportive therapy, achieved during the two decades which preceded the use of high-dose chemotherapy with stem cell rescue, have not changed the overall prognosis in multiple myeloma.

Age Factors↗
PubMed1999

Breast cancer risk after radiotherapy in infancy: a pooled analysis of two Swedish cohorts of 17,202 infants.

The incidence of breast cancer was studied in a cohort of 17,202 women irradiated for skin hemangioma in infancy at the Radiumhemmet, Stockholm, or the Sahlgrenska University Hospital, Gothenburg. A major part of the cohort had been treated with radium-226 applicators, and the mean absorbed dose to the breasts was 0.29 Gy (range <0.01-35.8 Gy). Two hundred forty-five breast cancers were diagnosed in the cohort during the period 1958-1993, and the standardized incidence ratio (SIR) was 1.20 (95% CI 1.06-1.36). Different dose-response models were tested, and a linear model gave the best fit. Neither age at exposure, breast dose rate, ovarian dose nor time since exposure had any statistically significant modifying effect, and breast dose was the only determinant of risk. The excess relative risk per gray (ERR/Gy) was 0.35 (95% CI 0.18-0.59), which is lower than in most other studies.

Adolescent↗
PubMed1998

Alanine screening mutagenesis establishes tyrosine 60 of bovine insulin-like growth factor binding protein-2 as a determinant of insulin-like growth factor binding.

The determinants of insulin-like growth factor (IGF) binding to its binding proteins (IGFBPs) are poorly characterized in terms of important residues in the IGFBP molecule. We have previously used tyrosine iodination to implicate Tyr-60 in the IGF-binding site of bovine IGFBP-2 (Hobba, G. D., Forbes, B. E., Parkinson, E. J., Francis, G. L., and Wallace, J. C. (1996) J. Biol. Chem. 271, 30529-30536). In this report, we show that the mutagenic replacement of Tyr-60 with either Ala or Phe reduced the affinity of bIGFBP-2 for IGF-I (4.0- and 8.4-fold, respectively) and for IGF-II (3.5- and 4.0-fold, respectively). Although adjacent residues Val-59, Thr-61, Pro-62, and Arg-63 are well conserved in IGFBP family members, Ala substitution for these residues did not reduce the IGF affinity of bIGFBP-2. Kinetic analysis of the bIGFBP-2 mutants on IGF biosensor chips in the BIAcore instrument revealed that Tyr-60 --> Phe bIGFBP-2 bound to the IGF-I surface 3.0-fold more slowly than bIGFBP-2 and was released 2.6-fold more rapidly than bIGFBP-2. We therefore propose that the hydroxyl group of Tyr-60 participates in a hydrogen bond that is important for the initial complex formation with IGF-I and the stabilization of this complex. In contrast, Tyr-60 --> Ala bIGFBP-2 associated with the IGF-I surface 5.0-fold more rapidly than bIGFBP-2 but exhibited an 18.4-fold more rapid release from this surface compared with bIGFBP-2. Thus both the aromatic nature and the hydrogen bonding potential of the tyrosyl side chain of Tyr-60 are important structural determinants of the IGF-binding site of bIGFBP-2.

Animals↗
PubMed1998

Soft tissue sarcoma after treatment for breast cancer--a Swedish population-based study.

The aim was to quantify the risk of post-treatment sarcoma in breast cancer patients. All 122,991 women with a breast cancer from 1958 to 1992 in the Swedish Cancer Register were followed up for soft tissue sarcomas and 116 were found, giving a standardised incidence ratio of 1.9 (95% CI 1.5-2.2). The absolute risk was 1.3 per 10(4) person-years. The sarcomas were located in the breast region or on the ipsilateral arm in 63% (67/106). There were 40 angiosarcomas and 76 sarcomas of other types. In a case-control study, angiosarcoma correlated significantly with lymphoedema of the arm, odds ratio (OR) 9.5 (95% CI 3.2-28.0), but no correlation with radiotherapy was observed. For other types of sarcoma there was a correlation with the integral dose. The dose-response relationship indicated that the risk increased linearly with the integral dose to 150-200 J and stabilised at higher energies. The OR was 2.4 (95% CI 1.4-4.2) for an energy of 50 J, approximately corresponding to the radiation of the breast after breast-conserving surgery. Thus, only oedema of the arm correlated with angiosarcoma, but for other types of sarcoma the integral dose of radiotherapy was a predictor of the risk.

Adult↗
PubMed1998

Prognostic value of bone marrow biopsy in operable breast cancer patients at the time of initial diagnosis: Results of a 20-year median follow-up.

From May 1975 until May 1980,128 operable breast cancer patients, clinical stage I-II, had a core bone marrow biopsy (BMB) from the posterior iliac crest as a part of the routine diagnostic work-up at the time of initial diagnosis. The mean age of the patients was 56 years, range 26-93. In a previous study on this material, 10 patients (7.8 per cent) were positive for tumor cells and 118 negative by conventional histopathology of BMB [1]. In 1996 we reexamined all BMB separately at two laboratories, using monoclonal antibodies against cytokeratins AE1-AE3, KL1, CAM 5-2 (DOP), and DC10, BA17 (MCI). The number of extrinsic cells in the bone marrow was graded positive for micrometastases when > or = 5 cells or suspicious when 1-4 cells per approximately 2 x 10(6) bone marrow cells were found, using high power field magnification. Micrometastases were detected in 17 patients (13.3 per cent) and another 8 patients were classified as suspicious. The presence of micrometastases was correlated to the axillary lymph node stage and primary tumor location. Median follow-up was 20 years. All 17 micrometastatic patients relapsed and died within 6 years of disease progression with evident osseous metastases. There was one disease-free survivor of the 8 patients with suspicious BMB after 17 years of follow-up. The median overall survival was significantly shorter in tumor-cell positive patients, being 1.9 years compared to 11.7 years in the BMB negative and BMB suspicious groups (p < 0.0001). Immunohistochemical analysis of core BMB taken postoperatively may be useful in predicting the prognosis in patients with breast cancer clinical stage I-II.

Adult↗
PubMed1998

DGGE screening of mutations in mismatch repair genes (hMSH2 and hMLH1) in 34 Swedish families with colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited syndrome which confers an increased risk for colorectal cancer and endometrial cancer as well as other tumors. It is caused by germline DNA mismatch repair (MMR) gene mutations in five MMR genes, hMSH2, hMLH1, hPMS1, hPMS2 and hMSH6. Finding mutations in these high risk families means that you can offer presymptomatic carrier diagnosis and thereby identify individuals with a very high risk for cancer. These persons benefit from counseling and should be offered surveillance. We have used DGGE to screen members from 34 families for mutations in hMLH1 and hMSH2. Six mutations in five families were found, five of these mutations are new. Besides, three new polymorphisms were identified. The mutations were found in two of seven Amsterdam criteria HNPCC families and in three of four families with at least one case of early onset of CRC (before 35), suggesting there are appropriate families to be chosen for mutation screening in MMR genes.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Long-term followup of a bladder carcinoma cohort: routine followup urography is not necessary.

PURPOSE: We evaluate whether routine excretory urography is needed in the long-term followup of patients with bladder carcinoma. MATERIALS AND METHODS: A total of 680 patients with an initial diagnosis of bladder carcinoma from 1987 to 1988 in western Sweden were prospectively registered and followed for at least 5 years. All carcinomas of the kidney, renal pelvis and ureter, and all surgically treated cases of ureteral stricture were registered. RESULTS: During followup renal pelvic or ureteral carcinoma developed in 16 patients, renal cell carcinoma was diagnosed in 2 and 6 underwent surgery for benign obstruction of the distal ureter. CONCLUSIONS: The low annual incidence of malignant upper urinary tract and renal tumors as well as ureteral strictures supports our opinion that routine imaging of the upper urinary tract is not indicated during followup of patients with bladder carcinoma. We recommend urography at initial diagnosis of bladder carcinoma, when tumor progression occurs and when symptoms or signs raise suspicion of upper urinary tract disease.

Aged↗
PubMed1998

Intracranial tumors after exposure to ionizing radiation during infancy: a pooled analysis of two Swedish cohorts of 28,008 infants with skin hemangioma.

The risk of intracranial tumors after exposure to ionizing radiation during infancy has been studied in a pooled analysis of two Swedish hemangioma cohorts (n = 28,008). The mean absorbed intracranial dose was low (7 cGy, range 0-11.5 Gy). The cohorts were followed up in the Swedish Cancer Register for incident intracranial tumors during the period 1958-1993. Eighty-eight tumors were found in 86 individuals compared to 60.72 expected [standardized incidence ratio (SIR) 1.42, 95% confidence interval (CI) 1.13-1.75]. The SIR increased significantly in ascending dose categories (P = 0.02). Dose-response analyses were performed with Poisson regression methods. There was a significant effect of dose, and the dose-effect relationship was negatively modified by age at first treatment. This indicates a higher risk for those exposed earlier in life. A linear dose-response model modified by age at first treatment resulted in the best fit. The excess relative risk (ERR) was 2.7/Gy (95% CI 1.0-5.6). The ERR/Gy was 4.5 if the treatment was given before 5 months of age, 1.5 if it was given at 5-7 months and 0.4 if it was given later. The study thus strongly indicates that there exists a dose-response relationship between absorbed dose in the brain and the subsequent risk of developing an intracranial tumor and that the risk is higher among infants exposed at younger ages.

Adult↗
PubMed1997

The importance of the depth of invasion in stage T1 bladder carcinoma: a prospective cohort study.

PURPOSE: We studied the depth of invasion in the lamina propria in all patients with primary stage T1 bladder cancer in a geographical region and related the findings to the long-term prognosis. MATERIALS AND METHODS: All 121 primary stage T1 tumors diagnosed in western Sweden between 1987 and 1988 were analyzed with respect to the depth of invasion in relation to the lamina muscularis mucosae. All clinical records were reviewed in 1994 and 1995. RESULTS: More than 90% of the histopathological specimens could be separated into superficially (pT1a) or deeply (pT1b) invasive stage T1 tumors. Grade 3 tumors were significantly more common among patients with stage pT1b disease (79 versus 40%, p < 0.001). Patients with stage pT1b grade 3 cancer had a higher progression rate (58 versus 36%, p > 0.05) and an almost doubled risk of dying of bladder carcinoma compared to those with stage pT1a grade 3 disease (45 versus 23%, p > 0.05). Carcinoma in situ at the primary operation was associated with an impaired prognosis in patients with grade 3 tumors regardless of the depth of invasion in the lamina propria. CONCLUSIONS: The prognosis is poor in patients with deep lamina propria invasion (stage pT1b) treated with transurethral resection alone. Patients treated with radical cystectomy had excellent survival regardless of the depth of invasion in the lamina propria. Radiotherapy was associated with poor survival.

Aged↗
PubMed1997

Fine mapping of the locus for nevoid basal cell carcinoma syndrome on chromosome 9q.

The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder, characterized by predisposition to multiple early basal cell carcinomas of the skin and several other tumours as well as frequent occurrence of developmental anomalies. The gene has previously been mapped to chromosome 9q22 and is believed to function as a tumour suppressor. We have applied linkage and haplotype analysis to four Swedish nevoid basal cell carcinoma syndrome families to refine the localization of the nevoid basal cell carcinoma syndrome gene. Information from critical recombinants localizes the gene proximal of marker D9S287, which in combination with analysis of loss of heterozygosity in a hereditary cardiac fibroma has allowed us to define a minimal candidate region of 1Mb or less for the nevoid basal cell carcinoma gene flanked by the markers D9S280 and D9S287 in the 9q22.3 area.

Adolescent↗
PubMed1997

Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer.

Previous studies of high-risk breast cancer families have proposed that two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may account for at least two-thirds of all hereditary breast cancer. We have screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using the protein-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained cases of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in breast tumors from three unrelated males with unknown family history, suggesting that at least one BRCA2 founder mutation exists in the Scandinavian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mutations (9 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated products. The relatively low frequency of BRCA1 and BRCA2 mutations in the present study could be explained by insufficient screening sensitivity to the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families, additional uncharacterized BRCA genes.

Adult↗
PubMed1997

Intracranial tumors after radium treatment for skin hemangioma during infancy--a cohort and case-control study.

The risk of developing intracranial tumors was studied in a Swedish cohort of 11,805 infants treated with 226Ra for hemangioma of the skin between 1930 and 1965. The cohort was followed up in the Swedish Cancer Register during the years 1958 through 1992, giving 402,958 person-years at risk. Forty-seven intracranial tumors developed in 46 individuals. The standardized incidence ratio (SIR) was 1.80 (95% CI 1.32-2.39). An excess number of cases was found for many histopathological subgroups, although the excess was statistically significant only for gliomas (n = 23, SIR 1.89, 95% CI 1.20-2.83) and meningiomas (n = 8, SIR 2.42, 95% CI 1.06-4.77). Absorbed doses to the brain have been calculated. The mean dose to the brain was only 7.2 cGy. The dose response was evaluated by Poisson regression methods. There was an excess of intracranial tumors in all dose categories, but no clear dose-response relationship could be seen for the data. This indicates that explanations other than irradiation may also be involved. The selection of the reference population has been studied and confirmed to be representative. For individuals treated before 7 months of age, however, the data could be fitted to both the linear and the linear-quadratic model. These results may indicate that the youngest infants may be more sensitive to ionizing radiation and that even very low doses to the brain may increase the risk for intracranial tumors.

Brain Neoplasms↗
PubMed1996

Prognostic factors for acute and late skin reactions in radiotherapy patients.

PURPOSE: Patients treated with identical radiotherapy schedules show a substantial variation in the degree of acute and late normal tissue reactions. To identify any possible contributing factors to this phenomenon, we have analyzed the treatments of 402 breast cancer patients. METHODS AND MATERIALS: The patients received adjuvant postoperative radiotherapy between 1972 and 1985 and have been followed up since then. Multivariate analyses were performed with peak reflectance erythema and peak acute reaction score as endpoints for the acute reactions, and with progression rate of telangiectasia as well as telangiectasia score as endpoints for the late reactions. Twenty patient- and treatment-related factors were tested such as age, menopausal status, hemoglobin level, serum calcium, smoking habits, hypothyroidism, diabetes, hypertension, blood pressure, cardiovascular and autoimmune disease, the influence of hormone therapy and chemotherapy, pretreatment reflectance value, acute skin reactions, radiation quality, individual dose, bilateral fields, and the total effect (TE) for the dose schedule applied. RESULTS: The TE was a strong prognostic factor for all endpoints. In addition to TE, blood pressure was prognostic for the peak erythema measured by reflectance spectrophotometry, and the pretreatment reflectance value was prognostic for the acute score. The only independent prognostic factors found for the progression of skin telangiectasia and telangiectasia score except for TE were the individual dose and the acute skin reactions. CONCLUSIONS: These factors explained at most about 30% of the variance describing the total patient-to-patient variability for each endpoint. The remaining variability is still unexplained but may be related to individual differences in cellular radiosensitivity, partly determined by genetic variations and partly by unknown epigenetic factors.

Adult↗
PubMed1996

Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation.

The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility, in particular to basal cell carcinoma. The human homologue of Drosophila patched (PTCH) was recently identified, mapped to the NBCCS locus on chromosome 9q22.3, and found mutated in patients with NBCCS and also in sporadic basal cell carcinomas. Here we show germ-line PTCH mutations in three families with NBCCS. We demonstrate that a germ-line PTCH frameshift deletion in one patient with NBCCS was accompanied by loss of the normal copy of PTCH in a tumor developed in the same patient. Another basal cell carcinoma from this patient did not show the loss of the normal copy of PTCH, instead a missense mutation in a highly conserved residue was identified in the nondeleted allele, illustrating two different mechanisms of PTCH inactivation in different tumors derived from the same NBCCS patient. We also show somatic PTCH mutations in 4 basal cell carcinomas identified by analyzing 18 non-NBCCS patients with sporadic tumors. These data provide further support for PTCH as an important tumor suppressor gene in the development of the most common human cancer.

Adult↗
PubMed1996

Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

Alleles↗
PubMed1996

Soft tissue sarcoma after treatment for breast cancer.

In a register study all women in the West of Sweden Health Care Region with a breast cancer diagnosed between 1960 and 1980 (n = 13,490) were followed up in the Swedish Cancer Register to the end of 1988 for later occurrence of a soft tissue sarcoma (STS). Nineteen sarcomas were reported, whereas 8.7 were expected and the relative risk (RR) was 2.2 (CI 95% 1.3-3.4). The absolute risk was 1.7/10(4) person years (PY) in comparison with 0.8 expected. To obtain a more detailed analysis of the associations between arm lymphoedema, radiotherapy and STS development, and to control the quality of the register data, a case control study was also performed. Clinical records from the different hospitals in the region were collected for all the 19 cases as well as for three selected controls per case. The histopathology of the cases were reviewed, and one of the cases was reclassified as a malignant melanoma and excluded from further analysis. Thirteen of the cases were clustered around the treated breast area. To quantify the exposure to radiotherapy, the integral dose was estimated. The presence of lymphedema was included as a binary variable in the analysis. The exact conditional randomisation test indicated a significant correlation between the integral dose and the development of an STS (p = 0.008) and this association was still significant after stratification for arm oedema. A conditional logistic regression analysis with STS as the dependent variable and the integral dose as the explanatory variable gave an odds ratio (OR) of 5.2/100 J (CI 95% 1.3-21.2), and if this regression was restricted only to the STS developing in the radiation fields the OR was 3.2/100 J (CI 95% 0.8-12.9). Thus, the excess of STS in this breast cancer cohort was very low (0.9/10(4) PY). However the integral dose correlates well to the development of STS and can be useful in quantifying even small risks of secondary malignancies in the breast cancer population.

Arm↗
PubMed1996

Physicians' attitudes toward clinical trials and their relationship to patient accrual in a Nordic multicenter study on myeloma.

Ninety-nine physicians participating in a Nordic multicenter trial on myeloma in 1990-1994 were surveyed, by means of a mailed questionnaire, with respect to their attitudes toward clinical trials and their opinions regarding the importance of certain factors influencing patient accrual. The inclusion rate of each participating clinic was recorded. Questions related to attitudes of presumed importance for patient accrual were analyzed for associations between the response distribution and the inclusion rate for the corresponding clinics. Ninety-three of the surveyed physicians responded to the questionnaire. The survey indicated that the physicians considered the scientific purpose of a trial to be the most important factor for patient accrual, followed by the simplicity of study protocol, the rightness of ethical aspects, the quality of communication with the study organization, and the degree of participation in investigators' meetings. A positive correlation to patient accrual was found for several attitudes held by the participating physicians, including their perception of the importance of a quality-of-life study in the protocol, their conception of the simplicity of the study protocol, their frequency of participation in investigators' meetings, and their awareness of cost and reimbursement levels for entered patients.

Attitude of Health Personnel↗