Biomedical subjects

L Holmberg

Publications and source records attributed to L Holmberg.

At least 109 records · Page 6Linked to original sources

PubMed1997

Arm morbidity after sector resection and axillary dissection with or without postoperative radiotherapy in breast cancer stage I. Results from a randomised trial. Uppsala-Orebro Breast Cancer Study Group.

The incidence and time course of arm morbidity after sector resection and axillary dissection with or without postoperative radiotherapy to the breast was assessed in a prospective randomised trial among 381 patients with stage I breast cancer. At 3-12 months, arm symptoms were reported by 59/110 of the patients who had > or = 10 lymph nodes found in the axillary specimen versus 85/253 in whom < 10 lymph nodes were found (P = 0.002); at 13-36 months, the corresponding figures were 35/106 versus 44/225 (P = 0.001). Postoperative wound complications increased the incidence of arm symptoms at 3-12 months from 104/283 to 39/79 at 3-12 months (P = 0.03). Employed patients and patients < 65 years of age reported arm symptoms at 3-12 months in 86/161 and 94/191 compared to 58/207 and 50/177 among retired patients and patients > or = 65 years of age, respectively (P = 0.0001 and P = 0.0002, respectively). In a multivariate logistic regression analysis at 3-12 months, only young age (relative risk = 0.93 per year of increasing age, 95% CI 0.91-0.97) and the number of lymph nodes found in the axillary specimen (relative risk = 1.11 per lymph node found, 95% CI 1.05-1.18) remained statistically significant. No negative impact on arm morbidity was found by the addition of postoperative radiotherapy only to the breast, either in univariate or multivariate models. We conclude that factors directly related to the extent of the surgical procedure and young age are determinants of arm morbidity after breast preserving treatment for stage I breast cancer. Arm symptoms are most common during the first year after treatment and are reduced over the subsequent 2-3 years by around 40-50%.

Age Factors↗

PubMed1997

Mammographic screening for breast cancer. What cancers do we find?

The aim of this study was to compare lymph node involvement of breast cancer cases detected at mammography screening with clinically-detected cases. During a 3-year period, 273 primary breast cancers were detected in a population-based screening programme, and 149 primary breast cancers were diagnosed clinically. Lymph node involvement was evaluated in univariate and multivariate logistic regression models correcting for tumour size, histological grade, steroid receptor status and DNA-ploidy. Patients with screen-detected cancers had a low relative risk of having lymph node metastases (univariate, OR = 0.31; 95% confidence interval = 0.19-0.52). In the multivariate logistic regression model, the relative risk was halved (OR = 0.47; 0.28-0.78). The reduced risk was more pronounced for women younger than 50 years of age compared to older women. The risk for screen-detected cases of having lymph node metastases at diagnosis was statistically significantly lower than for clinically-detected cases. The marked reduction, even when correcting for tumour size, makes it less likely that factors such as detection of clinically innocent tumours, length bias sampling or clinical symptoms related to axillary metastases can explain the whole difference. The results indicate at least part of the effect may be explained by tumour progression in the late preclinical detectable phase.

Adult↗

PubMed1997

Breast cancer mortality in relation to self-reported use of breast self-examination. A cohort study of 450,000 women.

The benefits of breast self-examination (BSE) for reducing mortality from breast cancer are uncertain. We conducted an analysis of the relationship between self-reported practicing of BSE and mortality from breast cancer over 13 years in a cohort of over 548,000 women. The report of practicing BSE was unrelated to breast cancer mortality. There was a small beneficial effect in those women who were the thinnest, but this effect was small and not statistically significant. BSE was otherwise equally ineffective in subgroups defined by obesity level and family history of breast cancer. We conclude that BSE, as practiced by American women in 1959, did not reduce the risk of mortality from breast cancer.

Adult↗

PubMed1997

Risk factors for local recurrence after conservative treatment in stage I breast cancer. Definition of a subgroup not requiring radiotherapy.

BACKGROUND: Risk factors for local recurrence after breast-conserving treatment of early breast cancer have not previously been evaluated in settings where mammography has been a major pathway to diagnosis of both primary tumour and recurrences or in patients treated surgically by a formal sector resection. PATIENTS AND METHODS: Three hundred eighty-one women with stage 1 primary breast cancer were randomised after a standardised sector resection to either a course of postoperative radiotherapy to 54 Gy to the breast (XRT group) or to surgery alone (non XRT group). At five years, 43 local recurrences, six of them in the XRT group, appeared. Patient characteristics collected from the medical records, histopathological characteristics determined by re-examination of slides, and mammographic characteristics from the pre-operative mammograms were evaluated as risk factors for recurrence by univariate and multivariate Cox proportional hazards models. Results are reported as relative hazards (RH) with 95% confidence intervals (95% CI). RESULTS: In the univariate analysis comedo cancer, RH 3.5 (95%, CI 18 6.7), lobular cancers RH 2.8 (95% CI 1.1 7.1), mammographic appearance as circular/oval shaped density, RH 2.3 (95% CI 1.1 4.51, and mammographic appearance as a stellate lesion with microcalcifications inside the lesion, RH 3.8 (95% CI 1.1-13.0) were identified as risk factors for local recurrence. Age, with a RH of 0.97 (95% CI 0.94 0.99) for each increasing year was inversely associated with risk. A multivariate analysis, which also took postoperative radiotherapy into account, only showed comedo cancers with a RH 2.6 (95% CI 1.3-5.0) and mammographic appearance of a stellate lesion with microcalcification inside the lesion RH 4.5 (95% CI 1.1-17.6) to be statistically significant. The estimates for age RH 0.98 (95% CI 0.95 1.01 and lobular cancers RH 2.5 (95%, CI 0.98 6.6) were marginally changed, with widened CIs. Patients > 60 years of age, without comedo or lobular carcinomas were found to be at low risk 15.9% at five years in Kaplan Meyer estimate) of local recurrence, even without postoperative radiotherapy. CONCLUSION: Low age, comedo and lobular cancers and mammographic appearance of the tumour as a stellate lesion with microcalcifications inside the lesion indicate an increased risk for local recurrence after sector resection in stage 1 tumours at five years. Patients > 60 years of age without comedo or lobular cancers are at low risk for local recurrence at five years even without postoperative radiotherapy.

Combined Modality Therapy↗

PubMed1997

Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center.

BACKGROUND: Little is known about factors related to prognosis in patients with carcinoid disease. In this study we have tried to identify such factors. PATIENTS AND METHODS: We have evaluated 301 consecutive carcinoid patients (256 midgut, 39 foregut and six hindgut) referred during 15 years for medical treatment with respect to tumor distribution, hormone production, prognostic factors and survival. RESULTS: Survival was significantly shorter in midgut carcinoid patients with > or = 5 liver metastases or with high levels of urinary 5-hydroxyindoleacetic acid, plasma chromogranin A or neuropeptide K. By univariate analysis, these variables together with the presence of carcinoid syndrome were related to a higher risk of dying. In multivariate analyses, performed in the 71 patients with full information on all variables, advanced age and plasma chromogranin A > 5000 micrograms/l were independent predictors of overall survival. CONCLUSIONS: Poor prognostic factors for midgut carcinoid patients were multiple liver metastases, presence of carcinoid syndrome and high levels of the tumor markers studied. In this study the only independent predictors of bad prognosis in midgut, carcinoid patients were advanced age, which however is inherently related to overall survival, and plasma chromogranin A > 5000 micrograms/l. Thus, chromogranin A may prove to be an important prognostic marker for patients with carcinoid tumors.

Adolescent↗

PubMed1997

The cost-effectiveness of routine postoperative radiotherapy after sector resection and axillary dissection for breast cancer stage I. Results from a randomized trial.

BACKGROUND: Cost-effectiveness of routine postoperative radiotherapy after breast-conserving surgery has not been prospectively evaluated earlier. In times of rationing of medical resources, valid assessments of cost-effectiveness are important for rational allocation of resources. PURPOSE: Cost and cost-effectiveness of routine postoperative radiotherapy was calculated in a prospective randomized trial comparing sector resection plus axillary dissection with (XRT group) or without (non-XRT group) postoperative radiotherapy in breast cancer stage I. Three hundred eighty-one patients were included. After a median follow-up of five years 43 local recurrences, six of them in the XRT-group occurred (P < 0.0001). No difference in regional and distant recurrence (P = 0.23) or survival (P = 0.44) was observed. PATIENTS AND METHODS: Direct medical costs as well as indirect costs in terms of production lost during the treatment period and travel expenses were estimated from data in the medical records and the national insurance registry of each patient. Average costs of different treatment activities and measures were estimated for the XRT-group and the non-XRT group respectively. From these estimates differences in costs and effectiveness between the groups were calculated and marginal cost-effectiveness ratios were estimated. For the construction of QALYs each life-year was quality-adjusted by a utility value depending on which health state the patient was considered to perceive. RESULTS: Taking into account the cost of primary treatment, the cost of follow-up, the cost of treatment of a local recurrence, travel expenses and indirect costs (production lost) excluding costs for treatment of regional and distant recurrence the cost per avoided local recurrence at five years was SEK 337,727 ($44,438, Pounds 27,018). Adjustment for quality of life showed a cost for every gained QALY to be SEK approximately 1.6 million, ($210,526, Pounds 128,000), range SEK 0.2-3.9 million ($26,315-513,158, Pounds 16,000-312,000). CONCLUSION: The cost of routine postoperative radiotherapy after sector resection and axillary dissection in breast cancer stage I per avoided local recurrence and gained QALY is high. The cost per gained QALY show great variation depending on utility value, which in this study was derived from external observers and not from the patients themselves. These results stress the importance of identifying risk factors for local recurrence, better understanding of impact on quality of life of a local recurrence and adding cost evaluations to clinical trials in early breast cancer.

Breast Neoplasms↗

PubMed1997

High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer.

The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens.

Adult↗

PubMed1997

Bernard-Soulier syndrome Karlstad: Trp 498-->Stop mutation resulting in a truncated glycoprotein Ib alpha that contains part of the transmembranous domain.

In Bernard-Soulier syndrome, a hereditary bleeding disorder, the platelets are deficient in the glycoprotein (GP) Ib-IX-V complex, a major receptor for the von Willebrand factor. The components of the complex are encoded by separate genes. Patients with this syndrome have a variable expression level of the receptor protein on platelets depending on the specific genetic abnormality. We describe a patient with life-long bleeding symptoms, who is homozygous for a unique stop mutation. Trp 498-->Stop in the GPIb alpha gene, resulting in a truncated GPIb alpha polypeptide chain. In contrast to previously reported truncated forms of GPIb alpha, this form contains a portion of the transmembranous domain as well as the juxtamembranous cysteines engaged in a disulphide bond with GPIb beta. Flow cytometry with GPIb alpha antibodies demonstrated the presence of GPIb on the patient's platelets, although in reduced amounts compared to normal controls. GPIX was similarly detectable. Immunoblotting demonstrated that the patient synthesized a truncated GPIb alpha of the expected size of 130 K, which was, however, sensitive to proteolysis. These studies show that GPIb alpha lacking the intracytoplasmic tail can be expressed at the platelet surface provided elements of the transmembranous domain are present.

Aged↗

PubMed1997

The influence of mammography screening on the pathological panorama of breast cancer.

The pathologist describes the biological domain of breast cancer in which the clinician works. Over the last 20 years there have been indications that the biological domain has shifted following the introduction of fine-needle biopsies, clinical mammography, and later screening mammography. The most commonly used parameters for staging, classification and grading of cancer in some respects probably reflect the biological domain. We describe how the pathological panorama of breast cancer has changed with the introduction of population-based mammography screening. Our experiences are based on a consecutive series of 1961 breast cancers diagnosed from 1977 to 1994 in a region where screening mammography was introduced in 1988. All results, including histological classification and grading were prospectively registered in a computerized data base. There were more comedo than tubuloductal carcinomas and there was a corresponding preponderance of grade III tumours in the youngest and a high incidence of tubuloductal, lobular and colloid cancers in the oldest age group. The proportion of women with comedo carcinoma decreased after 1987. Looking at changes in the grade distribution after 1987, the proportion of women with grade I tumours increased and grade III tumours decreased in women over 50 years of age, but in the youngest women only marginal changes were noted. Very few in situ carcinomas were diagnosed in the prescreening period. About 11% of all tumours were in situ after 1987. The percentage of node-positive cancer decreased in the screening period in all histological types of cancer regardless of tumour size. The percentage of small tumours < or = 20 mm increased with time, though less so for comedo carcinomas. Comedo carcinomas dominate among the largest cancers most frequently detected clinically. From a biological standpoint it is interesting to note that screening seems to entail a larger shift in the biological domain in older as compared to younger women. Furthermore, comedo carcinomas seem to be less well detected by the screening procedure.

Adult↗

PubMed1997

Effect of estrogen and estrogen-progestin replacement regimens on mammographic breast parenchymal density.

PURPOSE: Hormone replacement therapy (HRT) may increase the mammographic density with a possible reduction in the sensitivity or specificity. If so, the benefit of mammographic screening in women using HRT could be compromised. We evaluated the hypothesis that HRT regimens have differential effects on the mammographic density depending on treatment regimens or on age. PATIENTS AND METHODS: Among 31,498 Swedish women who received mammographic screening, we selected 554 women who started HRT after the first examination and who were current users at the second, and 554 age-matched women who had never received HRT. Mammograms were examined in a blinded review. The changes in density between the two examinations, graded as moderate or weak reduction, no change, or weak, moderate, or substantial increase, were assessed. We studied four HRT regimens-estradiol compounds only, estradiol compounds cyclically or continuously combined with progestins, and weak estrogens-and used descriptive statistics and logistic regression to analyze the association between HRT and density change. RESULTS: Density increased in 10% and 28% of women who received estradiol compounds with cyclically or continuously combined progestins, respectively, but in only 3% of unexposed women. Logistic regression analyses showed an elevated risk of a density increase (relative risk [RR] = 3.6; 95% confidence interval [CI], 1.6 to 7.7) in women who received cyclically combined regimens or continuously combined regimens (RR = 12.4; 95% CI, 6.3 to 24.4) compared with unexposed women. Women > or = 50 years of age had even stronger associations; RRs in women on estradiol only, the cyclically combined and the continuously combined regimens were 32.2 (95% CI, 3.9 to 267.5), 21.9 (95% CI, 1.9 to 251.5), and 176.9 (95% CI, 22.8 to 1,372.7), respectively. CONCLUSION: HRT with estradiol-progestin regimens, especially continuously combined, may increase the mammographic density in a substantial proportion of women.

Estradiol↗

PubMed1997

von Willebrand factor mediates increased platelet retention in recurrent thrombotic thrombocytopenic purpura.

The plasma cryoprecipitate of two brothers with recurrent thrombotic thrombocytopenic purpura (TTP) was previously found to mediate increased platelet retention and contain ultra-large von Willebrand factor (vWF) multimers during remissions. We conducted this study to examine if vWF is involved in the increased platelet retention in TTP. Platelet retention decreased when the patients' plasma was incubated with a monoclonal antibody directed to the vWF epitope which interacts with the platelet receptor glycoprotein Ib or when incubated with a Fab-fragment directed to the platelet receptor glycoprotein IIb/IIIa. Replacement of patient vWF with an equivalent concentration of a factor VIII/vWF concentrate containing no ultra-large vWF multimers was accompanied by a normalization of platelet retention. These results indicate that vWF is involved in the increased platelet retention. Analysis of polymorphic markers in the vWF gene demonstrated that a recessive mutation in this gene is unlikely.

Adolescent↗

PubMed1997

High-dose busulfan, melphalan, and thiotepa followed by autologous peripheral blood stem cell transplantation in patients with aggressive lymphoma or relapsed Hodgkin's disease.

The purpose of this study was to evaluate the efficacy of high-dose chemotherapy with busulfan (Bu), melphalan (Mel), and thiotepa (TT), and of autologous peripheral blood stem cell (PBSC) infusion in patients with aggressive non-Hodgkin's lymphoma (NHL) or relapsed Hodgkin's disease (HD). Forty patients, 23 with intermediate (n= 18) or high-grade (n=5) NHL and 17 with HD received Bu (12 mg/kg), Mel (100 mg/kg), TT (450-500 mg/m2) [corrected], and autologous PBSC infusion. Of 27 patients with more advanced disease, 16 had primary refractory disease, 8 were in refractory relapse, and 3 were in third remission. Of 13 patients with less advanced disease, 7 were in untreated or responding first relapse and 3 were in second remission, whereas 3 with high-grade NHL were in first remission. Twenty-nine patients (73%) had received prior radiotherapy (RT) prohibiting a total-body irradiation (TBI)-based conditioning regimen. The projected 2-year probabilities of survival, event-free survival, and relapse for all patients were 0.60, 0.46, and 0.31 (0.85, 0.85, and 0.15 for patients with less advanced disease and 0.48, 0.30, and 0.37 for patients with more advanced disease). The probability of nonrelapse mortality in the first 100 days was 0.17. Severe idiopathic pneumonia syndrome was not observed in any patients with less advanced disease and in only one patient with more advanced disease. A regimen of BuMelTT is well tolerated in patients with aggressive NHL or relapsed HD, and results obtained to date are at least equivalent to other published regimens, including TBI-based regimens. This regimen appears to be a particularly attractive alternative for patients who have already received dose-limiting RT and should be evaluated further in prospective, randomized studies.

Adolescent↗

PubMed1996

Trends in prostate cancer survival in Sweden, 1960 through 1988: evidence of increasing diagnosis of nonlethal tumors.

BACKGROUND: The incidence of prostate cancer has increased during the past 30 years but has been paralleled by increases in survival rates from this disease, despite the absence of documented major improvement in curative treatment. Since a high prevalence of microscopic prostate cancer has been observed in autopsied men and because many prostate cancers may never surface clinically, increased diagnostic activities might have led to increased detection of less aggressive tumors. PURPOSE: This study was conducted to elucidate whether the trends in prostate cancer incidence and patient survival may be due to increasing diagnoses of nonlethal tumors. METHODS: We analyzed a population-based cohort comprising all cases of prostate cancer (n = 80,901) detected in Sweden during the period of 1960 through 1988. Five hundred eighteen patients (0.64% of the total number) who could not be followed because of emigration or an incomplete national registration number were excluded. Observed and relative survival rates were calculated for the entire cohort of 80,383 assessable patients per 5-year age group in 5-year periods of diagnosis and according to diagnostic method and were compared between geographic areas with differences in incidence rates. To estimate the independent effects of these determinants, multivariate analyses were performed. RESULTS: For the 80,383 patients with complete follow-up, the 10- and 20-year observed survival rates were 17.5% (95% confidence interval [CI] = 17.2%-17.9%) and 3.5% (95% CI = 3.2%-3.7%), and the relative survival rates were 41.1% (95% CI = 40.3%-41.9%) and 28.6% (95% CI = 26.5%-30.1%), respectively. Relative survival rates improved markedly over time; 10-year relative survival rates increased from 29% (95% CI = 27%-31%) among case patients diagnosed in 1960 through 1964 to 45% (95% CI = 43%-46%) among those diagnosed in 1975 through 1979. Relative survival rates leveled off after about 18 years at 18% (95% CI = 15%-20%) among patients diagnosed in 1960 through 1964 and at 31% (95% CI = 28%-34%) among those diagnosed in 1970 through 1974. An even more favorable outlook was observed in those case patients diagnosed later. In areas with a high or low incidence of prostate cancer, the 10-year relative survival rates were 45% (95% CI = 44%-47%) and 36% (95% CI = 34%-38%), respectively. In the early 1960s, the calculated loss of life expectancy after diagnosis varied from about 68% (95% CI = 61%-75%) of the expected length of life in the youngest age group to about 48% (95% CI = 46%-50%) in the oldest age group. From 1960 through 1964 to 1985 through 1988, the loss of life expectancy decreased by more than 50% in all age groups. The differences in relative survival rates between age groups were small, with a gradual decrease in age groups more than 60-64 years of age. CONCLUSIONS: Most of the great temporal improvement and geographic variation in survival rates are quantitatively consistent, with likely increases in the rate of detection of nonlethal tumors. IMPLICATIONS: The increase in relative survival rates must be taken into consideration when evaluating the outcome of treatment of prostate cancer, since nonrandomized comparisons may be confounded by time trends. Diagnosis of nonlethal tumors raises concerns because the individual would suffer from the psychologic burden of a cancer diagnosis without any therapeutic benefit.

Age Distribution↗

PubMed1996

Depurination of A4256 in 28 S rRNA by the ribosome-inactivating proteins from barley and ricin results in different ribosome conformations.

Ribosomal function in protein synthesis requires dynamic flexibility of the ribosomal structure. The two translational inhibitors derived from seeds of ricin and barley destroy the dynamic properties of the ribosome by selective depurination of A4256 in the phylogenetically conserved alpha-sarcin/ricin loop of mouse 28 S rRNA. As the alpha-sarcin/ricin loop is involved in binding of elongation factors to the ribosome, depurination blocks the protein synthesis elongation cycle. Depurination by the barley translational inhibitor (BTI) mainly effects eEF-1 alpha related functions, while ricin interferes with the interaction of eEF-2 with the ribosome. Analysis of the ribosomal structure after inhibitor shows that the accessibility of the rRNAs for single-strand-specific chemical modification was altered. Reactivity changes were seen in domains I, II and V of 28 S rRNA and in 5 S rRNA. A majority of the reactivity changes were found in putative functional regions of the rRNAs, such as the regions involved in peptidyltransferase activity, subunit interaction and in the binding of elongation factors. Most of the observed structural changes made the rRNAs less accessible for chemical modification, suggesting that the ribosomal particles became less flexible after inhibitor treatment. Moreover, the modification patterns obtained from the two inhibitor-treated ribosomal particles were only partly overlapping, indicating that the structure of the large ribosomal subunit differed after ricin and BTI treatment. Surprisingly, depurination in the alpha-sarcin/ricin loop of 28 S rRNA also affected the structure of the 3' major domain in 18 S rRNA.

Adenine↗

PubMed1996

Defective dimerization of von Willebrand factor subunits due to a Cys-> Arg mutation in type IID von Willebrand disease.

The same heterozygous T -> C transition at nt 8567 of the von Willebrand factor (vWF) transcript was found in two unrelated patients with type III) von Willebrand disease, with no other apparent abnormality. In one family, both alleles were normal in the parents and one sister; thus, the mutation originated de novo in the proposita. The second patient also had asymptomatic parents who, however, were not available for study. The structural consequences of the identified mutation, resulting in the CyS2010 -> Arg substitution, were evaluated by expression of the vWF carboxyl-terminal domain containing residues 1366-2050. Insect cells infected with recombinant baculovirus expressing normal vWF sequence secreted a disulfide linked dimeric molecule with an apparent molecular mass of 150 kDa before reduction, yielding a single band of 80 kDa after disulfide bond reduction. In contrast, cells expressing the mutant fragment secreted a monomeric molecule of apparent molecular mass of 80 kDa, which remained unchanged after reduction. We conclude that CyS2010 is essential for normal dimerization of vWF subunits through disulfide bonding of carboxyl-terminal domains and that a heterozygous mutation in the corresponding codon is responsible for defective multimer formation in type III) von Willebrand disease.

Animals↗

PubMed1996

The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry.

BACKGROUND: Mutations in the p53 tumor suppressor gene (also known as TP53) have been detected in a wide variety of human cancers. In breast cancer, the presence of p53 gene alterations has been associated with worse prognosis. PURPOSE: We compared a complementary DNA (cDNA)-based sequencing method and an immunohistochemical (IHC) method for their abilities to detect p53 mutations in breast cancer specimens. In addition, we determined the prognostic value of information obtained when these two methods were used. METHODS: Specimens from 316 primary breast tumors were evaluated for the presence of mutant p53 protein by use of the mouse monoclonal antibody Pab 1801 (that recognizes both wild-type and mutant forms of p53) and standard IHC methods. In addition, the entire coding region of p53 genes expressed in these tumors was screened for mutations by combining reverse transcription, the polymerase chain reaction, and DNA sequencing. Probabilities for overall survival (OS), breast cancer-corrected survival (BCCS; death from breast cancer is the considered event), and relapse-free survival (RFS) were estimated by use of the Kaplan-Meier method, and survival curves for different patient subgroups were compared by use of the logrank method. All reported P values are from two-sided tests. RESULTS: Sixty-nine (22%) of 316 tumors had p53 gene mutations detected by the cDNA-based sequencing method; only 31 (45%) of these mutations were located in evolutionarily conserved portions of the p53 coding region. Sixty-four tumors (20% of the total) had elevated levels of p53 protein as detected by IHC, suggesting the presence of mutations. Of the sequencing-positive tumors (i.e., p53 mutant), 23 exhibited negative IHC reactions, indicating that IHC failed to detect 33% of the mutations. Furthermore, 19 of the IHC-positive tumors were sequencing negative (i.e., p53 wild-type), suggesting a 30% false-positive frequency with IHC. Four tumors (1.3% of the total) could not be analyzed by the cDNA-based sequencing method, and three tumors (1% of the total) could not be analyzed by IHC. The 5-year estimates for RFS, BCCS, and OS were significantly shorter for patients with p53 sequencing-positive tumors than for patients with sequencing-negative tumors (P = .001, P = .01, and P = .0003, respectively). Patients with IHC-positive tumors showed reduced survival in all three categories when compared with those with IHC-negative tumors, but the differences were not statistically significant. CONCLUSIONS: Use of a cDNA-based sequencing method to determine the status of the p53 gene in primary breast cancers yielded better prognostic information than IHC performed with the Pab 1801 monoclonal antibody.

Adult↗

PubMed1996

Assessment of proliferation indicators in residual prostatic adenocarcinoma cells after radical external beam radiotherapy.

BACKGROUND: Fifty-five patients who had received radical external beam radiotherapy (RRT) for clinically staged, localized prostatic adenocarcinoma were examined with systematic sextant mapping with the help of transrectal ultrasound-guided core biopsies. The average follow-up after RRT was 6.8 years. Residual cancer was found histopathologically in 67% (37/55) of the patients investigated. METHODS: In the present report, the viability of these tumor cells was studied using immunohistochemical staining methods with the monoclonal antibodies MIB1 and PC10, which are specific for the proliferation-associated antigens Ki-67 and PCNA. RESULTS: Available data concerning proliferating activity in the pretreatment situation in 12 of these patients revealed that proliferating activity was substantially reduced in the majority of cases after RRT. Post-RRT, Ki-67, and PCNA activity was nonetheless found to varying degrees in 64% and 94% of the 36 evaluable tumor-harboring specimens, respectively. In the majority of cases, the proportion of proliferating cells, designated "score", was low. However, Ki-67 scores of up to 8% and PCNA scores of up to 50% were obtained in 35% (8/23) and 97% (33/34) of the specimens, respectively, with proliferative activity. There was no significant correlation between tumor grade and proliferative score in the follow-up biopsies. In the 36 cases investigated, endocrine treatment did not influence the proliferation results. CONCLUSIONS: The present study demonstrates a proliferative capacity in residual tumor cells in a long-term follow-up after RRT, suggesting that these cancer cells might have a biological significance.

Adenocarcinoma↗

PubMed1996

Determinants of complications after multiple transrectal core biopsies of the prostate.

Transrectal ultrasound-guided biopsies of the prostate were performed on 347 consecutive men. All patients were given prophylactic antibiotics. The first 199 patients received 400 mg norfloxacin immediately after the biopsies were performed and 400 mg the same evening. The second group of 148 patients received 400 mg of norfloxacin 1 h before the examination followed by five doses administered twice daily. A total of 15 major complications were noted. In the first group the complication rate was 6.5% and in the second group 1.4%. The different regimes of prophylactic antibiotic treatment were the only parameters shown to have a statistically significant impact on the complication rate. The number of complications decreased, but were not eliminated, when prophylactic treatment with norfloxacin was given before the biopsies were taken and continued for a total of 3 days.

Adult↗