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This paper aims at studying the influence of single-nucleotide polymorphisms (SNPs) on cancer risk, tumor recurrence, and survival in head and neck (H&N) cancer patients. A total of 45 SNPs in 41 genes... more
This paper aims at studying the influence of single-nucleotide polymorphisms (SNPs) on cancer risk, tumor recurrence, and survival in head and neck (H&N) cancer patients. A total of 45 SNPs in 41 genes were investigated. A total of 174 Caucasian H&N cancer patients and 245 healthy blood donors were enrolled in the study. Ten SNPs were associated with H&N cancer risk, but the identified SNPs differed among males and females. Some of the SNPs were related to immune response genes. The immune response gene SNPs were also related to survival. In particular, we noted that the tumor necrosis factor alpha (TNFα) rs1800629 could have an influence on cancer risk, tumor recurrence as well as survival. Genetic variation of the TNFα rs1800629 might be useful as a biomarker in clinical decision-making since it was found to be related to cancer risk, tumor recurrence, and survival of H&N cancer patients.
... Page 155. Rutqvist: Stockholm Adjuvant Tamoxifen Trial 131 Acknowledgmen ts This study was supported by the King Gustaf V Jubilee Fund and the Swedish Cancer Society. ... Ryden, S., M. Ferno, T. Moller, K. Aspergren, L. Bergljung, D.... more
... Page 155. Rutqvist: Stockholm Adjuvant Tamoxifen Trial 131 Acknowledgmen ts This study was supported by the King Gustaf V Jubilee Fund and the Swedish Cancer Society. ... Ryden, S., M. Ferno, T. Moller, K. Aspergren, L. Bergljung, D. Killander, and T. Landberg. 1992. ...
The cDNA array technique is an efficient approach for studying the expression of a large number of genes in a single experiment. The cDNA array analysis indicates the relative level of corresponding gene expression from a specimen and a... more
The cDNA array technique is an efficient approach for studying the expression of a large number of genes in a single experiment. The cDNA array analysis indicates the relative level of corresponding gene expression from a specimen and a reference. Our investigation was performed to address the significance of reference RNA on the outcome of the cancer-related gene expression profile obtained from cDNA array analysis. Human head and neck squamous cell carcinoma (HNSCC) biopsies and 5 sources of RNA reference were used for this purpose. In these biopsies, each individual patient expressed a unique set of genes both in normal and tumour tissue. It is important to note that 5 striking patterns of tumour-related gene expression were obtained according to the 5 references used. Significant differences in 60%, 16%, 15% and 15% of the genes expressed were shown when autologous normal matched tissue biopsy references were compared to pooled cell lines, allogenic normal mixed cell types, tumo...
Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and... more
Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and genetic factors through VWF-dependent and -independent mechanisms. Single nucleotide polymorphisms (SNPs) of the coding and promoter sequence in the FVIII gene have been extensively studied for effects on FVIII synthesis, secretion, and activity, but impacts of non–disease-causing intronic SNPs remain largely unknown. We analyzed FVIII SNPs and FVIII activity in 10 434 healthy Americans of European (EA) or African (AA) descent in the Atherosclerosis Risk in Communities (ARIC) study. Among covariates, age, race, diabetes, and ABO contributed 2.2%, 3.5%, 4%, and 10.7% to FVIII intersubject variation, respectively. Four intronic FVIII SNPs associated with FVIII activity and 8 with FVIII-VWF ratio in a sex- and race-dependent manner. The FVIII haplotypes AT ...
Prophylactic treatment with the anti-estrogen tamoxifen may reduce the risk of breast cancer because estrogens are thought to act as promoters in the pathogenesis of the disease. This article presents results on the incidence of... more
Prophylactic treatment with the anti-estrogen tamoxifen may reduce the risk of breast cancer because estrogens are thought to act as promoters in the pathogenesis of the disease. This article presents results on the incidence of contralateral new primary tumors among 1846 postmenopausal breast cancer patients included in a randomized trial of adjuvant tamoxifen therapy for 2 or 5 years after surgery versus no adjuvant endocrine therapy. The median follow-up was 7 years (range, 3-13 years). There was a significant reduction of contralateral breast cancer in the 931 patients in the tamoxifen group versus that in the 915 control patients (29 versus 47 cases, respectively; P = .03). The cumulative incidence at 10 years in the tamoxifen group and the control group was 5% and 8%, respectively. Analysis of the relative hazard of contralateral tumor over time showed that the benefit with tamoxifen therapy was greatest during the first 1-2 years, but there was a continued risk reduction during the entire follow-up period, i.e., more than 10 years after cessation of treatment. There was no significant difference in the number of contralateral cancers in the patients randomly assigned to 2 or 5 years of treatment, but the 95% confidence interval of the relative hazard was wide. The proportion of estrogen receptor-negative contralateral breast cancers was higher in the tamoxifen group than in the control group. There was no difference, however, between the two groups in recurrence-free survival time from the diagnosis of the contralateral cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
The relationship between hormone receptor status and the effect of adjuvant tamoxifen in early breast cancer remains controversial. This article presents the results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 years)... more
The relationship between hormone receptor status and the effect of adjuvant tamoxifen in early breast cancer remains controversial. This article presents the results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no adjuvant endocrine therapy in postmenopausal patients. During 1976 to 1984, 1,407 patients were included in the study. Of these, 427 (30%) had high-risk tumors (pN + or pT greater than 30 mm) and were included in a concurrent randomized comparison of postoperative radiotherapy versus adjuvant polychemotherapy. The mean follow-up time was 61/2 years. Tamoxifen improved the recurrence-free survival (RFS) (P less than .01), but the overall survival difference in favor of the tamoxifen-allocated patients was not significant. Data on estrogen (ER) and progesterone receptor (PgR) content were available in 750 patients. Their mean follow-up time was 41/2 years. The effect of tamoxifen was significantly related to ER level (P less than .01). No benefit with tamoxifen was observed among ER-negative patients. The relation to PgR level was of borderline significance (P = .06). Multivariate analysis indicated that most of the interaction between treatment and receptor content was explained by the interaction with ER (P less than .01). The PgR status appeared to modify the effect of tamoxifen among the ER-positive patients and the greatest effect was observed among patients who were positive for both receptors. However, the additional predictive information provided by the PgR assay did not help to identify an unresponsive subgroup of patients.
Tamoxifen is being increasingly used for the treatment of breast cancer and is undergoing study for the primary prevention of breast cancer. However, concerns have been raised that the drug may increase the incidence of new primary... more
Tamoxifen is being increasingly used for the treatment of breast cancer and is undergoing study for the primary prevention of breast cancer. However, concerns have been raised that the drug may increase the incidence of new primary malignancies, such as endometrial, liver, and colorectal cancers. Our goal was to assess the carcinogenic risks associated with long-term use of tamoxifen in women with early stage breast cancer. The incidence of new primary cancers among 2729 women participants of the Stockholm Trial was determined at a median follow-up of 9 years. In this trial, after primary surgery, postmenopausal patients aged less than 71 years with unilateral invasive breast cancer were randomly allocated to receive either 2 years of adjuvant tamoxifen (40 mg daily) or no adjuvant endocrine therapy. Information on second cancers was obtained by retrospective linkage to the Swedish Cancer Registry. To increase statistical power, a joint analysis of the incidence of endometrial and gastrointestinal cancers was performed in the following three major studies in Scandinavia evaluating adjuvant tamoxifen therapy: the Stockholm Trial, the Danish Breast Cancer Group Trial, and the South-Swedish Trial. These studies included a total of 4914 patients with a median follow-up of 8-9 years. All P values were calculated from two-tailed tests of statistical significance. In the Stockholm Trial, there was a statistically significant (P = .008) reduction in the incidence of second primary cancers in the contralateral breast among the tamoxifen-treated patients. However, there was a nearly sixfold increase in endometrial cancers (P < .001) and a threefold increase in gastrointestinal cancers in the tamoxifen-treated patients. The results of the joint studies showed a statistically significant increase in endometrial cancers among the tamoxifen-treated patients (relative risk [RR] = 4.1; 95% confidence interval [CI] = 1.9-8.9). There was also an excess of gastrointestinal cancers associated with tamoxifen. Most of this excess involved colorectal cancers (RR = 1.9; 95% CI = 1.1-3.3) and stomach cancer (RR = 3.2; 95% CI = 0.9-11.7). There was no substantial increase in any other type of gastrointestinal cancer (e.g., liver cancer) among the tamoxifen-treated patients. The endometrium and gastrointestinal organs may be target sites for tamoxifen-induced carcinogenesis in humans. The increased incidence of colorectal and stomach cancers reported here should be regarded as tentative until supported by long-term data from a larger number of tamoxifen trials. Also, appropriate surveillance of cancer incidence is warranted for the protection of participants enrolled in current tamoxifen chemoprevention trials.
Background Tobacco-free nicotine pouches is a novel category of oral nicotine-delivery products. Among current tobacco users such pouches may serve as a low-risk alternative to cigarettes or conventional, tobacco-based oral products e.g.,... more
Background Tobacco-free nicotine pouches is a novel category of oral nicotine-delivery products. Among current tobacco users such pouches may serve as a low-risk alternative to cigarettes or conventional, tobacco-based oral products e.g., snus and moist snuff. In the United States (U.S.), the market leading nicotine-pouch brand is ZYN®. However, no data on the chemical characteristics of ZYN have been published. Methods We screened for 43 compounds potentially present in tobacco products in seven oral nicotine-delivery products: ZYN (dry and moist), snus (General®), moist snuff (CRP2.1 and Grizzly Pouches Wintergreen), and two pharmaceutical, nicotine replacement therapy products (NRTs, Nicorette® lozenge and Nicotinell® gum). Thirty-six of the tested compounds are classified as harmful and potentially harmful constituents (HPHCs) by the Center for Tobacco Products at the U.S. Food and Drug Administration (FDA-CTP). Five additional compounds were included to cover the GOTHIATEK® pro...
tors, is widely used as adjuvant therapy after surgery for early-stage breast cancer. Our previous randomized trial of adjuvant tamoxifen therapy for breast cancer showed a significant decrease of new, contralateral breast cancers in... more
tors, is widely used as adjuvant therapy after surgery for early-stage breast cancer. Our previous randomized trial of adjuvant tamoxifen therapy for breast cancer showed a significant decrease of new, contralateral breast cancers in patients who received tamoxifen. Tamoxifen may also influence risk factors for cardiac and thromboembolic disease (e.g., serum cholesterol and antithrombin III). Purpose: The purpose of this study was to assess morbidity from cardiac and thromboembolic disease among 2365 postmenopausal patients with early-stage breast cancer in the Stockholm randomized trial of adjuvant tamoxifen (40 mg daily for 2 or 5 years) versus no adjuvant endocrine therapy. Patients were entered in the study from November 1976 through December 1988. Methods: In our retrospective study, the analysis of
Some smokeless tobacco products, such as Swedish snus, are today considered to be associated with substantially fewer health hazards than cigarettes. This risk differential has contributed to the scientific debate about the possibilities... more
Some smokeless tobacco products, such as Swedish snus, are today considered to be associated with substantially fewer health hazards than cigarettes. This risk differential has contributed to the scientific debate about the possibilities of harm reduction within the tobacco area. Although current manufacturing methods for snus build on those that were introduced more than a century ago, the low levels of unwanted substances in modern Swedish snus are largely due to improvements in production techniques and selection of raw materials in combination with several programs for quality assurance and quality control. These measures have been successively introduced during the past 30-40 years. In the late 1990s they formed the basis for a voluntary quality standard for Swedish snus named GothiaTek ®. In recent years the standard has been accepted by the members of the trade organization European Smokeless Tobacco Council (ESTOC) so it has now evolved into an industrial standard for all sm...
juvant tamoxifen therapy for early stage breast cancer and second primary malignan-cies. Stockholm Breast Cancer Study Group [see comment citations in Medline]. Notes Editor's note' SEER is a set of geographically defined,... more
juvant tamoxifen therapy for early stage breast cancer and second primary malignan-cies. Stockholm Breast Cancer Study Group [see comment citations in Medline]. Notes Editor's note' SEER is a set of geographically defined, population-based central tumor registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Each registry annually submits its cases to the NCI on a computer tape. These computer tapes are then edited by the NCI and made available for analysis. Curtis et al. (/) described the incidence of second cancers among 14 358 breast cancer patients reported to the Surveillance, Epidemiology, and End Results (SEER) Program who received adjuvant tamoxifen therapy. They found a significant excess of endometrial cancer in accordance with several previous reports but no excess of stomach and colon cancers as reported from three Scandinavian adjuvant tamoxifen trials. Although the SEER data may provide r...
patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hor-mone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was... more
patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hor-mone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm pro-tocol, not shared with the HABITS trial, was to minimize the use of pro-gestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer
Background and Objective: The present study was undertaken to ascertain whether the modulatory effects of blueberries on cell proliferation induced by Swedish snus in the rat forestomach epithelium is mediated via abrogation of the... more
Background and Objective: The present study was undertaken to ascertain whether the modulatory effects of blueberries on cell proliferation induced by Swedish snus in the rat forestomach epithelium is mediated via abrogation of the PI3K/Akt/NFκB signaling axis that regulates cell fate decision. Methods: The transcript and protein expression of genes involved in cell cycle progression and apoptosis, as well as canonical PI3K/Akt/NF-κB signaling pathways, were analyzed by qRT-PCR, immunoblotting and ELISA. Expression profiling of noncoding RNAs (ncRNAs) that influence PI3K/Akt/NF-κB signaling was undertaken. TUNEL assay was performed using flow cytometry. Results: Administration of snus induced basal cell hyperplasia in the rat forestomach with increased cell proliferation and inhibition of apoptosis. This was associated with the activation of PI3K/Akt/NFκB signaling. Coadministration of blueberries significantly suppressed snus-induced hyperplasia. Analysis of the molecular mechanism...
... Page 155. Rutqvist: Stockholm Adjuvant Tamoxifen Trial 131 Acknowledgmen ts This study was supported by the King Gustaf V Jubilee Fund and the Swedish Cancer Society. ... Ryden, S., M. Ferno, T. Moller, K. Aspergren, L. Bergljung, D.... more
... Page 155. Rutqvist: Stockholm Adjuvant Tamoxifen Trial 131 Acknowledgmen ts This study was supported by the King Gustaf V Jubilee Fund and the Swedish Cancer Society. ... Ryden, S., M. Ferno, T. Moller, K. Aspergren, L. Bergljung, D. Killander, and T. Landberg. 1992. ...
This synthesis of the literature on radiotherapy for breast cancer is based on 97 scientific articles, including 5 meta-analyses, 38 randomized studies, and 27 retrospective studies. These studies involve 387 634 patients. Radiotherapy is... more
This synthesis of the literature on radiotherapy for breast cancer is based on 97 scientific articles, including 5 meta-analyses, 38 randomized studies, and 27 retrospective studies. These studies involve 387 634 patients. Radiotherapy is the most effective method for preventing locoregional recurrence following primary surgery for invasive breast cancer, and radiotherapy is currently more effective than adjuvant chemotherapy after either mastectomy or breast-conserving surgery (1, 2). Radiotherapy in patients at high risk for locoregional recurrence, eg, patients with spread to the axillary lymph nodes, leads to a significant increase in relapse-free survival (eg, 1, 3). Meta-analyses have shown that radiotherapy in these subgroups of patients can reduce the risk for distant metastasis and reduce the risk for cancer death (4, 5). These analyses have not statistically confirmed an improvement in total survival, probably because reduced mortality from breast cancer has been offset by...
ABSTRACT: Epidemiological studies suggest that smokeless tobacco in the form of Swedish snus has been used by many smokers in Scandinavia to quit smoking, but the efficacy of snus has so far not been evaluated in controlled clinical... more
ABSTRACT: Epidemiological studies suggest that smokeless tobacco in the form of Swedish snus has been used by many smokers in Scandinavia to quit smoking, but the efficacy of snus has so far not been evaluated in controlled clinical trials. We conducted a randomized, double-blind, placebo-controlled, clinical trial aimed at assessing the efficacy of snus to help adult cigarette smokers in Serbia to substantially reduce, and, eventually, completely stop smoking. The study enrolled 319 healthy smokers aged 20-65 years at two occupational health centers in Belgrade, Serbia. Most of them (81%) expressed an interest to quit rather than just reduce their smoking. Study products were used ad libitum throughout the 48-week study period. The main study objective during the first 24 weeks was smoking reduction. The primary end-point was defined as a biologically verified reduction of ≥ 50% in the average number of smoked cigarettes per day during week 21-24 compared to baseline. During week 2...
Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma. The Swedish Melanoma Study Group performed a... more
Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma. The Swedish Melanoma Study Group performed a prospective, randomized, multicenter study of patients with primary melanoma located on trunk or extremities and with a tumor thickness > 0.8 mm and </= 2 mm. Patients were allocated randomly to a 2-cm excision margin or a 5-cm excision margin. In total, 989 patients were recruited during the period 1982-1991. The median follow-up was 11 years (range, 7-17 years) for estimation of survival and 8 years (range, 0-17 years) for evaluation of recurrent disease. The crude rate of local recurrence, defined as a recurrence in the scar or transplant, was < 1% (8 of 989 patients). Twenty percent of the patients (194 of 989 patients) experienced any disease recurrence, and 15% (146 of 989 patients) died of melanoma. There were no statistically significant differences between the two treatment arms. In a multivariate Cox analysis with patients allocated to wide excision as the reference group, the estimated relative hazards for overall survival and recurrence free survival among those allocated to a 2-cm resection margin were 0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence interval, 0.80-1.30), respectively. In this long term follow-up study, local recurrences were found to be rare among patients with tumors > 0.8 mm thick and </= 2.0 mm thick. No difference in recurrence rate or survival between the two treatment groups was found. Patients in this category can be treated with a resection margin of 2 cm as safely as with a resection margin of 5 cm.
The prognostic value of nuclear DNA distribution pattern in relation to tumor size, axillary lymph node status, and estrogen receptor (ER) content was studied in 464 patients with primary, operable mammary adenocarcinoma. The median... more
The prognostic value of nuclear DNA distribution pattern in relation to tumor size, axillary lymph node status, and estrogen receptor (ER) content was studied in 464 patients with primary, operable mammary adenocarcinoma. The median follow-up time was 3 1/2 years. Slide cytophotometric DNA analysis was performed on morphologically identified Feulgen-stained tumor cells. The tumors were classified into four subgroups according to their DNA histogram type. DNA content was significantly related to tumor size and ER level but not to nodal status. When all variables were stimultaneously introduced into Cox's proportional hazards model, tumor size, nodal status, and DNA profile remained as significant predictors of recurrence. Restricting the analysis to node-negative patients, both DNA profile and tumor size showed a significant prognostic value. DNA did not contribute significant prognostic information in node-positive patients. However, the trends in recurrence-free survival were similar to those in the node-negative subgroup: patients with aneuploid tumors tended to fare worse than those with euploid carcinomas.
The use of adjuvant tamoxifen to treat postmenopausal breast carcinoma patients as an adjunct to primary surgery is well established. The current study reports the long term results for a low risk stratum in a randomized trial of adjuvant... more
The use of adjuvant tamoxifen to treat postmenopausal breast carcinoma patients as an adjunct to primary surgery is well established. The current study reports the long term results for a low risk stratum in a randomized trial of adjuvant tamoxifen. The main focus of this analysis was to determine whether tamoxifen would result in a reduced local failure rate for lymph node negative, postmenopausal patients treated with breast-conserving surgery and postoperative radiotherapy. The study population included 432 lymph node negative, postmenopausal patients with invasive breast carcinoma (classified as T1-T2) who underwent breast-conserving surgery followed by radiotherapy in Stockholm during the period 1976-1990. The patients constituted a separate stratum of the Stockholm Adjuvant Tamoxifen Trial, which included a total of 2729 patients. Of 432 patients, 213 received 40 mg of tamoxifen daily for either 2 or 5 years. The median follow-up time was 8 years (range, 5-19 years). At 10 years, the overall survival was 90% for the tamoxifen group and 88% for the control group. The event free survival at 10 years was 80% for the tamoxifen group and 70% for the control group (P=0.03). Tamoxifen reduced the overall rate of ipsilateral (hazard ratio=0.4, 95% confidence interval [CI]=0.2-0.9, P=0.02) and contralateral breast tumor recurrences (hazard ratio=0.4, 95% CI=0.1-1.1, P=0.06). Trends toward a reduced number of distant metastases (hazard ratio=0.6, 95% CI=0.3-1.2, P=0.1) and deaths due to breast carcinoma (hazard ratio=0.5, 95% CI=0.2-1.2, P=0.1) also were observed. CONCLUSIONS. The addition of tamoxifen to radiotherapy for postmenopausal, lymph node negative breast carcinoma patients treated with breast-conserving surgery resulted in a reduced rate of ipsilateral and contralateral breast tumor recurrences. The avoidance of salvage mastectomies, reexcisions, and new contralateral malignancies justifies the use of tamoxifen even in the treatment of patients with a 10-year survival rate of 90%.
The tumor cell content of the receptor for epidermal growth factor (EGF-R) and estrogen receptor (ER) was analyzed in 36 primary breast carcinomas and their metastatic deposits. Twenty-five percent of the primary tumors and 48 percent of... more
The tumor cell content of the receptor for epidermal growth factor (EGF-R) and estrogen receptor (ER) was analyzed in 36 primary breast carcinomas and their metastatic deposits. Twenty-five percent of the primary tumors and 48 percent of the metastases exhibited measurable levels of the receptor. The frequency of EGF-R positivity was the same for cutaneous and lymph node recurrences. No discrepancy was observed with respect to ER content between primary tumors and their metastases.
The outcome of patients with rectal cancer treated by abdominoperineal or anterior resection, with or without preoperative radiotherapy, was assessed to detect any differences attributable to the operative method and interactions between... more
The outcome of patients with rectal cancer treated by abdominoperineal or anterior resection, with or without preoperative radiotherapy, was assessed to detect any differences attributable to the operative method and interactions between radiotherapy and type of surgery. The study was based on 1292 patients included in two consecutive controlled randomized trials of preoperative radiotherapy in operable rectal carcinoma. The outcome was not related to surgical method. Radiotherapy increased postoperative mortality and complications and reduced local and distant recurrence, but had no effect on overall survival. Effects of radiotherapy were similar irrespective of the type of surgery, except that the increase in postoperative mortality in irradiated patients was greater in those treated with abdominoperineal resection. Sphincter-saving procedures appear to have no adverse effects on outcome of rectal cancer, but the optimum use of radiotherapy is still to be defined.

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