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Purpose: This study explores the prevalence of self-reported taste and smell changes (TSCs) during chemotherapy and relationships between TSCs and demographic and clinical factors.Materials and Methods: Consecutive patients who had received chemotherapy for > or =6 weeks at 11 outpatient chemotherapy units completed a questionnaire developed for this survey.Results: Seventy-five percent of the 518 participants reported TSCs, with TSCs more prevalent among women and younger patients. After adjustment for age and sex, we found that patients reporting TSCs more often reported: previous smell changes, less responsibility for cooking, concurrent medication, higher educational levels, and being on sick leave. Participants reporting oral problems, nausea, appetite loss, and depressed mood more frequently reported TSCs. Diagnosis and type of chemotherapy regimen did not predict TSCs.Conclusion: TSCs were found to be common during cancer chemotherapy and were related to sociodemographic rather than clinical factors. TSCs were also found to be closely related to many other side effects of chemotherapy. [ABSTRACT FROM AUTHOR]

For many years, loco-regional radiotherapy was the standard postoperative treatment for node positive breast cancer patients in Sweden. Because of encouraging results from trials of adjuvant chemotherapy in the mid 1970s, the Stockholm Breast Cancer Study Group decided to directly compare postoperative radiation (RT) with adjuvant CMF-type chemotherapy (CT). Long-term results are presented from two randomized trials of RT versus CT in pre- (n = 547) and postmenopausal (n = 679) patients, respectively, with node positive disease or a tumour diameter > 30 mm. RT substantially reduced loco-regional recurrences among both pre- and postmenopausal patients (relative hazard RT versus CT: 0.67 and 0.43, respectively). Among premenopausal patients distant metastases occurred less frequently in the CT group (relative hazard: 1.68, p > 0.001) resulting in an improved recurrence-free survival (p = 0.04). Overall survival was also better with CT (cumulative survival at 15 years: 50% and 44% in the CT and RT groups, respectively) but the difference was not statistically significant. Among the postmenopausal patients there were no substantial differences in terms of recurrence-free or overall survival between the treatment groups. The risk of a second primary malignancy, however, was doubled in the RT group (p > 0.01). The most pronounced excess concerned second lung cancers occurring after 10 years. The cumulative incidence at 20 years was estimated at 0.3% and 3.7% in the CT and RT groups, respectively. The trials illustrate the role of radiotherapy in preventing loco-regional recurrences among high-risk patients, as well as the need for systemic treatment to control the disease systemically. [ABSTRACT FROM AUTHOR]

The incidence of cutaneous malignant melanoma has been increasing in Sweden for several decades. In the Stockholm-Gotland area educational activities for healthcare professionals were started in the late 1970s and public primary and secondary prevention campaigns were initiated in the mid-1980s. Melanoma incidence trends have been studied in Sweden, with special reference to trends in the Stockholm-Gotland area where these prevention campaigns were first started. During 1976-1994 the average annual increase of age-standardized incidence in the Stockholm-Gotland area was about 5%, the increase being associated mainly with thin tumors and melanoma in situ. During the 1990s, the incidence among males leveled off. In contrast, no such shift in trend was observed among females, or among males or females residing outside the Stockholm-Gotland area. The campaigns may have contributed to a trend towards earlier diagnosis but there is still no clear effect of the primary prevention efforts. [ABSTRACT FROM AUTHOR]

Background: 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.Purpose: Our goal was to assess the carcinogenic risks associated with long-term use of tamoxifen in women with early stage breast cancer.Methods: 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.Results: 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.Conclusion: The endometrium and gastrointestinal organs may be target sites for tamoxifen-induced carcinogenesis in humans.Implications: 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. [ABSTRACT FROM AUTHOR]

Despite encouraging results from screening trials the efficacy of mammography in reducing mortality remains somewhat controversial. Five studies have been done in Sweden. This overview, based on 282,777 women followed for 5-13 years in randomised trials in Malmö, Kopparberg, Ostergötland, Stockholm, and Gothenburg, reveals a 24% (95% confidence interval 13-34%) significant reduction of breast cancer mortality among those invited to mammography screening compared with those not invited. To avoid the potential risk of differential misclassification causes of death were assessed by an independent end-point committee after a blinded review of all fatal breast cancer cases. The mortality reduction was similar, irrespective of the end-point used for evaluation ("breast cancer as underlying cause of death" or "breast cancer present at death"). There was a consistent risk reduction associated with screening in all studies, although the point estimate of the relative risk for all ages varied non-significantly between 0.68 and 0.84. The cumulative breast cancer mortality by time since randomisation was estimated at 1.3 per 1000 within 6 years in the invited group compared with 1.6 in the control group. The corresponding figures after 9 years are 2.6 and 3.3 and after 12 years 3.9 and 5.1. The largest reduction of breast cancer mortality (29%) was observed among women aged 50-69 at randomisation. Among women 40-49 there was a non-significant 13% reduction. In this younger age group cumulative breast cancer mortality was similar in the invited and control group during the first 8 years of follow-up. After 8 years there was a difference in favour of the invited women. There was no evidence of any detrimental effect of screening in terms of breast cancer mortality in any age group. Among women aged 70-74 years screening seems to have had only a marginal impact. [ABSTRACT FROM AUTHOR]

Background: Tamoxifen, which binds to estrogen receptors, 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 morbidity was based on data from a computerized, population-based register of hospital admissions and discharge diagnoses. Mortality data were obtained from the Swedish National Central Bureau of Statistics. In the Stockholm study, treatment with tamoxifen was initiated within 4-6 weeks of modified radical mastectomy or breast-conserving surgery including axillary lymph node dissection and postoperative radiation therapy to the breast. In that randomized trial, 755 patients at low risk of death from breast cancer received adjuvant tamoxifen only; 760 received no treatment. In addition, 628 high-risk patients were randomly assigned to receive adjuvant chemotherapy plus tamoxifen (173 patients) or postoperative radiotherapy plus tamoxifen (151) or, as a control, to receive chemotherapy (171) or postoperative radiation therapy (133), both without tamoxifen or other endocrine therapy. Median follow-up was 6 years.Results: Tamoxifen therapy resulted in a statistically significant reduced incidence of hospital admissions due to cardiac disease. The relative hazard (tamoxifen for 2 or 5 years versus control) was 0.68 (95% confidence interval [CI] = 0.48-0.97; P = .03). In the randomized comparison of 5 versus 2 years of tamoxifen, there was a statistically significant difference favoring the longer treatment (relative hazard = 0.37; 95% CI = 0.15-0.92; P = .03). There was little difference between the tamoxifen and control groups in terms of admissions due to thromboembolic disease.Conclusions: These findings suggest that long-term adjuvant treatment with tamoxifen may result in substantial reduction of cardiac morbidity in patients with low risk of death from breast cancer as well as in women in chemopreventive studies who have high risk of developing breast cancer.Implications: Our results support continuation of ongoing trials of tamoxifen therapy in these two groups of subjects. [ABSTRACT FROM AUTHOR]

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 ® product standard for Swedish snus and the last two compounds were chosen to include the four primary tobacco specific nitrosamines (TSNAs)., Results: The tested products contained nicotine at varying levels. The two ZYN products contained no nitrosamines or polycyclic aromatic hydrocarbons (PAHs) but low levels of ammonia, chromium, formaldehyde, and nickel. In the NRT products we quantified low levels of acetaldehyde, ammonia, cadmium, chromium, lead, nickel, uranium-235, and uranium-238. The largest number (27) and generally the highest levels of HPHCs were quantified in the moist snuff products. For example, they contained six out of seven tested PAHs, and seven out of ten nitrosamines (including NNN and NNK). A total of 19 compounds, none of which were PAHs, were quantified at low levels in the snus product. NNN and NNK levels were five to 12-fold lower in snus compared to the moist snuff products., Conclusions: No nitrosamines or PAHs were quantified in the ZYN and NRT products. Overall, the number of quantified HPHCs were similar between ZYN and NRT products and found at low levels., (© 2023. The Author(s).)

Introduction: Cigarette smoke is suggested to be a risk factor for coronary artery disease (CAD), urinary bladder cancer (UBCa) or lung cancer (LCa). However, not all heavy smokers develop these diseases and elevated cancer risk among first-degree relatives suggests an important role of genetic factor., Methods: Three hundred and ten healthy blood donors (controls), 98 CAD, 74 UBCa and 38 LCa patients were included in this pilot study. The influence of 92 single nucleotide polymorphisms (SNPs) and impact of cigarette smoking were analysed., Results: Out of 92 SNPs tested, differences in distribution of 14 SNPs were detected between controls and patient groups. Only CTLA4 rs3087243 showed difference in both CAD and UBCa patient group compared to control group. Stratified by smoking status, the impact of smoking was associated to frequencies of 8, 3 and 4 SNPs in CAD, UBCa, LCa patients, respectively. None of these 92 SNPs showed a statistically significant difference to more than one type of disease among smoking patients. In non-smoking patients, 7, 3 and 6 SNPs were associated to CAD, UBCa, LCa, respectively. Out of these 92 SNPs, CTLA4 rs3087243 was associated to both non-smoking CAD and UBCa. The XRCC1 rs25487 was associated to both non-smoking UBCa and LCa., Conclusion: SNPs might be important risk factors for CAD, UBCa and LCa. Distribution of the SNPs was specific for each patient group, not a random event. Impact of cigarette smoking on the disease was associated to the specific SNP sequences. Thus, smoking individuals with SNPs associated to risk of these serious diseases is an important target group for smoking cessation programs., Competing Interests: The autours have declared that no competing interests exist.

Background and Objectives: 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 mechanisms revealed that blueberries suppress the phosphorylation of Akt, NF-κB and IKKβ, prevent nuclear translocation of NF-κB and modulate the expression of microRNAs that influence PI3K/Akt/NF-κB signaling., Conclusion: Taken together, the results of the current study provide compelling evidence that blueberries exert significant protective effects against snus-induced soft tissue changes in the rat forestomach epithelium mediated by inhibiting key molecular players in the PI3K/Akt/NF-κB signaling axis. Long-term studies on the impact of snus exposure on various cellular processes, signaling pathways, and the interplay between genetic and epigenetic mechanisms are however warranted. The results of this investigation may contribute to the development of protection against soft tissue changes induced by smokeless tobacco in the human oral cavity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background/aim: Adjuvant radiotherapy (RT) damages multiple layers of skin, muscle, blood vessels and blood cells that are included within the RT area. Indirect, bystander systemic effects could also develop in cells not directly hit by radiation., Materials and Methods: Ninety-three female patients recovering from breast cancer surgery and 82 female healthy blood donors were analyzed. For identification of systemic adaptive and innate immune response, rapid and low-cost blood-based biomarkers were assayed., Results: Post-operated breast cancer patients had a decreased number of circulating adaptive immune response cells but increased number of circulating immunosuppressive myeloid subpopulations. RT decreased the number of T-cells and platelets without influencing the number of immunosuppressive myeloid subpopulations. Alterations in the number and phenotypes of T-cell subpopulations were associated with SNPs., Conclusion: The combination of RT and immunotherapy might provide optimal treatment for cancer patients., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Long term exposure to oral smokeless tobacco may induce lesions in the oral cavity characterized by a hyperplastic epithelium. The possible role of nicotine and the physical properties of oral tobacco for developing these lesions, as well as of dysplasia and neoplasia is unclear. Low nitrosamine Swedish snus as well as non-genotoxic butylated hydroxyanisole induces increased cellular proliferation in the rat forestomach epithelia. Using this model, we report here on the effects of nicotine, pH, and particle size. Snus with different properties had no impact on oxidative stress as determined by 8-oxo-7,8-dihydro-2'-deoxyguanosine, or on interleukin IL-1b. Whereas BHA boosted IL-6, probably due to the presence of nicotine. there was no significant enhancement of cell divisions with increasing particle size, although in individual samples the variations in proliferation rates increased greatly with increasing particle size. Conforming to human experience, the enhanced cell proliferation caused by snus was found to be completely reversible. A cacao bean extract had a protective action similar to that previously found for blueberries. The main cause of the observed tobacco induced cell proliferation could be mechanical irritation, possibly in combination with nicotine, whereas within the studied range, pH did not affect the rate of cell division., (Copyright © 2019. Published by Elsevier Inc.)

Independently of tumour and treatment modulation, the host immune response status plays an important role in the clinical outcome of patients with cancer. The influence of single nucleotide polymorphisms (SNPs) and adjuvant radiotherapy (RT) on the systemic immune response status of patients with breast cancer was investigated., Materials and Methods: Eighty-six female patients recovering from breast cancer surgery were investigated. As a control cohort, 82 healthy female blood donors were used. Blood-based SNPs, plasma C-reactive protein (CRP), cytokines and chemokines were analyzed for this purpose., Results: Independently of tumour stage and hormone receptor status, dysregulation of plasma CRP, chemokine (C-C motif) ligand 4 (CCL4) and interleukin 2 (IL2), but not CCL5, CCL2, platelet-derived growth factor, IL6, IL10, IL12, interferon-gamma or tumour necrosis factor alpha were detected in the patients when compared to controls. The extent of alteration in plasma levels of CRP and IL2 patients was significantly associated with SNPs in CRP rs1800947 and IL2 rs6822844, respectively. These SNPs had no influence on the levels of corresponding plasma biomarkers in the healthy controls. Adjuvant RT reduced plasma CRP and CCL5 levels in patients with regards to CRP rs1800947CC, CCL5 rs2107538GG and CCL5 rs2280789AA sequences., Conclusion: Dysregulation of immune responses, as indicated by plasma levels of CRP, CCL4 and IL2 were found in patients with breast cancer despite the removal of the tumour mass. The benefit of adjuvant RT, as indicated by reduced plasma amounts of inflammatory protein CRP and chemokine CCL5 were based on the SNPs of the patients. Analyses of blood-based SNPs, plasma CRP, IL2 and CCL5 are low cost, rapid and can be carried out using general laboratory facilities while requiring only a peripheral blood sample. The possibility of using these blood-based biomarkers as an indicator of patient immune status for selection of individual patient treatment warrants further investigation., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Cigarette smoke induces inflammation and remodels immune response. Genetic and epigenetic alterations might be involved in the pathogenesis of smoking related diseases. In this study, we investigated the effect of smoking on systemic inflammation biomarkers and epigenetic changes at microRNA (miRNA) expression level. We also examined if the levels of inflammatory biomarkers were associated with selected single nucleotide polymorphisms (SNPs)., Method: From 39 smokers and 101 non-smokers, levels of total white blood cells (WBCs) and its subpopulations, plasma cytokines/chemokines/proteins and miRNAs were analysed. For three biomarkers, C-reactive protein (CRP), MCP-1 and IFN-γ that were affected by smoking, the influence of SNPs was analyzed., Result: Elevated levels of total WBCs, neutrophils, monocytes, lymphocytes, CRP, MCP-1, IFN-γ and lower levels of miR-21 were detected in smokers. The elevated levels of IFN-γ in smokers was only statistically significantly associated with rs2069705 AG/GG SNP-genotype., Conclusions: A lower level of oncomir miRNA-21 and a higher level of immune modelling cytokine IFN-γ detected in smokers could be a protective immune response to cigarette smoke. The higher level of IFN-γ in smokers with a specific SNP genotype also suggests that a genetic interaction with smoking might predict the pathobiology of smoking related disease.

Cigarette smoke contains toxic and carcinogenic substances that contribute to the development of cancer and various diseases. Genetic variation might be important, because not all smokers develop smoking-related disease. The current study addressed the possible interactions among selected single nucleotide polymorphisms (SNPs) in genes related to systemic inflammation, smoking status, the levels of circulating immune response cells and plasma biomarkers of systemic inflammation. Sixty-four healthy blood donors were recruited, 31 of whom were current smokers and 33 were never-users of tobacco products, references. Compared to references, the smokers showed significantly increased levels of circulating total white blood cells, lymphocytes, monocytes, neutrophils, basophils and C-reactive protein (CRP). Smokers also more frequently exhibited circulating cell phenotypes that are associated with an immunocompromised state: CD8 dim cells in the lymphocyte group, CD13 +  CD11 + , CD13 +  CD14 + , CD13 +  CD56 + cells in the monocyte group and CD13 +  CD11 + , CD13 +  CD56 + cells in the neutrophil group. We observed an interaction among SNPs, smoking status and some of the studied biomarkers. The average plasma CRP level was significantly higher among the smokers, with the highest level found among those with the CRP rs1800947 CC genotype. Additionally, an increased CD8 +  GZB + cells in the CD8 dim group were found among smokers with the GZB rs8192917 AA genotype. Thus, smoking appears to be associated with systemic inflammation and increased levels of circulating immunosuppressive cells. The extent of these effects was associated with SNPs among the smokers. This observation may contribute to a better understanding of the genetic susceptibility of smoking-related disease and the variations observed in clinical outcomes., (© 2017 John Wiley & Sons Ltd.)

Head and neck (H&N) cancer is an aggressive disease and the incidence has increased in younger population worldwide. Tumour TNM staging is the main basis for treatment decision despite significant variation in clinical outcome. Survival time of these patients has marginally improved during the last 30 years. Various biomarkers with cumbersome analysis, high cost, time consumption and requirement of special laboratory facilities have been investigated. However, none of these biomarkers have been shown to be suitable to use for individual H&N cancer patient treatment selection in the clinic. For practical use in clinical settings, the given biomarkers must be simple to analyse, rapid, cost effective and available in routine laboratories. With this intension, we suggested the combination of standard TNM staging and biomarkers associated with inflammation such as neutrophils, neutrophil to lymphocyte ratio, plasma C-reactive protein or plasma tumour necrosis factor alpha (TNFa) and single-nucleotide polymorphism in TNFa rs1800629 using blood-based analysis. The optimal treatment outcome of H&N cancer by using combination of TNM stage and these blood-based biomarkers for individual patient selection need further investigation.

Objective: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2016 S. Karger AG, Basel.)

Long-term survival of H&N cancer patients has not improved significantly over the last 30 years. The possibility of using circulating blood cell phenotypes as a prognostic biomarker of H&N cancer patient was investigated in this study. Pre-treatment, circulating T lymphocyte subpopulations as well as the survival time of the patients in question were studied. Upregulated CD4+ perforin+ and CD8+ CD95+ but downregulated CD4+ CD28+ (p < 0.001) were detected in H&N cancer patients. With 3 years of follow-up time, an increase in the frequency of the pre-treatment, circulating CD4+ perforin+ cells and CD8+ perforin+ cells was showed to have reverse effects on the survival time in H&N cancer patients (p < 0.01). Detection of perforin+ frequency in CD4+ and CD8+ lymphocyte by FACS is fast, simple and cost-effective. A potential role of perforin expression in CD4+ and CD8+ cells as a prognostic biomarker for H&N cancer patient in the clinical setting was suggested.

Purpose: Tumor TNM staging is the main basis for prognosis and treatment decision for head and neck squamous cell carcinoma (HNSCC) despite significant heterogeneity in terms of outcome among patients with the same clinical stage. In this study, a possible role of plasma interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) as biomarkers for survival of HNSCC patients was investigated., Methods: In this prospective study, plasma levels of IL-2, IL-6, GM-CSF, TNF-α and CRP in patients (n = 100) and controls (n = 48) were analyzed., Results: Significantly elevated levels of CRP and TNF-α (p < 0.001) were found in the patients. Combination of upregulated CRP and TNF-α in the patient plasma was significantly related to shorter patient survival, independent of clinical stage., Conclusions: Our findings indicate that CRP and TNF-α might be suitable as biomarkers in combination with tumor TNM staging for predicting survival and individualized treatment of HNSCC patients. Plasma CRP and TNF-α analysis are simple, rapid, cost effective and suitable for clinical practice.

Introduction: Tobacco and ethanol consumption are crucial factors in the development of various diseases including cancer. In this investigation, we evaluated the combined effects of a number of single nucleotide polymorphisms (SNPs), with ethanol and tobacco products on healthy individuals., Methods: Pure nicotine, cigarette smoke extract, and Swedish snuff (snus) extract were used. The effects were examined by means of in vitro cell cycle progression and cell death of peripheral blood mononuclear cells (PBMCs) obtained from healthy donors., Results: After 3 days, in vitro, resting PBMCs entered the S and G2 stage in the presence of 100 µM nicotine. The PBMCs only proceeded to S stage, in the presence of 0.2% ethanol. The nicotine- and ethanol-induced normal cell cycle progression correlated to a number of SNPs in the IL12RB2, Rad 52, XRCC2, P53, CCND3, and ABCA1 genes. Certain SNPs in Caspases 8, IL12RB2, Rad 52, MMP2, and MDM2 genes appeared to significantly influence the effects of EtOH-, snus-, and snus + EtOH-induced cell death. Importantly, the highest degree of cell death was observed in the presence of smoke + EtOH. The amount of cell death under this treatment condition also correlated to specific SNPs, located in the MDM2, ABCA1, or GASC1 genes., Conclusions: Cigarette smoke in combination with ethanol strongly induced massive cell death. Long-term exposure to smoke and ethanol could provoke chronic inflammation, and this could be the initiation of disease including the development of cancer at various sites.

Background: The management of hormonal deficiency symptoms in breast cancer survivors is an unsolved problem. While hormone replacement therapy (HRT) may increase the risk of breast cancer in healthy women, its effects on recurrence is unclear. Observational studies have suggested decreased recurrence rates from HRT. The few clinical trials in this field have all been closed preterm., Methods: The Stockholm trial was started in 1997 and designed to minimise the dose of progestogen in the HRT arm. Disease-free women with a history of breast cancer were randomised to HRT (n=188) or no HRT (n=190). The trial was stopped in 2003 when another Swedish study (HABITS, the Hormonal Replacement After Breast Cancer - Is it Safe?) reported increased recurrence. However the Stockholm material showed no excess risk after 4 years of follow-up. A long term follow-up has now been performed., Findings: After 10.8 years of follow-up, there was no difference in new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio (HR)=1.3; 95% confidence interval (CI)=0.9-1.9). Among women on HRT, 11 had local recurrence and 12 distant metastases versus 15 and 12 for the controls. There were 14 contra-lateral breast cancers in the HRT group and four in the control group (HR=3.6; 95% CI=1.2-10.9; p=0.013). No differences in mortality or new primary malignancies were found., Interpretation: The number of new events did not differ significantly between groups, in contrast to previous reports. The increased recurrence in HABITS has been attributed to higher progestogen exposure. As both trials were prematurely closed, data do not allow firm conclusions. Both studies found no increased mortality from breast cancer or other causes from HRT. Current guidelines typically consider HRT contraindicated in breast cancer survivors. Findings suggest that, in some women symptom relief may outweigh the potential risks of HRT., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Long-term survival of this patient group has been marginally improved during the last 30 years. This is due to the high recurrence rate of local primary or development of second primary tumours in the patients. We found that normal-appearing surgical margins and distant mucosal tissue of HNSCC patients contained tumour suppressor genes DNA methylation. These cells might be the progenitors of the tumour recurrences. Such molecular abnormalities in the normal-appearing mucosa tissue were not possible to detect in the clinic or by standard histopathologically analysis. To improve clinical outcome, the convenient and cost-effective molecular analysis such as methylation-specific PCR should be added to the pathological diagnosis armamentarium for HNSCC patients. The beneficial effect of antimethylating agents as additional treatment or for cancer chemoprevention, in this high-risk patient group, warrants further investigation.

Background: Most smokers who quit typically do so unassisted although pharmaceutical products are increasingly used by those who want a quitting aid. Previous Scandinavian surveys indicated that many smokers stopped smoking by switching from cigarettes to smokeless tobacco in the form of snus. However, usage of various cessation aids may have changed in Sweden during recent years due to factors such as the wider availability of pharmaceutical nicotine, the public debate about the health effects of different tobacco products, excise tax increases on snus relative to cigarettes, and the widespread public misconception that nicotine is the main cause of the adverse health effects associated with tobacco use., Methods: A population-based, cross-sectional survey was done during November 2008 and September 2009 including 2,599 males and 3,409 females aged between 18 and 89 years. The sampling technique was random digit dialing. Data on tobacco habits and quit attempts were collected through structured telephone interviews., Results: The proportion of ever smokers was similar among males (47%) compared to females (44%). About two thirds of them reported having stopped smoking at the time of the survey. Among the former smokers, the proportion who reported unassisted quitting was slightly lower among males (68%) compared to females (78%). Among ever smokers who reported having made assisted quit attempts, snus was the most frequently reported cessation aid among males (22%), whereas females more frequently reported counseling (8%), or pharmaceutical nicotine (gum 8%, patch 4%). Of those who reported using snus at their latest quit attempt, 81% of males and 72% of females were successful quitters compared to about 50-60% for pharmaceutical nicotine and counseling., Conclusions: This survey confirms and extends previous reports in showing that, although most smokers who have quit did so unassisted, snus continues to be the most frequently reported cessation aid among male smokers, whereas usage of pharmaceutical nicotine was more prevalent among females. Use of snus at the latest quit attempt appeared to be associated with a higher success rate among both males and females than other reported methods, although statistically significant differences were mainly observed among males.

Three commercial brands of Swedish snus (SWS), an experimental SWS, and the 2S3 reference moist snuff were each tested in four in vitro toxicology assays. These assays were: Salmonella reverse mutation, mouse lymphoma, in vitro micronucleus, and cytotoxicity. Water extractions of each of the 5 products were tested using several different concentrations; the experimental SWS was also extracted using dimethyl sulfoxide (DMSO). Extraction procedures were verified by nicotine determinations. Results for SWS in the mutagenicity assays were broadly negative: there were occasional positive responses, but these were effectively at the highest concentration only (concentrations well above those suggested by regulatory guidelines), and were often associated with cytotoxicity. The 2S3 reference was unequivocally positive in one of the three conditions of the micronucleus assay (MNA), at the highest concentration only. Positive controls produced the expected responses in each assay. The SWS data are contrasted with data reported for combusted tobacco in the form of cigarettes, where strongly positive responses have been routinely reported for mutagenicity and cytotoxicity. These negative findings in a laboratory setting concur with the large amount of epidemiological data from Sweden, data showing that SWS are associated with considerably lower carcinogenic potential when compared with cigarettes.

Background: 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., Methods: 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 25-48 participants were actively instructed to stop smoking completely. Outcome measures of biologically verified, complete smoking cessation included 1-week point prevalence rates at clinical visits after 12, 24, 36, and 48 weeks, as well as 4-, 12- and 24-week continued cessation rates at the week 36 and 48 visits., Results: At the week 24 visit, the proportion of participants who achieved the protocol definition of a ≥ 50% smoking reduction was similar in the two treatment groups. However, the proportion that reported more extreme reductions (≥ 75%) was statistically significantly higher in the snus group than in the placebo group (p < 0.01). The results for biologically verified complete cessation suggested that participants in the snus group were more likely to quit smoking completely than the controls; the odds ratio (snus versus placebo) for the protocol estimates of cessation varied between 1.9 to 3.4, but these ratios were of borderline significance with p-values ranging from 0.04-0.10. Snus was well tolerated and only 2/158 (1.3%) participants in the snus group discontinued treatment due to an adverse event (in both cases unrelated to snus)., Conclusions: Swedish snus could promote smoking cessation among smokers in Serbia, that is, in a cultural setting without traditional use of oral, smokeless tobacco., Trial Registration: www.clinicaltrials.gov, identifier: NCT00601042.

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 smokeless tobacco products in Europe.The initial impetus for the mentioned changes of the production was quality problems related to microbial activity and formation of ammonia and nitrite in the finished products. Other contributing factors were that snus came under the jurisdiction of the Swedish Food Act in 1971, and concerns that emerged in the 1960s and 1970s about health effects of tobacco, and the significance of agrochemical residues and other potential toxicants in food stuffs.This paper summarizes the historical development of the manufacture of Swedish snus, describes the chemical composition of modern snus, and gives the background and rationale for the GothiaTek® standard, including the selection of constituents for which the standard sets limits. The paper also discusses the potential future of this voluntary standard in relation to current discussions about tobacco harm reduction and regulatory science in tobacco control.

Unlabelled: The adverse health effects of cigarette smoking are well established including the increased risk of various types of cancer. In this study, the direct effects of ethanol, pure nicotine, cigarette smoke extract and Swedish type smokeless tobacco (Snus) extract on normal cells were investigated., Materials and Methods: Primary normal adult human endothelial cells and fibroblasts at early passage were used. Upon exposure to pure nicotine, cigarette smoke extract, Snus extract and ethanol, these cells were assessed for DNA synthesis, gene expression profile and cellular morphology., Results: Normal human fibroblasts and endothelial cells have unique gene expression profiles. The effects of treatment with ethanol and nicotine from different sources was more prominent in endothelial cells than fibroblasts. The combination of alterated gene expressions and strongly inhibited DNA synthesis was only detected in cells exposed to smoke extract. In the presence and absence of ethanol, pure nicotine and Snus extract induced abnormalities in the cytoplasm without any significant degree of cell death. With similar doses of nicotine and ethanol, the additional components in smoke extract had a dominant effect. The smoke extract induced vast cellular abnormalities and massive cell death., Conclusion: Cigarette smoke induced massive cell death and various abnormalities at cellular and molecular levels in surviving endothelial cells and fibroblasts. The combination of genomic alterations and the chronic inflammatory microenvironment induced from massive cell death, will potentially promote tumourigenesis and various diseases in cigarette smokers.

Objective: The aims of this study were to generate new knowledge about factors predicting return to work (RTW) among women treated for early-stage breast cancer, and about changes in life satisfaction, and coping, and to examine the association between these concepts and RTW., Methods and Participants: A cohort of 102 women aged 18-64 were assessed six weeks, six months, and ten months after surgery using data from questionnaires and medical files., Results: Factors independently predicting no RTW at six months were: chemotherapy, > 30 days of sick leave during the previous 12 months, low satisfaction with activities of daily living, and not having been born in Sweden. No RTW at ten months was predicted by irradiation to breast/chest wall and regional nodes, and low satisfaction with vocational situation. Global life satisfaction was higher among the working women, both six months after surgery and ten months after surgery. The working women used more positive coping resources as compared to the sick-listed women, particularly sick-listed women treated with chemotherapy., Conclusion: Factors associated with RTW appear to include not only treatment-related factors such as chemotherapy and irradiation, but also psychosocial factors such as life satisfaction and coping resources. With increased understanding of the complex factors related to RTW after a breast cancer diagnosis, it will be possible to identify and support survivors who are at risk of being marginalized from the labor market.

Unlabelled: Long-term survival of head and neck squamous cell carcinoma (HNSCC) patients has not improved significantly during the last 20 years and recurrent disease is frequently observed. In this study, the potential presence of pre-malignant cells or rare malignant cells at the time of diagnosis in HNSCC was investigated., Patients and Methods: Fifty-nine biopsies obtained from 41 HNSCC patients were analysed. Eighteen of these biopsies were normal mucosal tissue, located at least 5 cm from the tumour margin. DNA content and DNA methylation of p16, DAPK and RASSF1A was examined., Results: Thirty-nine out of 41 (95%) tumour biopsies showed p16 methylation and 21 (51%) of them displayed aneuploidy. Of 18 distant normal mucosal biopsies, 6 (33%) of these showed evidence of aneuploidy and 15(83%) of them showed methylated p16 genes. Among paired samples, the highest frequencies of DNA methylation were found in tumours with aneuploidy. Regardless of DNA content, methylation at DAPK, RASSF1A or p16 were found in the corresponding distant mucosal biopsies., Conclusion: The cells with abnormal DNA content or DNA methylation in mucosal tissue were not detected clinically or by pathological macroscopic and microscopic examination. Thus, distant mucosal tissue DNA content and DNA methylation analyses in combination with histopathology will provide a better prognostic base for the evaluation and treatment of HNSCC patients.

The purpose of this qualitative study was to identify factors contributing to a successful return to the labour market after treatment for breast cancer from the women's own perspective. The study is based on 16 narratives - open-ended, in-depth interviews - about women's experiences and thoughts from the period after breast cancer surgery when they focused on their return to work. The women were recruited from participants of a multicentre trial, which allowed comparisons across a range of adjuvant therapies. The narratives of women who worked full time at a cut-off point of 1 year after surgery are analysed separately from the narratives of women still sick-listed at that point of time. The findings show that while all the women strove to belong to the labour market, the study also reveals changes in women's perceptions of the value of employment. The quality of social support received from employers and coworkers differed between women who returned to work and those still sick-listed 1 year after breast cancer treatment. A need to design interventions focusing on the work arena of women treated for breast cancer is pointed out.

cDNA microarray is an established technique. However, difficulties such as handling tissue samples under RNase-free conditions, the heterogeneous tumor composition, i.e. non-malignant versus malignant cells and different pathologic types of malignant cells, and lack of appropriate reference may limit the potentially benefit of this method in clinical use. In this study, we examined how standardization of gene expression to total mg RNA or mg tissue and tumor heterogeneity affect the final results. We found that the gene expression of human breast tumors was approximately 9 times higher in malignant tissue as compared to the non-malignant tissue when expressed per total mg RNA, but approximately 40 times higher when expressed per mg tissue. Genes that were expected to act as housekeeping genes (PUC18, RPL and beta-actin) varied between different parts of the tumor and also between non-malignant and malignant tissues, excluding them as reference genes. We also found that the gene expression differed in various parts of the breast tumor, probably due to a mixture of different types of cells, i.e. non-malignant and malignant cells. To find out if the variations in the gene expression were due to cell heterogeneity we used microdissection to collect malignant cells separately. We found that the gene expression was markedly different in the isolated malignant cells as compared to the gene expression of the bulk tumor tissue. Thus, to be able to evaluate results from cDNA array gene expression experiments it is, to our opinion, necessary to work with pure tumor cell populations, until solid information is available on the impact of stromal component. Housekeeping genes should be handling with care and mg tissue may be preferred instead of microg RNA for standardization.

Taste and smell changes (TSCs) are known side effects of chemotherapy, but smell changes (SCs) in the absence of taste changes are understudied. This study aims to explore SCs occurring without taste changes during chemotherapy, to better understand the characteristics of such changes, and how these experiences affect patients in their daily lives. Data derives from a qualitative interview study and a cross-sectional survey of 518 patients, with all patients receiving out-patient cancer chemotherapy in Sweden. Case studies of three patients with SCs and the 8% of survey participants with SCs only are in focus. All 43 participants with exclusively SCs reported increased sensitivity to one or several odors, with no participants reporting decreased sensitivity. Those reporting SCs significantly more often reported weight gain than those reporting TSCs, with oral problems and appetite loss significantly less common in the SC group. There were no differences in reported nausea between SC and TSC groups, but nausea was more common in the SC group than in those without TSCs. The case study reports were linked to and discussed in relation to possible explanatory models for increased olfactory sensitivity. SCs increase during chemotherapy, were often unpredictable and led to emotional consequences. The participants all reported heightened sensitivity to one or several odors which could not fully be explained by the potential explanatory models of anticipatory nausea and vomiting, pseudohallucinations, or increased chemical sensitivity.

Background: The most common female cancer in Western countries is breast cancer and women diagnosed with this disease are often under 65 years old. With increasing prevalence of survivors it is important to shed light on problems facing these women after diagnosis and treatment. The aim of this study was to assess factors predicting return to work (RTW) in women with early-stage breast cancer., Material and Methods: A cohort of 102 women aged 18-64 with early-stage breast cancer who had undergone curative primary surgery with or without systemic adjuvant therapy were followed for 10 months using data from questionnaires and medical files., Results: Ten months after primary surgery, 59% of the women had returned to work while 41% were sick-listed part-time or full-time. After adjusting for age, health status, life satisfaction, vocational situation, and irradiation to the breast/chest wall and regional nodes, a multivariate logistic regression revealed the following factors as being negatively associated with RTW: a high-demand job (OR=0.1, 95% CI 0.0-0.8), axillary node dissection (OR=0.1, 95% CI 0.0-0.6), and treatment with chemotherapy (OR=0.1, 95% CI 0.0-0.7)., Discussion: Treatment factors and high demands at work play an important role in RTW for women with early-stage breast cancer.

Background: Metastatic cancer from an unknown primary tumour (CUP) is a common and heterogeneous clinical entity. In Sweden like in many other countries, the continuum of care for such patients remains to be established., Material and Methods: Data on CUP cases reported to the Swedish Cancer Registry during 1960 through 2007 was used to assess time trends for incidence, survival, and histological tumour type., Results: There was an upward trend for the age-adjusted incidence until the late 1990s. This roughly paralleled the increase for all reported cancers during the same period. The increase of CUP mainly concerned patients aged above 50 years, and tumours classified as adenocarcinomas. The relative survival at 12 months after a diagnosis of CUP was estimated at 20%. However, after 12 months the relative survival levelled of and the 5-year estimate was 10-15% which suggests that a small proportion of CUP cases may be cured. Relative survival was highly dependent on age with substantially better outcome for young patients, particularly those aged below 30 years. We observed no time trend for survival., Discussion: Cases diagnosed as CUP includes patients with metastatic spread from a wide variety of tumours although certain tumour types probably are overrepresented, for example, cancers in sites that are difficult to examine clinically. Incidence trends probably represent the sum of trends for these cancers as well as diagnostic trends. The decreased incidence observed during the last decade might thus be explained in terms of a combination of improved diagnostic methods to detect primary tumours and decreasing incidence for e.g. pancreatic cancer and lung cancer among males. There is a need of evidence-based programs that define the continuum of care for CUP patients. Such a program is currently being developed through collaboration between all health care regions in Sweden.

Background: Both adjuvant therapy and mammography screening can decrease breast cancer mortality and there is a need of knowing to what extent those two modalities are used in the population. Screening coverage is well documented but there is a scarcity of population-based data on use of systemic adjuvant treatment., Aim: To describe the introduction, and trends in the use of adjuvant systemic therapy for breast cancer in two of six public health regions in Sweden., Material & Methods: Population-based data on use of adjuvant therapy were available from databases with documented high quality and high coverage data for Stockholm (1976-2005) and North Sweden (1980-2003, and 2005)., Results: The use of systemic treatment was infrequent before the late 1980s in both regions, but increased during the 1990s. In 2005, the proportion of operable breast cancer patients treated with adjuvant endocrine therapy in the ages 40-59 was around 60 to 80%. The proportion adjuvant chemotherapy was less than 15% for the ages 70-74. For the north region the use of endocrine therapy increased successively over time, with an exception for age group 40-49 were a more rapidly increase occurred in the late 1990s. In Stockholm the increment was higher and more rapidly. There was no clear difference in chemotherapy use between the regions, and the use increased from the mid 1980s in age group 40-49, and in the early 1990s for women aged 50-59. In age group's 60-69 and 70-74 the use was relatively infrequent., Conclusions: Trends in, and levels of the use of adjuvant systemic therapy for breast cancer varied over time in the two study regions, particularly for endocrine therapy. We consider that the differences between the regions mainly reflect different interpretations of new scientific evidence. We stress the importance of a good documentation of all new treatment protocols.

Many cancer patients continue to smoke past diagnosis and treatment, even though smoking in some cases may cause more side effects and increase the risk of treatment failure. We developed and evaluated a nurse-led smoking cessation programme on 50 patients with head and neck (H&N) cancer undergoing radiotherapy (RT) with 1-year follow-up. To evaluate the effectiveness of the programme (proportion of smoke-free patients), smoking status was tested by measuring carbon monoxide in expired air. Thirty-seven patients (74%) were tested smoke-free weekly during the RT period. At the 1-year follow-up visit, 28 patients (68%) were tested smoke-free. The results indicated that even H&N cancer patients with a heavy smoking history and multiple abuses could quit smoking with systematic support but a more sophisticated evaluation including larger study populations and control groups are needed.