Influence of single nucleotide polymorphisms among cigarette smoking and non-smoking patients with coronary artery disease, urinary bladder cancer and lung cancer.

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.

The Influence of Adjuvant Radiotherapy and Single Nucleotide Polymorphisms on Circulating Immune Response Cell Numbers and Phenotypes of Patients With Breast Cancer.

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.

The Influence of Single Nucleotide Polymorphisms and Adjuvant Radiotherapy on Systemic Inflammatory Proteins, Chemokines and Cytokines of Patients With Breast Cancer.

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.

Factors effecting the induction of rat forestomach hyperplasia induced by Swedish oral smokeless tobacco (snus).

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.

Cigarette smoking affects microRNAs and inflammatory biomarkers in healthy individuals and an association to single nucleotide polymorphisms is indicated.

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.

The use of rapid and cost-effective blood-based biomarkers in combination with tumour TNM stage for individual head and neck cancer patient treatment selection.

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.

Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients.

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.

Perforin, CD28 and CD95 expression in circulating CD4 and CD8 cells as predictors of head and neck (H&N) cancer patient survival.

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.

Plasma tumor necrosis factor-α and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma.

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.

DNA methylation in tumour and normal mucosal tissue of head and neck squamous cell carcinoma (HNSCC) patients: new diagnostic approaches and treatment.

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.

The combined effects of single-nucleotide polymorphisms, tobacco products, and ethanol on normal resting blood mononuclear cells.

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.

Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial.

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.

The in vitro toxicology of Swedish snus.

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.

Direct effects of pure nicotine, cigarette smoke extract, Swedish-type smokeless tobacco (Snus) extract and ethanol on human normal endothelial cells and fibroblasts.

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.

Work status and life changes in the first year after breast cancer diagnosis.

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.

DNA content and methylation of p16, DAPK and RASSF1A gene in tumour and distant, normal mucosal tissue of head and neck squamous cell carcinoma patients.

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 impact of RNA standardization and heterogeneous gene expression on the results of cDNA array of human breast carcinoma.

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.

Cancer patients without a known primary: incidence and survival trends in Sweden 1960-2007.

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.

Taste and smell changes in patients receiving cancer chemotherapy: distress, impact on daily life, and self-care strategies.

Few studies have described how patients receiving chemotherapy experience taste/smell changes (TSCs). Food and meal situations have important meaning beyond nutrition, so these common symptoms may affect daily lives. This study aims to investigate distress and impact on daily life from TSCs in patients receiving cancer chemotherapy, analyze reported levels of distress and impact on daily life from TSCs with regard to sociodemographic and clinical factors, and explore patients' reports of self-care strategies and communication with staff. The 340 patients reporting TSCs on a multicenter survey (n = 518) were grouped into subsets by level of TSC-related distress and impact on daily life, which served as the basis for statistical comparison. Written comments were analyzed inductively using content analysis. Nearly one-third of participating patients reported both high levels of distress and impact on daily life (high distress and high impact on daily life [HDHI]) from TSCs. The HDHI subset reported other symptoms more often than others did (P = .01) and also more often responded to open questions about distress, impact, and self-care strategies (P = .01). Taste/smell changes were not always reported to staff, even in the HDHI subset. The specific aspects of TSCs resulting in distress and impact on daily life varied greatly, affecting both psychological and somatic aspects, with little consensus and great individual differences described in self-care strategies. The variety of distress, impact, and strategies used to alleviate TSCs clarifies the importance of situational meaning.