Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer.

BACKGROUND: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. METHODS: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. RESULTS: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04). CONCLUSION: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

Is there an association between PONV and chemotherapy-induced nausea and vomiting?

BACKGROUND: Drug-induced nausea and vomiting, both post-operatively and following chemotherapy, is often distressing for the patients. Our clinical impression is that certain patients are not prone to but instead protected against both post-operative and chemotherapy-induced nausea and vomiting (CINV). If support for this hypothesis could be generated, it might be easier to identify such patients as low-risk patients and judge all other patients as high-risk patients by default. METHODS: All patients scheduled for breast cancer surgery at Danderyd Hospital, Stockholm, Sweden during 1 year (March 2003-March 2004) were asked to participate in this prospective, observational study. A number of women went on to receive adjuvant chemotherapy. Post-operatively, patients were assessed for 24 h with regard to the occurrence of post-operative nausea and vomiting (PONV). CINV was assessed for 5 days after start of chemotherapy. RESULTS: A total of 275 women were included, 33% were classified as PONV and 67% as non-PONV. Sixty-one of the 275 women included were later subjected to adjuvant chemotherapy. In the non-PONV group, 95% of the patients did not experience CINV, whereas the association between PONV and subsequent CINV was only 38%. CONCLUSIONS: A substantially stronger interrelationship was found between non-PONV and non-CINV than between both PONV and CINV. This may suggest that certain patients, instead of being prone to nausea and vomiting, in fact in some way are protected against these unpleasant side effects.

Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial.

Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin(®)) and paclitaxel (Taxol(®)) alone (ET) or in combination with capecitabine (Xeloda(®), TEX). Starting doses for ET were epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2), and for TEX epirubicin 75 mg/m(2), paclitaxel 155 mg/m(2), and capecitabine 825 mg/m(2) BID for 14 days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8 months for patients treated with ET, and 12.4 months for those treated with TEX (HR 0.84, 95% CI 0.65-1.07, P = 0.16); median OS was 26.0 months for women in the ET versus 29.7 months in the TEX arm (HR 0.84, 95% CI 0.63-1.11, P = 0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (χ(2) 3.66, P = 0.16). TTF was significantly longer for patients treated with TEX, 6.0 months, versus 5.2 months following ET (HR 0.73, 95% CI 0.58-0.93, P = 0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.

Prevention of tumour cell dissemination in diagnostic needle procedures.

BACKGROUND: A side effect of diagnostic needle biopsies is the possibility to disseminate tumour cells into the needle track, which may cause concern in certain malignant tumour types. METHODS: In order to prevent tumour cell dissemination we developed a technology that uses radiofrequency (RF) pulses to sterilise the needle track and denaturate tumour cells. To determine feasibility, we applied this technology to fine needle aspiration biopsy (FNAB) and used breast cancer as a model tumour. Routine FNAB was performed in 88 patients with adenocarcinoma and blood droplets passing the skin orifice were cytomorphologically analysed for the presence of tumour cells. RESULTS: The analysis showed the presence of tumour cells in 65/88 cases (74%). When using an experimental anti-seeding device in a subset of patients viable tumour cells were found in 0/31 cases (P<0.001). In all 31 patients blood passing the skin orifice was sparse. No degrading effect on the cytological sample inside the needle was detected and pain caused by the RF pulses was comparable to that of the biopsy procedure itself. CONCLUSION: The herein presented method has the potential to prevent the dissemination of viable tumour cells in the needle track and minimize bleeding without additional pain or degradation of the aspirate.

Individuals with an increased risk of colorectal cancer: perceived benefits and psychological aspects of surveillance by means of regular colonoscopies.

PURPOSE: To evaluate the psychological consequences of genetic counseling followed by a surveillance program using colonoscopy among individuals with increased risk of colorectal cancer. PATIENTS AND METHODS: Two hundred sixty-five individuals, participating in a surveillance program with colonoscopy, were mailed a survey questionnaire that assessed their experience of the surveillance program and their perception of the risk of colorectal cancer. The Hospital Anxiety and Depression scale and the Swedish Short Form-36 Health Survey was also included. RESULTS: Two hundred forty individuals completed the questionnaire and were divided into the following risk groups: risk group 1, an individual with a mutation in hMLH1 or hMSH2 and a lifetime colorectal cancer risk of 80% (n = 28); risk group 2, a lifetime colorectal cancer risk of 40% (n = 129); and risk group 3, a lifetime colorectal cancer risk of 20% (n = 83). Among all individuals, the mean for perceived benefit was 8.0, and the perception of discomfort was 3.3 on the visual analog scale (1-10). In risk group 1, 61% underestimated personal risks as being 40% or less. Approximately 50% of the subjects in risk groups 2 and 3 either under- or overestimated their lifetime risk. According to the Swedish Short Form-36 Health Survey and the Hospital Anxiety and Depression scale, the study sample resembled the reference population. CONCLUSION: A majority of the study sample understood why they were under surveillance, and regular colonoscopies were well-tolerated. The wide range of risk perception as well as low-risk perception in mutation positive subjects is acceptable, as long as these individuals adhere to surveillance programs and do not demonstrate increased levels of anxiety or depression.

Prevalence and incidence of hyperplastic polyps and adenomas in familial colorectal cancer: correlation between the two types of colon polyps.

BACKGROUND AND AIMS: Colorectal adenomas are recognised as precursors of colorectal carcinomas. The significance of hyperplastic (metaplastic) colorectal polyps is unknown. The relationship between hyperplastic polyps and adenomas, and the prevalence and incidence of these lesions were evaluated in individuals predisposed to familial colorectal cancer. METHODS: A total of 299 individuals participating in our surveillance programme during 1990-2000 were retrospectively evaluated. Subjects were classified into three groups: hereditary non-polyposis syndrome (HNPCC) (n=108), hereditary colorectal cancer (HCRC) (n=127), and individuals with empirical risk estimates-two close relatives (TCR) (n=64). Findings from 780 colonoscopies were evaluated regarding prevalence and incidence of hyperplastic polyps and adenomas. Correlations between hyperplastic polyps and adenomas were calculated by Pearson correlation. RESULTS: In total, 292 hyperplastic polyps and 186 adenomas were observed in 98 and 90 individuals, respectively. A positive correlation was found between the numbers of hyperplastic polyps and adenomas (r=0.40; p<0.001). Correlations between adenomas and hyperplastic polyps were similar in the three groups. The risk of detecting new hyperplastic polyps (odds ratio 5.41) or adenomas (OR 2.56) increased significantly when there was a positive finding at first colonoscopy. CONCLUSION: Hyperplastic polyps as well as adenomas may identify individuals with a high risk of colorectal cancer. This information is important when these individuals are selected and included in tailored surveillance programmes.

Structure-function relationships of glutamine synthetases.

As a highly regulated enzyme at the core of nitrogen metabolism, glutamine synthetase has been studied intensively. We review structural and functional studies of both bacterial and eukaryotic glutamine synthetases, with emphasis on enzymatic inhibitors.

High-dose chemotherapy with autologous stem cell support in patients with responding stage IV breast cancer.

Ninety-four patients underwent high-dose chemotherapy with stem cell support for stage IV breast cancer. The high-dose chemotherapy consisted of the Stamp V regimen in all patients comprising cyclophosphamide, thiotepa and carboplatin (CTCb). Twenty-three patients received sequential high-dose therapies with the first consisting of high-dose melphalan and the second of Stamp V. Two patients died from chemotherapy-related complications resulting in a transplant-related mortality at 100 days of 2.2%. The progression-free survival at 3 years was 36% in patients with no evidence of disease at the first course of high-dose therapy compared with 17% in patients with remaining disease at time of the high-dose therapy (P = 0.03). There was no difference in overall survival between patients with no evidence of disease and other patients. The source of stem cells, single or double courses of high-dose therapy, positive selection of CD34+ cells, or number of involved sites had no influence on either progression-free survival or overall survival. Further studies of more intensive induction chemotherapy followed by high-dose therapy with stem cell support are indicated.

Cancer survival in Estonian migrants to Sweden.

OBJECTIVE: To quantify the eventual extra loss of life incurred to cancer patients in Estonia compared with those in Sweden that was possibly attributable to differences in society. DESIGN: Population based survival of cancer patients in Estonia was compared with that of Estonian immigrants to Sweden and that of all cancer patients in Sweden. The cancer sites studied were female breast and ovary, male lung and prostate, and male and female stomach and colon. SETTING: Data on incident cases of cancer were obtained from the population based Swedish and Estonian cancer registries. PARTICIPANTS: Data from Estonian patients in Sweden, Estonian patients in Estonia, and patients from the total Swedish population were included in the study. MAIN RESULTS: Differences in survival among the three populations, controlling for follow-up time and age at diagnosis, were observed in breast, colon, lung, ovarian, and prostate cancers. The survival rates of Estonians living in Sweden and the total population of Sweden were better than that of the Estonians living in Estonia. For cancers of the breast and prostate, the excess mortality in the older age group (75 and above) was much greater in Estonia than in the other populations. CONCLUSIONS: Most differences in cancer survival between Estonian and Swedish populations studied could be attributed to a longer delay in diagnosis, and also to inferior treatment (including access to treatment) in Estonia compared with Sweden. Estonia's lag in socioeconomic development, particularly in its public health organisation and funding, is probably the main source of the differences observed.

Immune effects of relaxation during chemotherapy for ovarian cancer.

BACKGROUND: Psychological interventions, such as relaxation training, have been applied to strengthen resistance to disease. There is evidence that relaxation can modify immune parameters in healthy populations and in chemotherapy naive cancer patients. METHODS: In this study, 22 patients receiving chemotherapy for ovarian cancer were allocated to relaxation training with a clinical psychologist or to a control group. After 2 months' training, blood was sampled 2 days before chemotherapy in the patients' homes, and at the hospital prior to treatment. RESULTS: On average, the intervention group showed higher lymphocyte counts, and a tendency to higher white blood cell numbers as compared to the control group. No significant effects were found in proliferative responses to mitogen and natural killer cell activity after intervention. Relaxation training did not modify the magnitude of changes in immune variables between home samples and at the hospital in anticipation of treatment. CONCLUSIONS: The study suggests that relaxation training can positively affect immune parameters in cancer patients, even if training is performed during myelosuppressive therapy.

Social support and immune status during and after chemotherapy for breast cancer.

Social support and immune status were assessed in women treated with adjuvant chemotherapy for breast cancer. Perception of enhanced attachment was associated with an increased number of white blood cell levels three months after, but not during, chemotherapy. After treatment, patients with high attachment ratings had higher numbers and proportions of granulocytes, and lower proportions of lymphocytes and monocytes. It is concluded that the support experienced by a cancer patient can be associated with counts and proportions of leukocytes, but that this effect, if present during chemotherapy, is overridden by the biological factor that affects the haematopoetic process.

Adequate locoregional treatment for early breast cancer may prevent secondary dissemination.

PURPOSE: To analyze different events that determine event-free survival (EFS) in a randomized trial on adjuvant radiotherapy in early breast cancer patients with more than 15 years of follow-up evaluation. PATIENTS AND METHODS: The trial included 960 patients with a unilateral, operable breast cancer. Surgery consisted of a modified radical mastectomy. The trial compared three arms, as follows: preoperative radiotherapy, postoperative radiotherapy, and no adjuvant treatment. Events were analyzed by a competing-risk approach. A proportional hazards multiple regression model was used to analyze the effects of radiotherapy on the risk of distant metastasis. Similar analyses were performed separately for node-negative [N(-)] and node-positive [N(+)] patients in the two groups that did not include preoperative radiotherapy. RESULTS: Radiotherapy produced a fivefold decrease of the risk of local recurrence (P < .0001). In N(+) patients, postoperative radiotherapy decreased the risk of distant dissemination (relative risk, 0.63). When local recurrence was introduced in the model as a time-dependent covariate, this factor was predictive of distant dissemination (P < .0001) and nullified the effect of postoperative radiotherapy. This finding suggests that the decrease of distant metastases was related to the prevention of local recurrence. A similar effect was found in models that used overall survival as an end point. CONCLUSION: This study shows that postmastectomy radiotherapy in N(+) breast cancer patients may decrease the distant metastasis rate by preventing local recurrences and thus avoiding secondary dissemination.

Comparative X-ray structures of the major binding protein for the immunosuppressant FK506 (tacrolimus) in unliganded form and in complex with FK506 and rapamycin.

FK506 (tacrolimus) is a natural product now approved in the US and Japan for organ transplantation. FK506, in complex with its 12 kDa cytosolic receptor (FKBP12), is a potent agonist of immunosuppression through the inhibition of the phosphatase activity of calcineurin. Rapamycin (sirolimus), which is itself an immunosuppressant by a different mechanism, completes with FK506 for binding to FKBP12 and thereby acts as an antagonist of calcineurin inhibition. We have solved the X-ray structure of unliganded FKBP12 and of FKBP12 in complex with FK506 and with rapamycin; these structures show localized differences in conformation and mobility in those regions of the protein that are known, by site-directed mutagenesis, to be involved in calcineurin inhibition. A comparison of 16 additional X-ray structures of FKBP12 in complex with FKBP12-binding ligands, where those structures were determined from different crystal forms with distinct packing arrangements, lends significance to the observed structural variability and suggests that it represents an intrinsic functional characteristic of the protein. Similar differences have been observed for FKBP12 before, but were considered artifacts of crystal-packing interactions. We suggest that immunosuppressive ligands express their differential effects in part by modulating the conformation of FKBP12, in agreement with mutagenesis experiments on the protein, and not simply through differences in the ligand structures themselves.

[High-dose chemotherapy in breast cancer. Promising results in combination with stem cell support]. / Kemoterapi i högdos mot bröstcancer. Lovande resultat i kombination med stamcellsunderstöd.

Thirty-three women with breast cancer have undergone high dose chemotherapy with autologous stem cell support at Huddinge Hospital. Twenty-eight patients had stage IV disease while five patients had disease stage II or III with involvement of > 10 axillary lymph nodes. Patients who received peripheral stem cells had a shorter duration of neutropenia than patients who received autologous bone marrow (p < 0.001). The transplant related mortality was 3 per cent. The calculated progression free survival was 39 per cent at 24 months after high dose therapy in women with stage IV chemosensitive breast cancer. Patients who got a complete remission after standard dose chemotherapy had a better survival rate than patients who got a partial remission. All women with refractory disease progressed within five months from therapy. Four out of five patients with disease stage II or III are progression free with the longest follow-up time of 46 months. High dose chemotherapy with stem cell support can be given with acceptable toxicity. The follow-up time is short but the results are promising, in particular for women who obtain a complete remission before the high dose therapy starts.

Anticipatory immune changes in women treated with chemotherapy for ovarian cancer.

Immune parameters were assessed in 22 women before chemotherapy for ovarian cancer and compared with assessment made at home 2 days earlier. In the hospital, as compared to home measures, patients had a lower percentage of lymphocytes and monocytes and a higher percentage of granulocytes. Absolute numbers of lymphocytes were lower at the hospital as compared to at home. T-cell proliferative responses to concanavalin A were elevated for cells isolated from hospital blood samples as compared to home samples. The observed changes in immune parameters were not related to levels o r state anxiety at home or at the hospital. The results show anticipatory immune changes in a group of patients receiving chemotherapy that did not include cyclophosphamide.

Influence of radiation therapy on lung tissue in breast cancer patients. CT-assessed density changes 4 years after completion of radiotherapy.

CT-assessed density changes in lung tissues were measured in 22 disease-free breast cancer patients 4 years after completion of radiation therapy. All patients had previously undergone similar CT-examinations before treatment, 3 months, and 9 months after radiotherapy. In patients with visible areas of increased lung density at earlier CT-examinations a decrease of focal findings was observed at 4 years. In patients without focal findings, an increase in density relative to that before therapy was observed. The difference between the mean lung density values among those with visible radiological findings and those without was statistically significant both at 3 and 9 months after therapy. However, this difference did not persist at 4 years. These results may indicate a 2-phase development of radiation-induced lung damages--an acute phase and a late phase; the late phase emerging slowly, and in this study detectable 4 years after completion of radiation therapy.

Does informed adjuvant placebo chemotherapy for breast-cancer elicit immune changes.

To study psychological effects on the immune system, a saline infusion was administered to 24 fully informed patients who previously had received adjuvant chemotherapy for breast cancer. Blood samples were drawn before and after treatment, and compared to samples obtained at home two days earlier. Patients displayed a rise in natural killer-cell activity and a tendency to lowered percentage of suppressor/cytotoxic cells when assessed before treatment as compared to at home. Trait anxiety was associated with numbers of leukocytes. It is concluded that immune status partly reflects psychological factors.

Cancer incidence in Estonian migrants to Sweden.

Cancer incidence in Estonians who took refuge in Sweden in 1944-1945 has been compared with that in the total Swedish population and that among Estonians in Estonia in 1974-1985 using data from the Swedish and the Estonian countrywide population-based cancer registries. The vast majority of the Estonian immigrants studied had been living in Sweden for 30 years when the follow-up with respect to cancer incidence started in this investigation. In spite of the long residence in Sweden, differences in cancer incidence could be observed between these immigrants and the total Swedish population. The age-standardized incidence of stomach cancer was higher in the Estonian migrants than in the total Swedish population (SIR = 1.6 and 2.1 for males and females, respectively). Breast cancer incidence was lower in the migrant women (SIR = 0.75) and lung cancer incidence higher in migrant men (SIR = 1.5). An increased incidence of colorectal cancer was also found for both sexes in the migrant population (SIR = 1.4 for both males and females). A comparison between Estonians in Estonia and the total Swedish population revealed that the cancer incidence for the Estonians was lower than expected at age 70 and over. Male lung cancer and stomach cancer showed a higher incidence in the Estonian population than in the Swedish and in the migrant populations. The migrant population showed an intermediate incidence relative to Estonians in Estonia and the entire Swedish population. The colon-cancer risk in Estonian migrants to Sweden was higher than the risk for Estonians in Estonia and for the Swedish population. This contrasts with most findings in the present and other studies on intermediate risks of migrants compared to the risks in the country of origin and in the new country of residence.

Loss of heterozygosity in familial breast carcinomas.

Three loci have been implicated in the etiology of familial breast cancer; the BRCA1 locus on 17q, the p53 gene on 17p, and the androgen receptor gene on the X chromosome. However, it has been estimated that in approximately 50% of all breast cancer families the predisposing genetic defect is not linked to any of these three loci. In an attempt to identify chromosomal regions harboring putative breast cancer genes we performed allelotyping in 82 familial breast carcinomas. Polymorphic markers representing 45 different loci were analyzed and the most frequently involved chromosomal arms were 8p, 16q, 17p, 17q, and 19p.

Deletions on chromosome 16 in primary familial breast carcinomas are associated with development of distant metastases.

Genetic alterations that occur in human breast cancers are believed to be of importance for initiation as well as progression of the disease. In order to find a genetic alteration that may be used as a prognostic marker, 82 familial breast carcinomas were analyzed for loss of constitutional heterozygosity at polymorphic loci on all chromosomes. Frequently occurring allele losses were compared to estrogen receptor expression, lymph node metastases, tumor size at the time of operation, and distant metastases at the time of follow-up 2-15 years later. Loss of heterozygosity (LOH) on the long arm of chromosome 16 in the tumor at the time of operation was significantly correlated (P < 0.001) with the occurrence of distant metastases 1-13 years after the operation. In addition, LOH at 16q was not correlated with estrogen receptor status, lymph node positivity, or tumor size, nor was the occurrence of distant metastases correlated with any of these parameters. The results suggest the existence of a tumor suppressor gene on 16q that facilitates hematogenic spread of breast cancer and that LOH at this locus is an independent prognostic marker in breast cancer.