Showing papers in "British Journal of Cancer in 2003"
TL;DR: A majority of ICC was associated with HPV16 or 18 in all regions, but approximately a quarter of all ICC cases were associated with one of 16 other HPV types, their distribution varying by region.
Abstract: Epidemiological studies have clearly established human papilloma-virus (HPV) infection as the central cause of invasive cervical cancer (ICC). This is the second most common cancer among women worldwide and the most common female cancer in large areas of the developing world where an estimated 80% of new cases arise (Parkin et al, 1999). Studies in 22 countries, coordinated by the International Agency for Research on Cancer (IARC), identified HPV DNA in almost all (99.7%) (of about 1000) cases of cervical cancer (Walboomers et al, 1999).
1,551 citations
TL;DR: Multivariate survival analysis, a form of multiple regression, provides a way of doing this adjustment for patient-related factors that could potentially affect the survival time of a patient, and is the subject of the next paper in this series.
Abstract: Survival analysis is a collection of statistical procedures for data analysis where the outcome variable of interest is time until an event occurs. Because of censoring–the nonobservation of the event of interest after a period of follow-up–a proportion of the survival times of interest will often be unknown. It is assumed that those patients who are censored have the same survival prospects as those who continue to be followed, that is, the censoring is uninformative. Survival data are generally described and modelled in terms of two related functions, the survivor function and the hazard function. The survivor function represents the probability that an individual survives from the time of origin to some time beyond time t. It directly describes the survival experience of a study cohort, and is usually estimated by the KM method. The logrank test may be used to test for differences between survival curves for groups, such as treatment arms. The hazard function gives the instantaneous potential of having an event at a time, given survival up to that time. It is used primarily as a diagnostic tool or for specifying a mathematical model for survival analysis. In comparing treatments or prognostic groups in terms of survival, it is often necessary to adjust for patient-related factors that could potentially affect the survival time of a patient. Failure to adjust for confounders may result in spurious effects. Multivariate survival analysis, a form of multiple regression, provides a way of doing this adjustment, and is the subject the next paper in this series.
699 citations
TL;DR: A meta-analysis of published data suggests that HSILs infected with HPV16, 18 and 45 preferentially progress to SCC, which may have implications for follow-up protocols of future HPV-based cervical cancer screening programmes and for HPV vaccine trials.
Abstract: Particular types of human papillomavirus (HPV) infection may preferentially progress from high-grade squamous intraepithelial lesions (HSIL) to squamous cell carcinoma of the cervix (SCC). We performed a meta-analysis of published data to compare HPV type distribution in HSIL and SCC. HPV16, 18 and 45 were each more prevalent in SCC than HSIL, whereas the reverse was true for other oncogenic types including HPV31, 33, 52 and 58. These data suggest that HSILs infected with HPV16, 18 and 45 preferentially progress to SCC. This may have implications for follow-up protocols of future HPV-based cervical cancer screening programmes and for HPV vaccine trials.
689 citations
TL;DR: In conclusion, organ transplantation entails a persistent, about four-fold increased overall cancer risk, and the complex pattern of excess risk at many sites challenges current understanding of oncogenic infections that might become activated by immunologic alterations.
Abstract: A substantial excess risk of lymphomas and nonmelanoma skin cancer has been demonstrated following organ transplantation. Large sample size and long follow-up time may, however, allow more accurate risk estimates and detailed understanding of long-term cancer risk. The objective of the study was to assess the risk of cancer following organ transplantation. A nationwide cohort study comprising 5931 patients who underwent transplantation of kidney, liver or other organs during 1970-1997 in Sweden was conducted. Complete follow-up was accomplished through linkage to nationwide databases. We used comparisons with the entire Swedish population to calculate standardised incidence ratios (SIRs), and Poisson regression for multivariate internal analyses of relative risks (RRs) with 95% confidence intervals (CI). Overall, we observed 692 incident first cancers vs 171 expected (SIR 4.0; 95% CI 3.7-4.4). We confirmed marked excesses of nonmelanoma skin cancer (SIR 56.2; 95% CI 49.8-63.2), lip cancer (SIR 53.3; 95% CI 38.0-72.5) and of non-Hodgkin's lymphoma (NHL) (SIR 6.0; 95% CI 4.4-8.0). Compared with patients who underwent kidney transplantation, those who received other organs were at substantially higher risk of NHL (RR 8.4; 95% CI 4.3-16). Besides, we found, significantly, about 20-fold excess risk of cancer of the vulva and vagina, 10-fold of anal cancer, and five-fold of oral cavity and kidney cancer, as well as two- to four-fold excesses of cancer in the oesophagus, stomach, large bowel, urinary bladder, lung and thyroid gland. In conclusion, organ transplantation entails a persistent, about four-fold increased overall cancer risk. The complex pattern of excess risk at many sites challenges current understanding of oncogenic infections that might become activated by immunologic alterations.
654 citations
TL;DR: A score based on the combination of the systemic inflammatory response and albumin hazards ratio (HR) was comparable in prognostic value to that based on stage and performance status in patients with inoperable non-small-cell lung cancer.
Abstract: A score based on the combination of the systemic inflammatory response and albumin hazards ratio (HR) 1.70, 95% CI 1.23 - 2.35, P=0.001) was comparable in prognostic value to that based on stage and performance status (HR 1.48, 95% CI 1.12 - 1.95, P=0.006) in patients with inoperable non-small-cell lung cancer. The former is simple to measure and well standardised.
619 citations
TL;DR: Survival Analysis Part II: Multivariate data analysis – an introduction to concepts and methods.
Abstract: Survival Analysis Part II: Multivariate data analysis – an introduction to concepts and methods
570 citations
TL;DR: The results strongly highlight the necessity to delineate the indications of 131I treatment in thyroid cancer patients in order to restrict its use to patients in whom clinical benefits are expected and to evaluate the risk of second primary malignancies.
Abstract: The late health effects associated with radioiodine ((131)I) given as treatment for thyroid cancer are difficult to assess since the number of thyroid cancer patients treated at each centre is limited. The risk of second primary malignancies (SPMs) was evaluated in a European cohort of thyroid cancer patients. A common database was obtained by pooling the 2-year survivors of the three major Swedish, Italian, and French cohorts of papillary and follicular thyroid cancer patients. A time-dependent analysis using external comparison was performed. The study concerned 6841 thyroid cancer patients, diagnosed during the period 1934-1995, at a mean age of 44 years. In all, 17% were treated with external radiotherapy and 62% received (131)I. In total, 576 patients were diagnosed with a SPM. Compared to the general population of each of the three countries, an overall significantly increased risk of SPM of 27% (95% CI: 15-40) was seen in the European cohort. An increased risk of both solid tumours and leukaemias was found with increasing cumulative activity of (131)I administered, with an excess absolute risk of 14.4 solid cancers and of 0.8 leukaemias per GBq of (131)I and 10(5) person-years of follow-up. A relationship was found between (131)I administration and occurrence of bone and soft tissue, colorectal, and salivary gland cancers. These results strongly highlight the necessity to delineate the indications of (131)I treatment in thyroid cancer patients in order to restrict its use to patients in whom clinical benefits are expected.
565 citations
TL;DR: The overall results showed that higher PPRI scores of physician attentiveness and empathy were associated with greater patient satisfaction, increased self-efficacy, and reduced emotional distress following the consultation, suggesting that communication is a core clinical skill in oncology.
Abstract: The aim of the study was to investigate the association of physician communication behaviours as perceived by the patient with patient reported satisfaction, distress, cancer-related self-efficacy, and perceived control over the disease in cancer patients. Questionnaires measuring distress, self-efficacy, and perceived control were completed prior to and after the consultation by 454 patients attending an oncology outpatient clinic. After the consultation, the patients also rated the physicians' communicative behaviours by completing a patient-physician relationship inventory (PPRI), and the physicians were asked to estimate patient satisfaction. The overall results showed that higher PPRI scores of physician attentiveness and empathy were associated with greater patient satisfaction, increased self-efficacy, and reduced emotional distress following the consultation. In contrast, lower PPRI scores were associated with reduced ability of the physician to estimate patient satisfaction. The results confirm and expand previous findings, suggesting that communication is a core clinical skill in oncology.
538 citations
TL;DR: The rate of AR gene amplification and/or an increase in AR protein expression during androgen resistant is too low to wholly explain the development of androgen resistance.
Abstract: This study examined androgen receptor (AR) gene amplification and protein expression in 102 matched paired hormone sensitive and resistant tumours from 51 patients. AR gene amplification and X chromosome copy number were assessed by fluorescent in situ hybridisation, and protein expression was assessed by immunohistochemistry. All tumours were stained for PSA protein expression. Significantly more tumours exhibited AR amplification following the development of hormone resistance (20%, 10 out of 49) compared to matched hormone-sensitive tumours from the same patient (2%, one out of 48) (P=0.0085). The level of AR expression was significantly higher in hormone-resistant tumours compared to matched hormone-sensitive tumours from the same patient (130, interquartile range, 55-167 vs 94.5 interquartile range, 55-120, P=0.019). AR expression levels in hormone-resistant tumours with and without AR amplification were not significantly different. However, an increase in AR expression was seen with the development of AR amplification in paired tumours. The rate of AR gene amplification and/or an increase in AR protein expression during androgen resistant is too low to wholly explain the development of androgen resistance. Alternative mechanisms for modulating the function of the AR, or other signalling pathways, must be considered as key factors in the development of hormone-resistant prostate.
433 citations
TL;DR: Combined estimates of risk for total and saturated fat intake, and for meat intake, all indicate an association between higher intakes and an increased risk of breast cancer.
Abstract: Animal experiments and human ecological studies suggest that dietary fat intake is associated with a risk of breast cancer, but individual-based studies have given contradictory results. We have carried out a meta-analysis of this association to include all papers published up to July 2003. Case–control and cohort studies that examined the association of dietary fat, or fat-containing foods, with risk of breast cancer were identified. A total of 45 risk estimates for total fat intake were obtained. Descriptive data from each study were extracted with an estimate of relative risk and its associated 95% confidence interval (CI), and were analysed using the random effects model of DerSimonian and Laird. The summary relative risk, comparing the highest and lowest levels of intake of total fat, was 1.13 (95% CI: 1.03–1.25). Cohort studies (N=14) had a summary relative risk of 1.11 (95% CI: 0.99–1.25) and case–control studies (N=31) had a relative risk of 1.14 (95% CI 0.99–1.32). Significant summary relative risks were also found for saturated fat (RR, 1.19; 95% CI: 1.06–1.35) and meat intake (RR, 1.17; 95% CI 1.06–1.29). Combined estimates of risk for total and saturated fat intake, and for meat intake, all indicate an association between higher intakes and an increased risk of breast cancer. Case–control and cohort studies gave similar results.
367 citations
TL;DR: P protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.
Abstract: Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O(6)-alkylguanine-DNA alkyltransferase (AGAT), has demonstrated anticancer activity on protracted schedules. Protracted schedules may lead to an 'autoenhancement' of temozolomide's inherent cytotoxic potential by cumulative reduction of the cell's capacity for AGAT-mediated DNA repair and resistance. This study was undertaken to characterise AGAT inactivation and regeneration in the peripheral blood mononuclear cells (PBMCs) of patients treated on two protracted temozolomide schedules. O(6)-alkyl guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on two phase I protracted temozolomide studies. Patients were treated daily for either 7 days every 2 weeks (Schedule A) or 21 days every 4 weeks (Schedule B). The effects of various temozolomide doses (75-175 mg m(-2)), treatment duration (7-21 days), and temozolomide plasma levels on AGAT inactivation and regeneration, as well as the relation between AGAT inactivation and toxicity, were studied. O(6)-alkyl guanine-DNA alkyltransferase activity in PBMCs was measured serially in 52 patients. Marked inactivation of AGAT occurred following 7 days of temozolomide treatment, with mean AGAT activity decreasing by 72% (P<0.0001). Similarly, mean AGAT activity decreased by 63 and 73% after 14 and 21 days of treatment, respectively (P<0.001 for both comparisons). O(6)-alkyl guanine-DNA alkyltransferase inactivation was greater after 7 days of treatment with higher doses of temozolomide than lower doses and remained markedly reduced 7 days post-treatment. However, AGAT inactivation following temozolomide treatment for 14 and 21 days was similar at all doses. On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.3+/-5.5 vs 72.5+/-16.1%, P<0.045). In conclusion, protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.
TL;DR: It is concluded that overexpression of LDH-5 is a common event in non-small-cell lung cancer, can be easily assessed in paraffin-embedded material and provides important prognostic information, particularly when combined with other endogenous markers of hypoxia and acidity.
Abstract: Lactate dehydrogenase-5 (LDH-5) catalyses the reversible transformation of pyruvate to lactate, having a principal position in the anaerobic cellular metabolism. Induction of LDH-5 occurs during hypoxia and LDH-5 transcription is directly regulated by the hypoxia-inducible factor 1 (HIF1). Serum LDH levels have been correlated with poor prognosis and resistance to chemotherapy and radiotherapy in various neoplastic diseases. The expression, however, of LDH in tumours has never been investigated in the past. In the present study, we established an immunohistochemical method to evaluate the LDH-5 overexpression in tumours, using two novel antibodies raised against the rat muscle LDH-5 and the human LDH-5 (Abcam, UK). The subcellular patterns of expression in cancer cells were mixed nuclear and cytoplasmic. In direct contrast to cancer cells, stromal fibroblasts were reactive for LDH-5 only in a minority of cases. Serum LDH, although positively correlated with, does not reliably reflect the intratumoral LDH-5 status. Lactate dehydrogenase-5 overexpression was directly related to HIF1alpha and 2alpha, but not with the carbonic anhydrase 9 expression. Patients with tumours bearing high LDH-5 expression had a poor prognosis. Tumours with simultaneous LDH-5 and HIF1alpha (or HIF2alpha) overexpression, indicative of a functional HIF pathway, had a particularly aggressive behaviour. It is concluded that overexpression of LDH-5 is a common event in non-small-cell lung cancer, can be easily assessed in paraffin-embedded material and provides important prognostic information, particularly when combined with other endogenous markers of hypoxia and acidity.
TL;DR: Survival Analysis Part III: Multivariate data analysis – choosing a model and assessing its adequacy and fit and how it is fitted to the real-world situation.
Abstract: Survival Analysis Part III: Multivariate data analysis – choosing a model and assessing its adequacy and fit
TL;DR: The findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on B RCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting.
Abstract: Germline mutations of the tumour suppressor gene BRCA1 are involved in the predisposition and development of breast cancer and account for 20-45% of all hereditary cases There is an increasing evidence that these tumours are characterised by a specific phenotype and pattern of gene expression We have hypothesised that differences in chemosensitivity might parallel molecular heterogeneity of hereditary and sporadic breast tumours To this end, we have investigated the chemosensitivity of the BRCA1-defective HCC1937 breast cancer cell line, and the BRCA1-competent MCF-7 (hormone-sensitive) and MDA-MB231 (hormone-insensitive) breast cancer cell lines using the MTT assay The 50% inhibitory concentration (IC(50)) for the individual compounds were derived by interpolate plot analysis of the logarithmic scalar concentration curve after a 48 h exposure HCC1937 cells were significantly (P 2 microM for HCC1937, 01-02 microM for MCF-7 and 001-002 microM for MDA-MB231) (P<0001) Full-length BRCA1 cDNA transfection of BRCA1-defective HCC1937 cells led to the reconstituted expression of BRCA1 protein in HCC1937/(WT)BRCA1-derived cell clone, but did not reduce tumour cell growth in soft agar BRCA1 reconstitution reverted the hypersensitivity to CDDP (P<002), and restored the sensitivity to Dox (P<005) and Tax (P<0001), compared with parental HCC1937 cells Taken together, our findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on BRCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting
TL;DR: The overall results show that 12 – 15 months postintervention, clinicians had integrated key communication skills into clinical practice and were applying others, the first RCT to show an enduring effect of communication skills training with transfer into the clinic.
Abstract: The efficacy of a communication skills training programme was shown through a randomised trial. Oncologists (N=160) from 34 cancer centres were allocated to written feedback plus course; course alone; written feedback alone or control. Each clinician had 6 - 10 interviews with patients videotaped at baseline and 3 months postintervention. Analysis of videotapes revealed improvements in the communication skills of clinicians randomised to training (n=80) compared with others (n=80). A 12-month follow-up assessment is reported here. Robust Poisson conditional analyses of counts of changes in communication behaviours revealed no demonstrable attrition in those who had shown improvement previously, including fewer leading questions, appropriate use of focused and open-ended questions and responses to patient cues. Additional skills, not apparent at 3 months, were now evident; the estimated effect sizes corresponded to 81% fewer interruptions (P=0.001) and increased summarising of information to 38% (P=0.038). However, expressions of empathy (54%, P=0.001) declined. The overall results show that 12 - 15 months postintervention, clinicians had integrated key communication skills into clinical practice and were applying others. This is the first RCT to show an enduring effect of communication skills training with transfer into the clinic.
TL;DR: In women aged 20–39 years, even annual screening is not as effective as 3-yearly screening in older women, and 3 years after screening cancer rates return to those in unscreened women, which calls into question the policy of having a uniform screening interval from age 20 to 64 years and stresses the value of screening in middle-aged women.
Abstract: While most experts agree that cervical screening is effective, there remains controversy over the most appropriate screening interval. Annual screening is common in North America. In England, some argue for 3-yearly screening while others believe 5-yearly screening is adequate, and the frequency varies from one part of the country to another. Screening histories of 1305 women aged 20–69 years, diagnosed with frankly invasive cervical cancer and 2532 age-matched controls were obtained from UK screening programme databases. Data were analysed in terms of time since last negative, and time since last screening smear. Five-yearly screening offers considerable protection (83%) against cancer at ages 55–69 years and even annual screening offers only modest additional protection (87%). Three-yearly screening offers additional protection (84%) over 5-yearly screening (73%) for cancers at ages 40–54 years, but is almost as good as annual screening (88%). In women aged 20–39 years, even annual screening is not as effective (76%) as 3-yearly screening in older women, and 3 years after screening cancer rates return to those in unscreened women. This calls into question the policy of having a uniform screening interval from age 20 to 64 years and stresses the value of screening in middle-aged women.
TL;DR: The studies presented here serve to underscore the importance of amino-acid 482 in defining the substrate specificity of the ABCG2 protein and raise the possibility that amino- acid 482 mutations in human cancers could affect the clinical application of antagonists forABCG2.
Abstract: Recent studies have shown that mutations at amino-acid 482 in the ABCG2 gene affect the substrate specificity of the protein. To delineate the effects of these mutations clearly, human embryonic kidney cells (HEK-293) were stably transfected with wild-type 482R or mutant 482G and 482T ABCG2. By flow cytometry, mitoxantrone, BODIPY-prazosin, and Hoechst 33342 were found to be substrates of all ABCG2 proteins, while rhodamine 123, daunorubicin, and LysoTracker Green were transported only by mutant ABCG2. In cytotoxicity assays, all ABCG2 proteins conferred high levels of resistance to mitoxantrone, SN-38, and topotecan, while mutant ABCG2 also exhibited a gain of function for mitoxantrone as they conferred a four-fold greater resistance compared to wild type. Cells transfected with mutant ABCG2 were 13- to 71- fold resistant to the P-glycoprotein substrates doxorubicin, daunorubicin, epirubicin, bisantrene, and rhodamine 123 compared to cells transfected with wild-type ABCG2, which were only three- to four-fold resistant to these compounds. ABCG2 did not confer appreciable resistance to etoposide, taxol or the histone deacetylase inhibitor depsipeptide. None of the transfected cell lines demonstrated resistance to flavopiridol despite our previous observation that ABCG2-overexpressing cell lines are cross-resistant to the drug. Recently reported inhibitors of ABCG2 were evaluated and 50 microM novobiocin was found to reverse wild-type ABCG2 completely, but only reverse mutant ABCG2 partially. The studies presented here serve to underscore the importance of amino-acid 482 in defining the substrate specificity of the ABCG2 protein and raise the possibility that amino-acid 482 mutations in human cancers could affect the clinical application of antagonists for ABCG2.
TL;DR: There is a need from the women's perspective to improve communication about sexual issues, although the most appropriate approach to this remains to be investigated.
Abstract: Gynaecological cancer has been shown to affect women's sexual functioning, yet evidence suggests that healthcare professionals rarely discuss sexual issues with women diagnosed with a gynaecological cancer. Few studies have investigated why there is a lack of communication between healthcare professionals and women about sexual issues. Our study investigated the attitudes and behaviours of the 27 doctors and 16 nurses treating women with ovarian cancer in our centre towards the discussion of sexual issues, and also investigated women's experiences of such communication. Our findings showed that although most healthcare professionals thought that the majority of women with ovarian cancer would experience a sexual problem, only a quarter of doctors and a fifth of nurses actually discussed sexual issues with the women. Reasons for not discussing sexual issues included 'it is not my responsibility', 'embarrassment', 'lack of knowledge and experience' and 'lack of resources to provide support if needed'. While some of these reasons were also viewed as barriers by the women, the results demonstrate that there is a need from the women's perspective to improve communication about sexual issues, although the most appropriate approach to this remains to be investigated.
TL;DR: The ability of PDT using the second-generation photosensitiser 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) to induce proinflammatory cytokines and chemokines, as well as adhesion molecules, known to be involved in neutrophil migration is examined, in mice.
Abstract: Photodynamic therapy (PDT) of tumour results in the rapid induction of an inflammatory response that is considered important for the activation of antitumour immunity, but may be detrimental if excessive. The response is characterised by the infiltration of leucocytes, predominantly neutrophils, into the treated tumour. Several preclinical studies have suggested that suppression of long-term tumour growth following PDT using Photofrin® is dependent upon the presence of neutrophils. The inflammatory pathways leading to the PDT-induced neutrophil migration into the treated tumour are unknown. In the following study, we examined, in mice, the ability of PDT using the second-generation photosensitiser 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) to induce proinflammatory cytokines and chemokines, as well as adhesion molecules, known to be involved in neutrophil migration. We also examined the role that these mediators play in PDT-induced neutrophil migration. Our studies show that HPPH-PDT induced neutrophil migration into the treated tumour, which was associated with a transient, local increase in the expression of the chemokines macrophage inflammatory protein (MIP)-2 and KC. A similar increase was detected in functional expression of adhesion molecules, that is, E-selectin and intracellular adhesion molecule (ICAM)-1, and both local and systemic expression of interleukin (IL)-6 was detected. The kinetics of neutrophil immigration mirrored those observed for the enhanced production of chemokines, IL-6 and adhesion molecules. Subsequent studies showed that PDT-induced neutrophil recruitment is dependent upon the presence of MIP-2 and E-selectin, but not on IL-6 or KC. These results demonstrate a PDT-induced inflammatory response similar to, but less severe than obtained with Photofrin® PDT. They also lay the mechanistic groundwork for further ongoing studies that attempt to optimise PDT through the modulation of the critical inflammatory mediators.
TL;DR: Evidence is provided that the risk of pancreatic cancer may be weakly associated with obesity, but the small magnitude of the summary risk means the possibility of confounding cannot be excluded.
Abstract: Smoking and diabetes are the only established risk factors for pancreatic cancer. Findings from recent studies suggest that obesity may also be associated with an increased risk of pancreatic cancer, but several earlier studies were less conclusive. We examined this relationship in a meta-analysis of published data. Six case-control and eight cohort studies involving 6391 cases of pancreatic cancer were identified from a computer-based literature search from 1966 to 2003. The relative risk per unit increase in body mass index was estimated for each of the studies from the published data. In a random effects model, the summary relative risk per unit increase in body mass index was 1.02 (95% CI: 1.01-1.03). There was some evidence of heterogeneity between the studies' results (P=0.1). The summary relative risk estimates were slightly higher for studies that had adjusted for smoking and for case-control studies that had not used proxy respondents. The estimated per unit increase in body mass index would translate into a relative risk of 1.19 (95% CI: 1.10-1.29) for obese people (30 kg m(-2)) compared to people with a normal body weight (22 kg m(-2)). These results provide evidence that the risk of pancreatic cancer may be weakly associated with obesity. However, the small magnitude of the summary risk means the possibility of confounding cannot be excluded.
TL;DR: Results indicate that serum IL-6 levels correlate to poor survival in patients with hormone-refractory metastatic breast cancer, and Vascular endothelial growth factor serum and plasma levels are not useful indicators of prognosis for these patients.
Abstract: Prediction of survival for patients with metastatic breast cancer is often inaccurate and may be helped by new biological parameters. Tumour growth being angiogenesis-dependent, it has been hypothesised that the assessment of angiogenic factor production might reflect the clinical behaviour of cancer progression. This study was designed to investigate the clinical significance of vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in hormone-refractory metastatic breast cancer. Serum and plasma concentrations of VEGF and serum concentration of IL-6 were measured in 87 patients with a fully documented history of metastatic breast cancer using an enzyme-linked immunoassay. All patients had detectable levels of VEGF, whereas 39% patients had detectable serum levels of IL-6. There was a positive correlation between IL-6 levels and the theoretical VEGF load of platelets (P<0.001). The presence of high levels of serum IL-6, but not VEGF, was significantly correlated to a shorter survival. In a multivariate analysis along with clinical prognostic parameters, serum IL-6 was identified as an independent adverse prognostic variable for overall survival (P&<0.001). These results indicate that serum IL-6 levels correlate to poor survival in patients with hormone-refractory metastatic breast cancer. Vascular endothelial growth factor serum and plasma levels are not useful indicators of prognosis for these patients.
TL;DR: It is suggested that tumour vascular function and tumour uptake of anticancer drugs improve with VEGF-blocking therapy, and the relevance for further investigations is indicated.
Abstract: Promising preclinical activity with agents blocking the function of vascular endothelial growth factor (VEGF) has been observed in various cancer types, especially with combination therapy. However, these drugs decrease microvessel density, and it is not known whether this reduced vessel density (VD) results in decreased delivery of concomitantly administered classical anticancer drugs. We designed an in vivo study to investigate the relation between VEGF-blocking therapy, tumoral blood vessels, and intratumoral uptake of anticancer drugs. Nude NMRI mice bearing colon adenocarcinoma (HT29) were treated with the anti-VEGFmAb A4.6.1 or placebo. After 1 week, CPT-11 was administered 1 h prior to killing the animals. In A4.6.1 treated tumours, there was a significant decrease in VD, more pronounced with potentially functional large vessels than endothelial cords. Interestingly, a trend to increased intratumoral CPT-11 concentration was observed (P=0.09). In parallel, we measured an increase in tumour perfusion, as estimated by high-performance liquid chromatography determination of intratumoural Hoechst 33342 concentration. In the growth delay study, CPT-11 was at least equally effective with or without pretreatment with A4.6.1. These data suggest that tumour vascular function and tumour uptake of anticancer drugs improve with VEGF-blocking therapy, and indicate the relevance for further investigations.
TL;DR: Data show that HPV testing is of value for the detection or exclusion of prevalent CIN in a routine cervical cancer-screening setting and could be used for further risk classification of women for follow-up management.
Abstract: In a prospective cohort study 8466 women attending routine cervical cancer screening were recruited. Colposcopy was performed on women with any degree of atypia on cytology and/or a positive high-risk human papillomavirus (HPV)-DNA test (HC2; Hybrid Capture 2((c))), and for a randomly selected sample of 3.4% women with negative findings on both. Quality control included reviews of cytology, histology, colposcopy images and retesting of samples with polymerase chain reaction. Test diagnostic performances were based on 7908 women who had complete baseline and follow-up results. Routine histology identified 86 women with high-grade cervical intraepithelial neoplasia (CIN2+), which was confirmed by review histology in only 46 cases. Sensitivity of routine cytology for the detection of CIN2+ was 43.5%, with a specificity, positive predictive value (PPV), negative predictive value (NPV) of 98.0, 11.4 and 99.7%, respectively. Sensitivity of the HC2 test for the detection of CIN2+ was 97.8%, with a specificity, PPV and NPV, of 95.3, 10.9 and 100%, respectively. No high-grade neoplasia was detected in the randomly selected control group. A negative HPV-test result, even in combination with a positive Papanicolaou (Pap) result, virtually excluded any risk of underlying high-grade disease, but this was not the case for a negative Pap result. These data show that HPV testing is of value for the detection or exclusion of prevalent CIN in a routine cervical cancer-screening setting and could be used for further risk classification of women for follow-up management.
TL;DR: Clinical and pathological response assessments are poorly associated into breast cancer response to chemotherapy, and tumour response and marker expression did not predict disease-free or overall survival.
Abstract: The aim of this study was to provide a better insight into breast cancer response to chemotherapy. Chemotherapy improves outcome in breast cancer patients. The effect of cytotoxic treatment cannot be predicted for individual patients. Therefore, the identification of tumour characteristics associated with tumour response and outcome is of great clinical interest. We studied 97 patients, who received anthracycline-based neoadjuvant chemotherapy. Tumour samples were taken prior to and after chemotherapy. We quantified the response to chemotherapy clinically and pathologically and determined histological and molecular tumour characteristics. We assessed changes in the expression of Bcl-2, ER, P53 HER2 and Ki-67. Association with response and outcome was tested for all parameters. The experimental results showed 15 clinical (17%) and three (3%) pathological complete remissions. There were 18 (20%) clinical vs 29 (33%) pathological nonresponders. The expression of most markers was similar before and after chemotherapy. Only Ki-67 was significantly decreased after chemotherapy. Factors correlated with response were: large tumour size, ER negativity, high Ki-67 count and positive P53 status. Tumour response and marker expression did not predict disease-free or overall survival. In conclusion, clinical and pathological response assessments are poorly associated. Proliferation decreases significantly after chemotherapy. ER negativity and a high proliferation index are associated with better response. HER2 status does not predict response, and outcome is not related to tumour response.
TL;DR: The carbonic anhydrases, CAIX and CAXII, are expressed in a wide variety of malignancies and appear to be tightly regulated by microenvironmental hypoxia, which may inhibit tumour growth and invasion, with consequent therapeutic potential.
Abstract: The carbonic anhydrases (CAs) comprise a family of evolutionarily ancient enzymes found ubiquitously in nature. They have important roles in facilitating transport of carbon dioxide and protons in the intracellular space, across biological membranes and in the unstirred layers of the extracellular space. The tumour-associated isoenzymes, CAIX and CAXII, are expressed in a wide variety of malignancies and appear to be tightly regulated by microenvironmental hypoxia. CAIX expression is linked to poor prognosis in a number of human tumours, and may be a marker of aggressive malignant phenotype and a mechanism of progression. Inhibitors of CA may inhibit tumour growth and invasion, with consequent therapeutic potential.
TL;DR: This regimen is considered to be active against AGC with acceptable toxicity, and the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC).
Abstract: A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m(-2) b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m(-2) depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m(-2), because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m(-2). In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1-8). The incidences of severe (grades 3-4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9-90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.
TL;DR: It is suggested that, although betel quid chewing was a major cause for both OL and OSF, its effect might be difference between the two diseases, and cigarette smoking has a modifying effect in the development of oral leukoplakia.
Abstract: In areas where the practise of betel quid chewing is widespread and the chewers also often smoke and drink alcohol, the relation between oral precancerous lesion and condition to the three habits is probably complex To explore such association and their attributable effect on oral leukoplakia (OL) and oral submucous fibrosis (OSF), a gender–age-matched case–control study was conducted at Kaohsiung, southern Taiwan This study included 219 patients with newly diagnosed and histologically confirmed OL or OSF, and 876 randomly selected community controls All information was collected by a structured questionnaire through in-person interviews A preponderance of younger patients had OSF, while a predominance of older patients had OL Betel quid chewing was strongly associated with both these oral diseases, the attributable fraction of OL being 732% and of OSF 854% While the heterogeneity in risk for areca nut chewing across the two diseases was not apparent, betel quid chewing patients with OSF experienced a higher risk at each exposure level of chewing duration, quantity and cumulative measure than those who had OL Alcohol intake did not appear to be a risk factor However, cigarette smoking had a significant contribution to the risk of OL, and modified the effect of chewing based on an additive interaction model For the two oral premalignant diseases combined, 865% was attributable to chewing and smoking Our results suggested that, although betel quid chewing was a major cause for both OL and OSF, its effect might be difference between the two diseases Cigarette smoking has a modifying effect in the development of oral leukoplakia
TL;DR: It is concluded that, as a noninvasive therapy, HIFU could be effective, safe, and feasible in the extracorporeal treatment of localised breast cancer.
Abstract: A randomised clinical trial of high-intensity focused ultrasound ablation for the treatment of patients with localised breast cancer
TL;DR: It is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression, an important prognostic factor.
Abstract: When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P=0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P=0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.
TL;DR: Results show that survivin is frequently overexpressed in primary breast cancer, and nuclear expression is most common and is an independent prognostic indicator of good prognosis.
Abstract: Survivin is a member of the inhibitor of apoptosis (IAP) family, and is also involved in the regulation of cell division. Survivin is widely expressed in foetal tissues and in human cancers, but generally not in normal adult tissue. This study examined the expression of surviving protein in a series of 293 cases of invasive primary breast carcinoma. Survivin immunoreactivity was assessed using two different polyclonal antibodies, and evaluated semiquantitatively according to the percentage of cells demonstrating distinct nuclear and/or diffuse cytoplasmic staining. Overall, 60% of tumours were positive for survivin: 31% demonstrated nuclear staining only, 13% cytoplasmic only, and 16% of tumour cells demonstrated both nuclear and cytoplasmic staining. Statistical analysis revealed that survivin expression was independent of patient's age, tumour size, histological grade, nodal status, and oestrogen receptor status. In multivariate analysis, nuclear survivin expression was a significant independent prognostic indicator of favourable outcome both in relapse-free and overall survival (P<0.001 and P=0.01, respectively). In conclusion, our results show that survivin is frequently overexpressed in primary breast cancer. Nuclear expression is most common and is an independent prognostic indicator of good prognosis.