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David Cameron

Publications and source records attributed to David Cameron.

At least 19 recordsLinked to original sources
PubMed2026

Manual, digital, and AI tumour-infiltrating lymphocyte scoring: a secondary analysis of the APHINITY randomised trial.

BACKGROUND: Stromal tumour-infiltrating lymphocytes (sTILs) are prognostic in early-stage HER2-positive breast cancer, but their role in the context of dual HER2 blockade remains undefined. We evaluated manual, digital, and artificial intelligence (AI)-based sTIL quantification, together with AI-derived spatial metrics, for prognostic and treatment-benefit stratification using tumour samples from the phase 3 APHINITY trial. METHODS: In the APHINITY trial, 4805 patients were randomly assigned to receive chemotherapy plus trastuzumab with pertuzumab or chemotherapy plus trastuzumab with placebo. Median follow-up was 74&#xb7;1 months (IQR 68&#xb7;3-75&#xb7;4). We analysed 4262 haematoxylin and eosin-stained images using manual assessment, an automated digital approach, AI-based lymphocyte quantification (AI percentage lymphocytes), and two AI-derived spatial features (AI-TIL and immune hotspot). Interobserver reproducibility was assessed in 262 randomly chosen tumour samples scored independently by five pathologists. Multivariable Cox models were used to assess associations between TIL levels and invasive disease-free survival (primary outcome in APHINITY), distant recurrence-free interval, and overall survival. The heterogeneity of pertuzumab benefit was evaluated using subgroup analyses, subpopulation treatment effect pattern plot analyses, and nested Cox models with treatment-by-biomarker interaction terms. FINDINGS: Manual scoring showed high interobserver reproducibility (intraclass correlation coefficient 0&#xb7;84 [95% CI 0&#xb7;79-0&#xb7;88]). Concordance between manual and automated methods was modest. AI-based scoring (AI percentage lymphocytes) reclassified 120 (11&#xb7;6%) of 1035 node-positive tumours from immune-low (by manual scoring) to immune-high; this subgroup of patients showed greater separation of 5-year invasive disease-free survival curves between pertuzumab and placebo groups compared with patients whose tumours were concordantly classified as immune-low by both manual and AI-based approaches. Higher levels of TILs were associated with improved invasive disease-free survival for all sTIL measurement approaches and spatial measurements (hazard ratios [HRs] 0&#xb7;41-0&#xb7;93). Pertuzumab was associated with improved invasive disease-free survival at higher sTIL levels across all measurement approaches (HRs 0&#xb7;36-0&#xb7;48), but was not associated with higher values of spatial measures. The largest 6-year absolute improvements with pertuzumab were observed in patients with node-positive disease whose tumours scored in the highest level of immune infiltration of manual sTIL scoring (&#x2265;70&#xb7;0%; mean absolute improvement 12&#xb7;1 percentage points [SD 2&#xb7;8]). In nested prognostic and predictive models, AI-based immune hotspot scores provided the most consistent additional information when combined with any sTIL measurement (all p<0&#xb7;010). INTERPRETATION: Standardised manual sTIL scoring was reproducible, and digital and AI-based methods showed consistent prognostic stratification and potential for treatment-benefit stratification despite only modest correlation between platforms. AI spatial metrics provided complementary information beyond sTIL density and could support more scalable immune assessment. Future studies are needed to validate these approaches in independent cohorts and to clarify their clinical utility for stratifying contemporary HER2-directed therapies. FUNDING: None.

Humans↗
PubMed2007

2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.

BACKGROUND: Trastuzumab--a humanised monoclonal antibody against HER2--has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drug's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study. METHODS: HERA is an international multicentre randomised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer. 5102 women participated in the trial; we analysed data from 1703 women who had been randomised for treatment with trastuzumab for 1 year and 1698 women from the control group, with median follow-up of 23.5 months (range 0-48 months). The primary endpoint of the trial was disease-free survival. Here, we assess overall survival, a secondary endpoint. Analyses were done on an intent-to-treat basis. This trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS: 97 (5.7%) patients randomised to observation alone and 58 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up. 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47-0.91; p=0.0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54-0.76; p<0.0001). INTERPRETATION: Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years. The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer.

Adult↗
PubMed2006

Lapatinib plus capecitabine for HER2-positive advanced breast cancer.

BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. RESULTS: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. CONCLUSIONS: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).

Adult↗
PubMed2006

Cognitive Ethology and exploring attention in real-world scenes.

We sought to understand what types of information people use when they infer the attentional states of others. In our study, two groups of participants viewed pictures of social interactions. One group was asked to report where the people in the pictures were directing their attention and how they (the group) knew it. The other group was simply asked to describe the pictures. We recorded participants' eye movements as they completed the different tasks and documented their subjective inferences and descriptions. The findings suggest that important cues for inferring attention of others include direction of eye gaze, head position, body orientation, and situational context. The study illustrates how attention research can benefit from (a) using more complex real-world tasks and stimuli, (b) measuring participants' subjective reports about their experiences and beliefs, and (c) observing and describing situational behavior rather than seeking to uncover some putative basic mechanism(s) of attention. Finally, we discuss how our research points to a new approach for studying human attention. This new approach, which we call Cognitive Ethology, focuses on understanding how attention operates in everyday situations and what people know and believe about attention.

Adult↗
PubMed2006

Stability of the gross motor function classification system.

The aim of this study was to assess the stability of the Gross Motor Function Classification System (GMFCS) by examining whether children with cerebral palsy (CP) remain in the same level over time. Participants were 610 children with CP (342 males, 268 females; mean age 6y 9mo [SD 2y 10mo]), range 16mo-13y). Children were assessed 2 to 7 times (mean 4.3) at 6-month (children <6y old) or 12-month(children >or=6y old) intervals. Seventy-three per cent of children remained in the same level for all ratings. The weighted kappa coefficient between the first and last ratings was 0.84 for children less than 6 years old and 0.89 for children at least 6 years old, indicating excellent chance-corrected agreement. Children initially classified in Levels I and V were least likely to be reclassified. There was a tendency for children younger than 6 years who were reclassified to be done so to a lower level of ability. The results provide evidence of stability of the GMFCS.

Child↗
PubMed2006

Thymic function in severely immunodeficient HIV type 1-infected patients receiving stable and effective antiretroviral therapy.

The role of the thymus in long-term immune reconstitution has not been addressed in HIV patients who were severely immunodeficient prior to successful treatment with combination antiretroviral therapy (ART). Adult HIV-1 patients (n = 78) with nadir CD4+ T cell counts <100 T cells/microl, at least 12 months on ART and 6 months of complete viral suppression (<50 HIV RNA copies/ml) were selected from a patient database. The cohort was divided according to current CD4+ T cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. Thymic volume was assessed by spiral computed tomography. Naive (CD45RA+CD62L+) and replicating (Ki67+) T cells were quantitated by flow cytometry, T cell receptor excision circles (TREC) were assessed by real-time PCR, and serum IL-7 and testosterone by immunoassay. Patients with low CD4+ T cell counts had smaller thymuses [0(0-5.3) vs. 3.5(0-15.6) cm(3), p = 0.04] and were more likely to have no detectable thymus. They had similar proportions of replicating cells, but fewer naive CD4+ and CD8+ T cells and less TREC in CD4+ and CD8+ T cells/ml of blood than patients with high CD4+ T cell counts. However, some patients with no detectable thymus had high numbers of naive and TREC-bearing T cells. Thus, the recovery of CD4+ T cells in severely immunodeficient HIV patients with a virological response to ART is probably limited by thymic function. However, the data are consistent with extrathymic T cell production contributing to the naive T cell pool in some patients.

Adult↗
PubMed2006

Sternotomy reconstruction with omentum followed by large diaphragmatic hernia.

Poststernotomy mediastinitis carries significant morbidity and mortality. Aggressive wound debridement combined with a pedicled omental flap, with or without a pedicled muscle flap, has gained acceptance in the management of difficult sternal wound infections. Two cases of poststernotomy mediastinitis and sternal wound reconstruction with a pedicled omental flap were complicated by a large anterior diaphragmatic hernia containing the large bowel.

Aged↗
PubMed2006

Ibandronate: its role in metastatic breast cancer.

Bisphosphonates are the most effective agents for treating and/or preventing complications of bone metastases and are the standard of care in this setting. Currently, four bisphosphonates are available for metastatic bone disease (MBD): clodronate, pamidronate, zoledronic acid, and ibandronate. Although all four of these bisphosphonates have been shown to reduce the incidence of skeletal-related events in patients with bone metastases, there are substantial differences among these agents in their potency, dose and route of administration, and side effects. Ibandronate and zoledronic acid, the two newer aminobisphosphonates, appear to have similar biochemical efficacies when phase III trial data are compared. Both agents were equally effective in reducing markers of bone resorption in the only prospective comparative trial carried out to date, but no data on relative clinical efficacy are available from head-to-head comparisons. Both the oral and i.v. formulations of ibandronate have also shown long-term efficacy in managing metastatic bone pain (MBP), but the onset of action of standard bisphosphonate treatment is not sufficient when rapid relief of pain is required. Because of its favorable renal safety profile, i.v. ibandronate can be administered daily for 3 days, as a so-called "loading dose." This dosing regimen has allowed rapid and effective relief of MBP without the unwanted side effects associated with opioids and other analgesics. Ibandronate is thus an effective, flexible, and well-tolerated bisphosphonate that can meet the varying requirements of patients with MBD.

Bone Density Conservation Agents↗
PubMed2005

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.

BACKGROUND: Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. METHODS: This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. RESULTS: Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. CONCLUSIONS: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)

Adult↗
PubMed2005

Identification of molecular apocrine breast tumours by microarray analysis.

Previous microarray studies on breast cancer identified multiple tumour classes, of which the most prominent, named luminal and basal, differ in expression of the oestrogen receptor alpha gene (ER). We report here the identification of a group of breast tumours with increased androgen signalling and a 'molecular apocrine' gene expression profile. Tumour samples from 49 patients with large operable or locally advanced breast cancers were tested on Affymetrix U133A gene expression microarrays. Principal components analysis and hierarchical clustering split the tumours into three groups: basal, luminal and a group we call molecular apocrine. All of the molecular apocrine tumours have strong apocrine features on histological examination (P=0.0002). The molecular apocrine group is androgen receptor (AR) positive and contains all of the ER-negative tumours outside the basal group. Kolmogorov-Smirnov testing indicates that oestrogen signalling is most active in the luminal group, and androgen signalling is most active in the molecular apocrine group. ERBB2 amplification is commoner in the molecular apocrine than the other groups. Genes that best split the three groups were identified by Wilcoxon test. Correlation of the average expression profile of these genes in our data with the expression profile of individual tumours in four published breast cancer studies suggest that molecular apocrine tumours represent 8-14% of tumours in these studies. Our data show that it is possible with microarray data to divide mammary tumour cells into three groups based on steroid receptor activity: luminal (ER+ AR+), basal (ER- AR-) and molecular apocrine (ER- AR+).

Apocrine Glands↗
PubMed2004

Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial.

BACKGROUND: Breast cancer patients with four or more positive axillary lymph nodes who are treated with conventional adjuvant therapy have a poor prognosis. In uncontrolled studies, high-dose chemotherapy produced much better results than conventional therapy. We compared the benefits of a single cycle of high-dose chemotherapy and the benefits of conventional chemotherapy in patients with high-risk breast cancer in a prospective, unblinded, randomized trial. METHODS: Between February 23, 1995, and June 29, 1999, 605 patients with breast cancer who had four or more positive lymph nodes were randomly assigned to treatment (307 to high-dose therapy and 298 to conventional therapy). The conventional chemotherapy regimen was four cycles of doxorubicin (75 mg/m2) followed by eight cycles of CMF (cyclophosphamide [600 mg/m2], methotrexate [50 mg/m2], and 5-fluorouracil [600 mg/m2]), all given intravenously on day 1 of a 21-day cycle. The high-dose regimen was four cycles of doxorubicin (75 mg/m2), followed by a single cycle of intermediate-dose cyclophosphamide (4000 mg/m2) supported by filgrastim (300 microg/day) for up to 10 days followed by high-dose cyclophosphamide (6000 mg/m2) and thiotepa (800 mg/m2). Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle. Log-rank tests were used to compare survival rates. All statistical analyses were two-sided. RESULTS: At a median follow-up of 6 years, no statistically significant differences were detected between the arms in 5-year relapse-free survival (high-dose arm = 57%, 95% confidence interval [CI] = 51% to 63%; conventional-dose arm = 54%, 95% CI = 48% to 61% (P =.73) or in 5-year overall survival (high-dose arm = 62%, 95% CI = 56% to 68%; conventional-dose arm = 64%, 95% CI = 57% to 70%) (P =.38). CONCLUSION: Autograft-supported, high-dose therapy is not superior to conventional chemotherapy in patients with breast cancer who have multiple involved lymph nodes. This conclusion should be viewed in the context of improving the success of conventional chemotherapy.

Adult↗
PubMed2004

Tamoxifen treatment failure in cancer and the nonlinear dynamics of TGFbeta.

The process of cancer invasion involves a complex interplay between cell-cell and cell-medium adhesion, proteolytic enzyme secretion, cell birth and death processes, random and directed motility, and immune response, as well as many other factors. The growth factor TGF beta is known to have a complex effect on this process. It inhibits mitosis and promotes apoptosis in a concentration-dependent manner in vitro, and it is for this reason that its secretion is thought to be helpful in inhibiting tumour growth. However, recent in vitro and in vivo results have shown a significant effect of this growth factor in promoting the sensitivity of malignantly transformed cells to gradients of extracellular matrix proteins--an effect which tends to increase invasiveness. The drug tamoxifen has been demonstrated to be therapeutically effective in the treatment of patients with breast cancer; however, it is known also that many patients become resistant to the effect of this drug after a few years, and the reasons for this remain controversial. In this work we take our established model of cancer invasion (J. Theor. Biol. 216(1) (2002) 85), and extend it to include the effect of TGF beta. In so doing we demonstrate that a tamoxifen-stimulated upregulation of the secretion of TGF beta may give rise to a tumour which has a smaller number of cells but which has a greater invasiveness, greater metastatic potential, and a tumour histology which is known to correlate with a poorer prognosis. These data suggest that tamoxifen-stimulated secretion of TGF beta might explain treatment failure in some patients.

Anticarcinogenic Agents↗