Improvements in Survival and Clinical Benefit With Gemcitabine as First-Line Therapy for Patients With Advanced Pancreas Cancer: A Randomized Trial.

PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

Mutation of chromatin modifiers; an emerging hallmark of germinal center B-cell lymphomas.

Subtypes of non-Hodgkin's lymphomas align with different stages of B-cell development. Germinal center B-cell (GCB)-like diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Burkitt's lymphoma (BL) each share molecular similarities with normal GCB cells. Recent next-generation sequencing studies have gained insight into the genetic etiology of these malignancies and revealed a high frequency of mutations within genes encoding proteins that modifying chromatin. These include activating and inactivating mutations of genes that perform post-translational modification of histones and organize chromatin structure. Here, we discuss the function of histone acetyltransferases (CREBBP, EP300), histone methyltransferases (KDM2C/D, EZH2) and regulators of higher order chromatin structure (HIST1H1C/D/E, ARID1A and SMARCA4) that have been reported to be mutated in ⩾5% of DLBCL, FL or BL. Mutations of these genes are an emerging hallmark of lymphomas with GCB-cell origins, and likely represent the next generation of therapeutic targets for these malignancies.

BSACI guideline for the diagnosis and management of cow's milk allergy.

This guideline advises on the management of patients with cow's milk allergy. Cow's milk allergy presents in the first year of life with estimated population prevalence between 2% and 3%. The clinical manifestations of cow's milk allergy are very variable in type and severity making it the most difficult food allergy to diagnose. A careful age- and disease-specific history with relevant allergy tests including detection of milk-specific IgE (by skin prick test or serum assay), diagnostic elimination diet, and oral challenge will aid in diagnosis in most cases. Treatment is advice on cow's milk avoidance and suitable substitute milks. Cow's milk allergy often resolves. Reintroduction can be achieved by the graded exposure, either at home or supervised in hospital depending on severity, using a milk ladder. Where cow's milk allergy persists, novel treatment options may include oral tolerance induction, although most authors do not currently recommend it for routine clinical practice. Cow's milk allergy must be distinguished from primary lactose intolerance. This guideline was prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) and is intended for clinicians in secondary and tertiary care. The recommendations are evidence based, but where evidence is lacking the panel of experts in the committee reached consensus. Grades of recommendation are shown throughout. The document encompasses epidemiology, natural history, clinical presentations, diagnosis, and treatment.

From the stressed adolescent to the anxious and depressed adult: investigations in rodent models.

Anxiety and depression are the most prevalent of the psychiatric disorders. The average age of onset of these disorders is in adolescence, and stressful experiences are recognized as an important pathway to such dysfunction. Until recently, however, most animal models of these disorders involved adult males. We provide a brief overview of anxiety and depression and the extent to which adolescent rodents are a valid model for their investigation, and briefly review the main measures of anxiety-like and depressive behaviour in rodents. The focus of the review is investigations in which adolescent rodents were exposed to chronic stressors, describing our research using social instability stress and that of other researchers using various social and non-social stressors. The evidence to date suggests stress in adolescence alters the trajectory of brain development, and particularly that of the hippocampus, increasing anxiety and depressive behaviour in adulthood.

A novel immunodeficiency disorder characterized by genetic amplification of interleukin 25.

Many primary immunodeficiency disorders of differing etiologies have been well characterized, and much understanding of immunological processes has been gained by investigating the mechanisms of disease. Here, we have used a whole-genome approach, employing single-nucleotide polymorphism and gene expression microarrays, to provide insight into the molecular etiology of a novel immunodeficiency disorder. Using DNA copy number profiling, we define a hyperploid region on 14q11.2 in the immunodeficiency case associated with the interleukin (IL)-25 locus. This alteration was associated with significantly heightened expression of IL25 following T-cell activation. An associated dominant type 2 helper T cell bias in the immunodeficiency case provides a mechanistic explanation for recurrence of infections by pathogens met by Th1-driven responses. Furthermore, this highlights the capacity of IL25 to alter normal human immune responses.

BRAF V600E mutation and the tumour suppressor IGFBP7 in atypical genital naevi.

BACKGROUND: Atypical genital naevi (AGN) are naevi of special sites with atypical histological features that overlap with those of malignant melanoma. Activating BRAF mutations, identified in the majority of banal melanocytic naevi and cutaneous melanomas, are reportedly uncommon in naevomelanocytic proliferations in nonsun-exposed sites. We have recently shown that constitutive activation of the BRAF-MEK-ERK signalling pathway in oncogenic BRAF-positive naevi increases expression and secretion of IGFBP7, which induces senescence and apoptosis. OBJECTIVES: To ascertain the frequency of BRAF V600E mutations in AGN compared with banal naevi without atypia. An additional aim was to assess the expression of IGFBP7 in oncogenic BRAF-positive AGN. METHODS: Genomic DNA was isolated per protocol from seven genital naevi without atypia and 13 AGN for BRAF genotyping. Immunohistochemical staining for IGFBP7 was performed on all cases. RESULTS: The BRAF V600E mutation was identified in 43% of genital naevi without atypia and 23% of AGN (P = 0.61). In both groups, IGFBP7 expression was maintained in 67% of BRAF V600E-positive cases. CONCLUSIONS: The prevalence of BRAF V600E in AGN suggests that ultraviolet exposure is not essential for generating the mutation. The BRAF V600E mutational status appears to be of limited diagnostic utility in distinguishing genital naevi that exhibit atypia from those that do not. Similar to oncogenic BRAF-positive common naevi without atypia, enhanced expression of the tumour suppressor IGFBP7 in oncogenic BRAF-positive AGN supports that they are biologically inert.

Serendipitous evidence of T lymphocyte activation in close female relatives of patients with systemic lupus erythematosus.

A well-recognized characteristic of the autoimmune disease, systemic lupus erythematosus (SLE), is the high level of activated T cells present in the blood. Because of the increased size and granularity of activated T cells, in flow cytometry one might expect to find increased numbers of cells falling outside a standard light-scatter lymphocyte gate, and indeed we now report that the percentage of T lymphocytes in the gate (% TiG) was below the normal range in 23 of 58 (40%) female patients because of increased scatter values. However, the surprising additional observation was made that 18 of 30 (60%) female first-degree relatives of the patients also fell below the normal % TiG range, suggesting the presence of T cell activation in these relatives. This view is strengthened by the strong inverse correlation between plasma total immunoglobulin G(IgG), which was raised in some relatives, and % TiG, as T cell activation is a requirement for IgG production. Conversely, there was no correlation with IgM, which has no comparable link with T cell activation. While a definitive interpretation must await the demonstration of activation antigen expression in relatives, these findings suggest the existence of a T cell activation trait, not harmful in itself, which, however, contributes to the development of disease in patients with SLE.

Polyethylene glycol 3350 plus electrolytes for chronic constipation in children: a double blind, placebo controlled, crossover study.

OBJECTIVES: To assess the efficacy and safety of polyethylene glycol 3350 plus electrolytes (PEG+E) for the treatment of chronic constipation in children. DESIGN: Randomised, double blind, placebo controlled crossover trial, with two 2-week treatment periods separated by a 2-week placebo washout. SETTING: Six UK paediatric departments. PARTICIPANTS: 51 children (29 girls, 22 boys) aged 24 months to 11 years with chronic constipation (lasting > or =3 months), defined as < or =2 complete bowel movements per week and one of the following: pain on defaecation on 25% of days; > or =25% of bowel movements with straining; > or =25% of bowel movements with hard/lumpy stools. 47 children completed the double blind treatment. MAIN OUTCOME MEASURES: Number of complete defaecations per week (primary efficacy variable), total number of complete and incomplete defaecations per week, pain on defaecation, straining on defaecation, faecal incontinence, stool consistency, global assessment of treatment, adverse events and physical examination. RESULTS: The mean number of complete defaecations per week was significantly higher for children on PEG+E than on placebo (3.12 (SD 2.05) v 1.45 (SD 1.20), respectively; p<0.001). Further significant differences in favour of PEG+E were observed for total number of defaecations per week (p = 0.003), pain on defaecation (p = 0.041), straining on defaecation (p<0.001), stool consistency (p<0.001) and percentage of hard stools (p = 0.001). Treatment related adverse events (all mild or moderate) occurred in similar numbers of children on PEG+E (41%) and placebo during treatment (45%). CONCLUSIONS: PEG+E is significantly more effective than placebo, and appears to be safe and well tolerated in the treatment of chronic constipation in children.

Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and Leukemia Group B Study 39902.

BACKGROUND: This phase II study evaluated the efficacy and safety of the irinotecan/gemcitabine combination in patients with relapsed/refractory small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with measurable tumor who had received one previous chemotherapy or chemotherapy/radiation regimen were eligible. Gemcitabine 1000 mg/m(2) was administered i.v. over 30 min followed immediately by irinotecan 100 mg/m(2) i.v. over 90 min, both on days 1 and 8 every 21 days. Patients were stratified based on response to initial treatment [i.e. primary sensitive disease with progression >or=3 months (group A), or refractory disease (group B)]. RESULTS: Seventy-three patients were enrolled but one never received treatment and one ineligible patient did not have SCLC. Median patient ages of the remaining patients were 61 and 63 years in groups A (n = 35) and B (n = 36), respectively, with performance status of 0 or 1 in 85% of 71 patients. Primary grade 3/4 toxic effects in groups A versus B were neutropenia (36% versus 43%), thrombocytopenia (36% versus 26%), nausea (12% versus 11%), vomiting (0 versus 11%), diarrhea (12% versus 9%), and pulmonary (12% versus 12%). Two patients had fatal events including pneumonitis (n = 1) and acute respiratory distress syndrome (n = 1). Responses occurred in 11 group A [two complete responses and nine partial responses (PRs)] and four group B (all PRs) patients, for response rates of 31% [95% confidence interval (CI) 17%, 49%) and 11% (95% CI 3%, 26%), respectively. Median survival and progression-free survival times were 7.1 (95% CI 6, 10.5) versus 3.5 (95% CI 3.1, 5.7) months, and 3.1 (95% CI 1.6, 5.3) versus 1.6 (95% CI 1.4, 2.8) months for group A versus B. CONCLUSION: The irinotecan/gemcitabine combination is active and well tolerated as second-line therapy in SCLC patients. Additional studies are warranted as second-line therapy in patients who progressed 90 days or more after first-line therapy. However, the observed efficacy results in refractory SCLC patients indicate that this regimen should not be further explored in this population.

Defective maturation of dendritic cells in common variable immunodeficiency.

Monocyte-derived dendritic cells (MdDCs) from many patients with common variable immunodeficiency (CVID) have been shown recently to have reduced expression of surface molecules associated with maturity. Using flow cytometry and confocal microscopy, we now show that this is due to a partial failure to fix Class II DR molecules on the surface during procedures that induce full maturation in vitro in cells from normal subjects. Major histocompatibility complex (MHC) class I, CD86 and CD83 expression were expressed normally, but CD40 was reduced. These abnormalities are unlikely to be due to prior in vivo exposure of monocytes to lipopolysaccharide (LPS), as addition of LPS to monocytes from normal subjects in vitro caused a different pattern of changes. CVID MdDCs retained Class II DR in the cytoplasm during maturation, showed increased internalization of cross-linked Class II DR surface molecules and were unable to polarize DR within a lipid raft at contact sites with autologous lymphocytes. These cells retained some features of monocytes, such as the ability to phagocytose large numbers of fixed yeast and fluorescent carboxylated microspheres and expression of surface CD14. These abnormalities, if reflected in vivo, could compromise antigen presentation and may be a fundamental defect in the mechanism of the antibody deficiency in a substantial subset of CVID patients.

Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer.

BACKGROUND: Abraxane (ABI-007) is a novel 130-nm, albumin-bound (nab) particle form of paclitaxel designed to utilize endogenous albumin pathways to increase intratumor concentrations of the active drug. This multicenter phase II study was designed to evaluate the efficacy and safety of Abraxane 260 mg/m2 every 3 weeks in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with histologically confirmed, measurable NSCLC received Abraxane as first-line therapy. RESULTS: Forty-three patients were enrolled. The overall response rate was 16%; the disease control rate was 49%. Median time to progression was 6 months, and median survival was 11 months. The probability of not having progressed by 1 year was 13%; the probability of surviving 1 year was 45%. No severe hypersensitivity reactions were reported despite the lack of premedication; 95% of patients were treated without dose reduction. Two patients (5%) discontinued therapy because of treatment-related toxicities (neuropathy, fatigue [1 each]). No grade 4 treatment-related toxicity occurred. CONCLUSIONS: Abraxane 260 mg/m2 administered IV over 30 min without premedication was well tolerated. Significant tumor responses and prolonged disease control were documented in this group of patients with NSCLC. Exploration of higher doses of ABI-007 alone and in combination with other drugs active in NSCLC is warranted.

Natural killer cell activity in families of patients with systemic lupus erythematosus: demonstration of a killing defect in patients.

Natural killer (NK) cell cytotoxic activity and cell frequency, expressed as a percentage of total lymphocytes, have been determined in peripheral blood mononuclear cells from first-degree relatives of patients with systemic lupus erythematosus (SLE), the patients themselves, a group of rheumatoid arthritis (RA) patients and controls. Low levels of killing activity relative to controls were found in some members of all groups with the extent of depression falling into two ranges. Moderate reductions were seen in female (3/31, 10%) and male (4/14, 29%) relatives of SLE patients, female (12/60, 20%) and male (3/4, 75%) SLE patients and female RA patients (6/17, 35%). A more profound depression of killing activity was confined to other female SLE patients (15/60, 25%). There were strong correlations in all groups between killing activity and percentage of NK cells, but analysis of the ratio of these parameters and studies with purified preparations of NK cells suggest that the reduced activity in SLE frequently involves a defect in the killing capacity of the individual cells in addition to the reduced levels of NK cells. Azathioprine (AZA), which was used in treatment of 12 SLE patients, was invariably associated with low values of killing activity. It appears to substantially reduce the percentage of NK and B cells in an action unconnected with the NK cell abnormalities associated with SLE. The finding of low killing activity in relatives and a correlation between their activity and that of their patients support the view that NK cell deficiency is a genetic determinant of SLE. NK cells in SLE may produce insufficient levels of cytokines required for the regulation of IgG production.

Monocyte derived dendritic cell responses in common variable immunodeficiency.

The phenotype and function of monocyte derived dendritic cells (MdDC) were investigated in 25 patients with common variable immunodeficiency (CVID) to test for abnormalities that might help explain the failure of antibody production. Using MHC class II DR and CD86 as markers of maturation, DCs from the majority of CVID patients were normal. However 5 patients, the majority of whom had affected family members who had previously been shown to have a susceptibility genetic locus in the MHC region, expressed abnormally low levels of DR on repeated testing, in some cases associated with a reduced capacity to support antigen stimulated T cell proliferation; nevertheless costimulatory molecules for production of IL-13, IL-10 and IFN-gamma from T cells were intact. In contrast to DCs from healthy donors, DCs from many CVID patients had high spontaneous production of IL-8 and lipopolysaccharide stimulation often caused a reduction in DR expression. Expression of other cytokines (IL-1a, IL-6 and IL-12), either before or after LPS stimulation, was normal. The data suggests there is a fundamental defect in the maturation of MdDCs in a subset of CVID patients that may compromise antigen presentation and subsequent antibody production.

Combined modality trials of the Cancer and Leukemia Group B in stage III non-small-cell lung cancer: analysis of factors influencing survival and toxicity.

BACKGROUND: Combined modality therapy (CMT) is the standard of care for patients with unresectable stage III non-small-cell lung cancer (NSCLC); however, insufficient data are available regarding prognostic factors in this disease setting. PATIENTS AND METHODS: Six hundred and ninety-four patients included in five trials conducted by the Cancer and Leukemia Group B evaluating CMT in stage III NSCLC were included in this analysis. The primary objective was to identify factors that were predictors of survival and selected radiation-related toxicities using Cox regression models and logistic regression analysis. RESULTS: The Cox model shows that performance status (PS) 1 [hazard ratio (HR) 1.24; 95% confidence interval (CI) 1.06-1.45; P=0.009] and thoracic radiation therapy (TRT) only (HR 1.58; 95% CI 1.22-2.05; P=0.001) predicted for poorer survival, while baseline hemoglobin >/=12 g/dl predicted for improved survival (HR 0.67; 95% CI 0.55-0.81; P 5% weight loss (OR 2.9; 95% CI 1.3-6.6; P=0.008) and patients receiving concurrent chemoradiation (OR 7.3; 95% CI 3.4-15.6; P=0.0001). CONCLUSIONS: Baseline hemoglobin and PS, as well as the use of CMT, have the greatest effect on survival in unresectable stage III NSCLC. The use of concurrent chemoradiation increases the risk of esophagitis, which remains the primary radiation-related toxicity.

Randomized phase II trial of gemcitabine plus irinotecan or docetaxel in stage IIIB or stage IV NSCLC.

BACKGROUND: To evaluate the activity and tolerability of gemcitabine plus irinotecan or docetaxel as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients with chemotherapy-naïve stage IIIB or IV NSCLC were randomized to receive gemcitabine 1000 mg/m2 on days 1 and 8, plus either irinotecan 100 mg/m2 or docetaxel 40 mg/m2 on days 1 and 8. Treatment was administered every 3 weeks. RESULTS: Of the 80 enrolled patients with stage IIIB or IV NSCLC, 78 were evaluable for activity and safety. Overall response rates, consisting of partial responses, were 12.8% [95% confidence interval (CI) 4% to 35%] for gemcitabine-irinotecan and 23.1% (95% CI 10% to 42%) for gemcitabine-docetaxel. Median overall survival was 7.95 months (95% CI 5.2-10.2) and 12.8 months (95% CI 7.9-17.1) for gemcitabine-irinotecan and gemcitabine-docetaxel, respectively. The corresponding estimated 1-year survivals were 23% and 51%, respectively. The 2-year survival rate in arm A (gemcitabine-irinotecan) is not currently estimable. The 2-year survival rate for arm B (gemcitabine-docetaxel) is 22% (95% CI 6% to 37%). Both combinations were well tolerated; the most common hematological toxicity was neutropenia, which occurred in 26% of patients in each treatment arm. CONCLUSIONS: These results suggest that gemcitabine plus docetaxel or irinotecan is well tolerated in patients with chemotherapy-naïve advanced NSCLC. The survival data with the combination gemcitabine-docetaxel are promising. Gemcitabine-docetaxel combination therapy may be particularly useful for patients who have experienced toxicities with a platinum regimen or in patients who may be more susceptible to platinum-related toxicity.

The role of ATF/CREB family members in cell growth, survival and apoptosis.

Programmed cell death is an integral part of the mechanisms regulating tissue homeostasis. Defects in the apoptotic signaling pathway are often associated with uncontrolled cell proliferation, high mutation rate and malignant transformation. Transcription factors, such as the mammalian ATF/CREB family of transcriptional regulators, have diverse functions in controlling cell proliferation and apoptosis. One particular ATF/CREB family member, ATFx, is an anti-apoptotic factor that plays an essential role in cell survival. Current observations indicate that one mechanism by which ATFx inhibits cell death and promotes cell survival is by disrupting signal transmission from activated "death receptors" to initiator caspases. A better understanding of ATFx function should provide new insight into the processes that control apoptotic cascades.