An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

Analysis of a National Programme for Selective Internal Radiation Therapy for Colorectal Cancer Liver Metastases.

AIMS: Patients with chemotherapy-refractory colorectal cancer liver metastases have limited therapeutic options. Selective internal radiation therapy (SIRT) delivers yttrium 90 microspheres as a minimally invasive procedure. This prospective, single-arm, observational, service-evaluation study was part of National Health Service England Commissioning through Evaluation. METHODS: Patients eligible for treatment had histologically confirmed carcinoma with liver-only/liver-dominant metastases with clinical progression during or following oxaliplatin-based and irinotecan-based chemotherapy. All patients received SIRT plus standard of care. The primary outcome was overall survival; secondary outcomes included safety, progression-free survival (PFS) and liver-specific PFS (LPFS). RESULTS: Between December 2013 and March 2017, 399 patients were treated in 10 centres with a median follow-up of 14.3 months (95% confidence interval 9.2-19.4). The median overall survival was 7.6 months (95% confidence interval 6.9-8.3). The median PFS and LPFS were 3.0 months (95% confidence interval 2.8-3.1) and 3.7 months (95% confidence interval 3.2-4.3), respectively. During the follow-up period, 143 patients experienced an adverse event and 8% of the events were grade 3. CONCLUSION: Survival estimates from this pragmatic study show clinical outcomes attainable in the National Health Service comparable with previously published data. This study shows the value of a registry-based commissioning model to aid national commissioning decisions for highly specialist cancer treatments.

A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO).

BACKGROUND: Elderly patients are commonly under-represented in cancer clinical trials. The 321GO was undertaken in preparation for a definitive phase three trial assessing different chemotherapy regimens in a frail and/or elderly population with advanced gastroesophageal (GO) cancer. METHODS: Patients with advanced GO cancer considered unfit for conventional dose chemotherapy were randomly assigned in a 1 : 1 : 1 ratio to: epirubicin, oxaliplatin and capecitabine (EOX); oxaliplatin and capecitabine (OX); and capecitabine alone (X) (all 80% of full dose and unblinded). The primary end point was patient recruitment over an 18-month period. A registration study recorded treatment choice for all patients with advanced GO cancer at trial centres. RESULTS: A total of 313 patients were considered for palliative chemotherapy for GO cancer over the 18-month period: 115 received full dose treatment, 89 less than standard treatment or entered 321GO and 111 no treatment. Within 321GO, 55 patients were randomly assigned (19 to OX and X; 17 to EOX). Progression-free survival (PFS) for all patients was 4.4 months and by arm 5.4, 5.6 and 3.0 months for EOX, OX and X, respectively. The number of patients with a good overall treatment utility (OTU), a novel patient-centred endpoint, at 12 weeks was 3 (18%), 6 (32%) and 1 (6%) for EOX, OX and X, respectively. At 6 weeks, 22 patients (41%) had experienced a non-haematologic toxicity ⩾grade 3, most commonly lethargy or diarrhoea. The OTU was prognostic for overall survival in patients alive at week 12 (logrank test P=0.0001). CONCLUSIONS: It is feasible to recruit elderly and/or frail patients with advanced GO cancer to a randomised clinical trial. The OX is the preferred regimen for further study. Overall treatment utility shows promise as a comparator between treatment regimens for feasibility and randomised trials in the elderly and/or frail GO cancer population.

Sorafenib for the Treatment of Advanced Hepatocellular Cancer - a UK Audit.

AIMS: Sorafenib is the current standard treatment for advanced hepatocellular carcinoma. We carried out a national audit of UK patients treated with sorafenib as standard-of-care and those treated with systemic therapy in first-line trials. MATERIALS AND METHODS: Sorafenib-treated and trial-treated patients were identified via the Cancer Drugs Fund and local databases. Data were collected retrospectively from medical records according to a standard case report form. The primary outcome measure was overall survival, estimated by the Kaplan-Meier method. RESULTS: Data were obtained for 448 sorafenib-treated patients from 15 hospitals. The median age was 68 years (range 17-89) and 75% had performance status ≤ 1. At baseline, 77% were Child-Pugh A and 16.1% Child-Pugh B; 38% were albumin-bilirubin grade 1 (ALBI-1) and 48% ALBI-2; 23% were Barcelona Clinic Liver Classification B (BCLC-B) and 72% BCLC-C. The median time on sorafenib was 3.6 months, with a mean daily dose of 590 mg. The median overall survival for 448 evaluable sorafenib-treated patients was 8.5 months. There were significant differences in overall survival comparing Child-Pugh A versus Child-Pugh B (9.5 versus 4.6 months), ALBI-1 versus ALBI-2 (12.9 versus 5.9 months) and BCLC-B versus BCLC-C (13.0 versus 8.3 months). For trial-treated patients (n=109), the median overall survival was 8.1 months and this was not significantly different from the sorafenib-treated patients. CONCLUSION: For Child-Pugh A patients with good performance status, survival outcomes were similar to those reported in global randomised controlled trials. Patients with ALBI grade > 1, Child-Pugh B or poor performance status seem to derive limited benefit from sorafenib treatment.

Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study.

BACKGROUND: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC. PATIENTS AND METHODS: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis. RESULTS: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%). CONCLUSION: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity. CLINICAL TRIAL NUMBER: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Musculoskeletal aspects of hypoadrenalism: just a load of aches and pains?

Musculoskeletal signs and symptoms of hypoadrenalism are less well described in the literature compared to other endocrine disorders such as diabetes mellitus and thyroid disease. This may in part be due to the difficulties associated with making a definitive diagnosis of hypoadrenalism where the general symptoms and signs can be very subtle. Hence, suspecting hypoadrenalism in a patient with mainly musculoskeletal features can be difficult and delayed. To illustrate this point, we present three cases of hypoadrenalism with varying degrees of rheumatological symptoms and signs. This article reviews all the cases of hypoadrenalism in the English, French and Spanish language medical literature, going back to the time of Thomas Addison. All the important clinical and laboratory features have been summarised to help clinicians diagnose and treat this disease.

A phase II clinical trial of gemcitabine and split dose cisplatin in advanced non-small cell lung cancer in an outpatient setting.

In response to increasing pressure on inpatient services and a meta-analysis indicating that cisplatin (C) is superior to carboplatin, we report a phase II trial of gemcitabine (G) and split-dose C in advanced non-small cell lung cancer (NSCLC) in an outpatient setting. Patients with stage IIIB/IV NSCLC received: G/C 1250/40 mg/m(2); G and C were given on day (d) 1 and d8 in a 21d cycle. Patients with performance status 0-2, adequate bone marrow function and calculated glomerular filtration rate (GFR) >50 ml/min were eligible. Forty-two patients were enrolled: 25 male; median age 62 (range 37-78) years. There were 26 patients (62%) with stage IV disease. One hundred and thirty-eight cycles of chemotherapy were delivered. Chemotherapy was well tolerated, allowing maintenance of planned dose intensity (DI) with mean dose delivered of 780.1 mg/m(2) (93%) and 25.6 mg/m(2) (96%) for G and C, respectively. The overall response rate was 43%. Median survival was 12.5 months with a median follow-up of 13.5 months. One year survival rate was 51%. G plus C both given on d1 and d8 (q21d) is a very active, well tolerated and convenient outpatient schedule, which maintains DI.

EGFR expression: associations with outcome and clinicopathological variables in malignant pleural mesothelioma.

Malignant mesothelioma (MM) is a fatal tumour of increasing incidence which is related to asbestos exposure. This work evaluated expression in MM of Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry in 168 tumour sections and its correlations with clinicopathological and biological factors. The microvessel density (MVD) was derived from CD34 immunostained sections. Hematoxylin and eosin stained sections were examined for intratumoural necrosis. COX-2 protein expression was evaluated with semi-quantitative Western blotting of homogenised tumour supernatants (n=45). EGFR expression was correlated with survival by Kaplan-Meier and log rank analysis. Univariate and multivariate Cox proportional hazards models were used to compare the effects of EGFR with clinicopathological and biological prognostic factors and prognostic scoring systems. EGFR expression was identified in 74 cases (44%) and correlated with epithelioid cell type (p<0.0001), good performance status (p<0.0001), the absence of chest pain (p<0.0001) and the presence of TN (p=0.004), but not MVD or COX-2. EGFR expression was a good prognostic factor in univariate analysis (p=0.01). Independent indicators of poor prognosis in multivariate analysis were non-epithelioid cell type (p=0.0001), weight loss, performance status and WBC>8.3x10(9)L(-1). EGFR status was not an independent prognostic factor. EGFR expression in MM correlates with epithelioid histology and TN. EGFR may be a target for selective therapies in MM.

Cyclooxygenase-2 protein levels are independent of epidermal growth factor receptor expression or activation in operable non-small cell lung cancer.

UNLABELLED: Both cyclooxygenase (COX)-2 and epidermal growth factor receptor (EGFR) are thought to play important roles in the pathogenesis of non-small cell lung cancer (NSCLC). A number of in vitro studies have postulated a link between EGFR activation and subsequent COX-2 upregulation. The relationship between these factors has not been established in patients with NSCLC. COX-2 and EGFR expression were studied in 172 NSCLC specimens using standard immunohistochemical techniques. Western blotting was used to determine COX-2 and EGFR levels in five NSCLC cell lines. The effect of treatment with EGF on COX-2 expression in A549 cells was assessed. RESULTS: Both EGFR and COX-2 are overexpressed in NSCLC. The predominant pattern of COX-2 and EGFR staining was cytoplasmic. Membranous EGFR staining was seen in 23.3% of cases. There was no relationship between COX-2 and EGFR expression and survival or any clinicopathological features. No correlation was seen between EGFR expression and COX-2 expression in the immunohistochemical series or in the cell lines. Treatment with EGF did not upregulate COX-2 levels in A549 cells, either in serum free or serum-supplemented conditions. CONCLUSIONS: Although COX-2 and EGFR are over-expressed in NSCLC neither was of prognostic significance in this series of cases. There is no correlation between these two factors in either tumour samples or cell lines. Although these factors show no correlation in NSCLC, they remain potential, though independent targets for treatment.

Coexpression of epidermal growth factor receptor with related factors is associated with a poor prognosis in non-small-cell lung cancer.

The epidermal growth factor receptor (EGFR) is commonly expressed in non-small-cell lung cancer (NSCLC) and promotes a host of mechanisms involved in tumorigenesis. However, EGFR expression does not reliably predict prognosis or response to EGFR-targeted therapies. The data from two previous studies of a series of 181 consecutive surgically resected stage I-IIIA NSCLC patients who had survived in excess of 60 days were explored. Of these patients, tissue was available for evaluation of EGFR in 179 patients, carbonic anhydrase (CA) IX in 177 patients and matrix metalloproteinase-9 (MMP-9) in 169 patients. We have previously reported an association between EGFR expression and MMP-9 expression. We have also reported that MMP-9 (P=0.001) and perinuclear (p)CA IX (P=0.03) but not EGFR expression were associated with a poor prognosis. Perinuclear CA IX expression was also associated with EGFR expression (P<0.001). Multivariate analysis demonstrated that coexpression of MMP-9 with EGFR conferred a worse prognosis than the expression of MMP-9 alone (P<0.001) and coexpression of EGFR and pCA IX conferred a worse prognosis than pCA IX alone (P=0.05). A model was then developed where the study population was divided into three groups: group 1 had expression of EGFR without coexpression of MMP-9 or pCA IX (number=21); group 2 had no expression of EGFR (number=75); and group 3 had coexpression of EGFR with pCA IX or MMP-9 or both (number=70). Group 3 had a worse prognosis than either groups 1 or 2 (P=0.0003 and 0.027, respectively) and group 1 had a better prognosis than group 2 (P=0.036). These data identify two cohorts of EGFR-positive patients with diametrically opposite prognoses. The group expressing either EGFR and or both MMP-9 and pCA IX may identify a group of patients with activated EGFR, which is of clinical relevance with the advent of EGFR-targeted therapies.

Towards a biological staging model for operable non-small cell lung cancer.

Non-small cell lung cancer is the most common cause of cancer-related death in North America and Europe. Despite improvements in the diagnosis and treatment of the disease the prognosis remains poor, the overall 5-year survival being 4-14%. An increased understanding of the molecular biology of the disease may identify novel targets for drug development. We evaluated epidermal growth factor receptor (EGFR), HER-2/neu, matrix metalloproteinase (MMP)-2, MMP-9, p53 and bcl-2 expression and microvessel density (MVD) in patients who underwent surgery with curative intent in our department between 1991 and 1996. Co-expression of EGFR/MMP-9, MVD and bcl-2 were found to be independent prognostic variables, which allowed prediction of patient outcome independent of surgical stage. Other prognostic factors identified in our series were gender, surgical stage, platelet count, extent of necrosis, the hypoxia marker carbonic anhydrase-9 and beta-catenin. In collaboration with groups in Oxford and Greece, we were also able to establish the angiogenic growth factors vascular endothelial growth factor and platelet-derived endothelial growth factor as prognostic variables. The inter-relationships between these factors are currently being examined in an expanded patient series. Through this work we hope to be able to construct an integrated biological prognostic model which can be tested in prospective studies. This work has identified several potential targets for novel therapeutic agents currently in development.

Male osteoporosis associated with longterm cyproterone treatment.

A 58-year-old man with previous dorsal vertebral fractures was referred for continuing management of osteoporosis. He was treated in the past with cyproterone acetate for hypersexuality. There were no other risk factors for osteoporosis. A dual energy radiographic absorptiometry scan confirmed osteoporosis. Treatment with alendronate 10 mg/day improved bone density and back pain. Patients receiving longterm treatment with cyproterone might be at risk for developing osteoporosis and would benefit from regular bone density monitoring.

Corticosteroids do not alter the threshold for vertebral fracture.

Corticosteroid use is one of the most important secondary causes of osteoporosis. Generally, it has been believed that in addition to its effect on bone mineral density (BMD), it also causes an alteration in bone quality that means that fractures occur at a lower BMD than might be expected. To establish if this is the case, we have compared the relationship between BMD and vertebral fracture in patients receiving corticosteroids with that in patients who had never received such therapy. Information was gathered on those patients who had been referred to the participating centers and had both BMD measurements and lateral thoracolumbar radiographs. In all, 452 patients (391 female) were identified; of these 82 (63 female) were receiving corticosteroids. There was no significant difference in BMD between the patients on corticosteroids and those with other suspected causes of osteoporosis. Vertebral fractures were present in 53% of patients on steroids compared with 35% of those who had no such treatment (p = 0.0035). The fractures were more likely to be multiple in patients on corticosteroids (p = 0.0042). However, if the relationship between bone density and fracture is investigated by plotting the cumulative prevalence of fracture against the bone density, measured by T score, the median BMD for fractures actually was marginally lower in patients on steroids, -2.74 (95% confidence interval [CI], -2.77 to -2.70) compared with -2.65 (95% CI, -2.66 to -2.65) in those who had not received steroids. Our results fail to support the notion that the fracture threshold is altered in patients on long-term steroids and suggest that the same diagnostic criteria should be used for osteoporosis in patients whether or not they are taking corticosteroid therapy.

Defective antibody production in patients with rheumatoid arthritis and bronchiectasis.

Bronchiectasis (BR) occurs in about 3% of patients with rheumatoid arthritis (RA). Defective antibody production is a rare but well-recognised cause of both BR and inflammatory arthritis. We examined the hypothesis that subtle specific antibody defects might play a role in the pathogenesis of BR associated with RA. Identification of defects in antibody production is important because substantial benefits may be gained from immunoglobulin replacement. Specific antibody production was assessed in 20 patients with RA and BR, 20 with BR alone, 20 with RA alone and 20 healthy controls (all groups matched for age and sex). All had normal total IgG. IgA and IgM and IgG subclass levels. Specific antibody production was assessed by assay of antibodies to representative polysaccharide and protein antigens. Subjects with subprotective titres were challenged with the appropriate vaccine. Defective antibody production was defined as a subprotective level despite immunisation. Three out of 20 patients with RA and BR had a defective IgG2 response to the polysaccharide antigen, but normal responses to the protein antigen. All of the subjects in the BR alone or healthy control group had normal antibody production. Two out of 20 patients with RA alone had defective production of antibodies against both protein and polysaccharide antigens; both were receiving gold therapy, a recognised cause of functional antibody defects. It was concluded that some patients with RA and BR have functional antibody defects and may benefit from antibody replacement. An unexpectedly high proportion of patients with RA alone also have functional antibody defects, possibly secondary to gold therapy.

Treatment of Felty's syndrome with the haemopoietic growth factor granulocyte colony-stimulating factor (G-CSF).

Felty's syndrome (FS) (rheumatoid arthritis with neutropenia and splenomegaly) has a poor prognosis, largely because of the high risk of severe infection. Granulocyte colony-stimulating factor (G-CSF) is an emerging treatment for chronic neutropenia. We prospectively monitored its use in eight patients with recurrent infections or who required joint surgery. Significant side-effects were documented in five, including nausea, malaise, generalized joint pains, and in one patient, a vasculitic skin rash. In two patients treatment had to be stopped, and in these cases G-CSF had been started at full vial dosage (300 micrograms/ml filgrastim or 263 micrograms/ml lenograstim) alternate days or daily. G-CSF treatment was continued in three patients by restarting at reduced dose, and changing the proprietary formulation. G-CSF raised the neutrophil count, reduced severe infection, and allowed surgery to be performed. A combined clinical and laboratory index suggested that long-term treatment (up to 3.5 years) did not exacerbate the arthritis. Once on established treatment, it may be possible to use smaller weekly doses of G-CSF to maintain the same clinical benefit. One of the three patients whose FS was associated with a large granular T-cell lymphocytosis showed a reduction in this subset of lymphocytes during G-CSF treatment.

Decreased survival in patients with co-existent rheumatoid arthritis and bronchiectasis.

The aim was to compare the 5 yr survival in patients with rheumatoid arthritis (RA) alone, bronchiectasis (Br) alone and RA plus Br (RA-Br). A case-control study was carried out in which 32 patients with RA-Br were matched for age (within 5 yr), sex and (where possible) disease duration with 32 patients with RA alone. An additional comparison group of 31 unselected patients with Br was chosen. All patients were followed for 5 yr. Patients with RA-Br were 7.3 times more likely to die than the general population, 5.0 times more likely than the RA group and 2.4 times more likely than the Br group. An increased risk of death within the RA-Br group was associated with a history of smoking, more severe RA and steroid usage. The co-existence of RA and Br is associated with a poor 5 yr survival.

An unusual association of Felty syndrome and TCR gamma delta lymphocytosis.

Felty syndrome, comprised of neutropenia, rheumatoid arthritis and splenomegaly, occurs in approximately 1% of patients with rheumatoid arthritis. Up to one third of these patients have an increased number of large granular lymphocytes. The usual immunophenotype of these cells is CD3+, CD8+, CD57+, T cell receptor (TCR) alpha beta. A patient with Felty syndrome and large granular lymphocytosis, who had an unusual immunophenotype CD3+, CD4-, CD8-, TCR gamma delta, is described. Her neutropenia responded to treatment with granulocyte colony stimulating factor (G-CSF), which was given in order to raise her neutrophil count prior to bilateral knee replacement surgery. Thus, Felty syndrome with large granular lymphocytosis is a heterogeneous condition, one in which TCR gamma delta large granular lymphocytosis may be found, and also shows a response to treatment with G-CSF.

Bronchiectasis and rheumatoid arthritis: a clinical study.

OBJECTIVES: To examine the relation between rheumatoid arthritis (RA) and bronchiectasis (BR). METHODS: Disease activity, outcome, extra-articular manifestations, and laboratory features were compared in 32 patients with BR and RA (RA-BR group), 32 matched patients with RA without BR (RA group), and 31 patients with BR but without arthritis (BR group). RESULTS: In 30 of the 32 (94%) patients with RA-BR, BR preceded RA. There was no functional or radiological difference between the RA-BR and RA groups, and except for xerophthalmia, which was more common in patients with RA-BR than patients with RA, there was no difference in extra-articular or laboratory features. CONCLUSIONS: Bronchiectasis does not lead to a more aggressive disease course in RA and, despite the recognised association, BR is not an extra-articular manifestation of rheumatoid disease.