Objective: The primary aim of this prospective 2‐year study was to explain the wide variability in joint damage progression in patients with rheumatoid arthritis (RA) from measures of pathologic changes in the synovial membrane.Methods: Patients underwent clinical measurements and joint damage assessments by magnetic resonance imaging (MRI) and radiography at enrollment and at year 2. Synovial membrane was obtained by knee biopsy and assessed histologically by hematoxylin and eosin staining. Interleukin‐1β (IL‐1β), IL‐10, IL‐16, IL‐17, RANKL, tumor necrosis factor α (TNFα), and interferon‐γ (IFNγ) messenger RNA (mRNA) expression was determined by quantitative reverse transcription–polymerase chain reaction. The relationship of synovial measurements to joint damage progression was determined by multivariate analysis.Results: Sixty patients were enrolled. Histologic features had no relationship to damage progression. Multivariate analysis by several different methods consistently demonstrated that synovial membrane mRNA levels of IL‐1β, TNFα, IL‐17, and IL‐10 were predictive of damage progression. IL‐17 was synergistic with TNFα. TNFα and IL‐17 effects were most pronounced with shorter disease duration, and IL‐1β effects were most pronounced with longer disease duration. IFNγ was protective. These factors explained 57% of the MRI joint damage progression over 2 years.Conclusion: We have demonstrated for the first time in a prospective study that synovial membrane cytokine mRNA expression is predictive of joint damage progression in RA. The findings for IL‐1β and TNFα are consistent with results of previous clinical research, but the protective role of IFNγ, the differing effects of disease duration, and IL‐17–cytokine interactions had only been demonstrated previously by animal and in vitro research. These findings explain some of the variability of joint damage in RA and identify new targets for therapy.

The wingless-type (Wnt) signalling transduction pathway is essentially a network of a number of separate but interacting pathways. Specific Wnt ligands bind to their target 'frizzled' membrane receptor and interfere with the multi-protein destruction complex, resulting in downstream activation of gene transcription by β-catenin. Simplistically, the multiprotein destruction complex involves Axin and APC serving as scaffolds binding both β-catenin and GSK3, to facilitate phosphorylation of β-catenin by GSK-3β. Phosphorylated β-catenin is degraded in proteasomes by the ubiquination machinery. Unphosphorylated β-catenin accumulates and associates with nuclear transcription factors leading to the eventual transcription and expression of target genes such as c-myc, c-jun, Fra and cyclin D1. There are several regulatory mechanisms for the down-regulation of the Wnt/β-catenin signal, perhaps reflecting the pivotal nature of the pathway and the detrimental consequences of inappropriate activation. There has been intense investigation into the role of Wnt genes in human cancer. Although no documentation is made of any mutation or amplification of genes encoding Wnt ligands or receptors linked to human cancer to date, several components of the Wnt pathway have been implicated in carcinogenesis, especially APC and β-catenin.

Background and aims: Intraductal papillary mucinous tumours (IPMT) of the pancreas constitute a unique pathological entity with an overall incidence of associated invasive malignancy of 20%. The malignant potential of an individual IPMT cannot be accurately predicted. Preoperative estimation of the risk of associated invasive malignancy with IPMT would be of significant clinical benefit. As aberrations in cell cycle regulatory genes are associated with the progression of precursor pancreatic ductal lesions to invasive adenocarcinoma, we examined expression of key cell cycle regulatory genes in the cyclin D1/retinoblastoma pathway and the transforming growth factor β/Smad4 signalling pathway in a cohort of patients with surgically resected IPMT. Methods: Sections of formalin fixed paraffin embedded pancreatic tissue from a cohort of 18 patients with IPMT were examined using immunohistochemistry for protein expression of cell cycle regulatory genes p16^INK4A, p21^CIP1, p27^KIP1, cyclin D1, pRb, and p53, as well as the cell signalling molecule Smad4. A comparison of expression levels was made between adenoma/borderline IPMT (10 patients) and intraductal papillary mucinous carcinoma (IPMC) (eight patients, four of whom harboured invasive carcinoma). Statistical analysis was performed using the χ² and Fisher's exact tests. Results: Aberrant expression of the proteins examined increased in frequency from adenoma/borderline IPMT to IPMC. Specifically, there was a significantly greater incidence of loss of p16^INK4A expression in IPMC: 8/8 lesions (100%) compared with 1/10 (10%) adenoma/borderline IPMT (p<0.001). Similarly, loss of Smad4 expression was associated with IPMC: 3/8 (38%) versus adenoma/borderline IPMT 0/10 (p<0.03). Loss of Smad4 expression within the IPMT was the best marker for the presence of invasive carcinoma (p<0.001). Conclusions: These data indicate that loss of p16^INK4A and Smad4 expression occur more frequently in IPMC alone, or with associated invasive carcinoma, compared with adenoma/borderline IPMT. Aberrant protein expression of these cell cycle regulatory genes in IPMT and pancreatic intraepithelial neoplasia in the current model of pancreatic cancer progression suggest similarities in their development and may also represent the subsequent risk of invasive carcinoma.

PURPOSE: Prognostic indicators in pancreatic cancer (PC) are poorly defined and difficult to quantify preoperatively, hence they may lead to inappropriate patient selection for treatment. We examined the protein expression of key cell-cycle regulatory and cell-signaling molecules that occur at high frequency in PC and assessed their relationship to clinicopathologic parameters, response to operative resection, and outcome. PATIENTS AND METHODS: We identified 348 patients with pancreatic ductal adenocarcinoma and assessed the influence of reported clinicopathologic prognostic factors and the expression of the cell-cycle regulatory genes p21^WAF1/CIP1 (CDKN1A), cyclin D1 (CCND1), p53, and p16^INK4A (CDKN2) and the cell-signaling molecule DPC4/Smad4 (MADH4) using immunohistochemistry in a subgroup of 129 patients. RESULTS: Independent prognostic factors in resected patients were tumor size greater than 45 mm (P = .0015), involvement of surgical margins (P < .0001), and perineural invasion (P = .014). Loss of DPC4/Smad4 expression cosegregated with resectability (P < .0001) and was associated with improved survival after resection (P < .0001), whereas resection did not improve survival in patients whose tumor expressed DPC4/Smad4 (P = .5). Aberrant expression of p21^WAF1/CIP1, cyclin D1, p53, or p16^INK4A was not associated with a difference in survival. CONCLUSION: Tumor size (> 45 mm), resection margin involvement, and perineural invasion were independent prognostic factors. Preoperative assessment of DPC4/Smad4 expression has potential as a prognostic indicator in patients with PC since resection did not benefit those patients whose cancers expressed DPC4/Smad4 and accurate assessment of DPC4/Smad4 expression, unlike tumor size, margin status, and perineural invasion, does not require resection.

This study examines the prognostic significance of human papillomavirus (HPV) in patients with locally advanced oropharyngeal squamous cell carcinoma (SCC) treated primarily with surgery or definitive radiotherapy. One hundred and ninety-eight patients with Stage 3/4 SCC were followed up for recurrence in any form or death from any cause for between 1 and 235 months after diagnosis. HPV status was determined using HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Cox's regression with censoring at follow-up dates. Forty-two per cent of cancers were HPV-positive (87% type 16). HPV predicted loco-regional control, event-free survival and overall survival in multivariable analysis. Within the surgery with adjuvant radiotherapy (n=110), definitive radiotherapy-alone (n=24) and definitive radiotherapy with chemotherapy (n=47) groups, patients with HPV-positive cancers were one-third or less as likely to have loco-regional recurrence, an event or to die of any cause as those with HPV-negative cancers after adjusting for age, gender, tumour grade, AJCC stage and primary site. The 14 patients treated with surgery alone were considered too few for multivariable analysis. HPV status predicts better outcome in oropharyngeal cancer treated with surgery plus adjuvant radiotherapy as well as with definitive radiation therapy±chemotherapy.