Gene expression profile predictive of response to chemotherapy in metastatic colorectal cancer

Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip^® HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan^®Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-institutional cohort (53 mCRC patients). Seven of these genes were confirmed as significant predictors of response. Patients with a favorable predictive signature had significantly greater response rate (58% vs 13%, p = 0.024), progression-free survival (61% vs 13% at 1 year, HR = 0.32, p = 0.009) and overall survival (32 vs 16 months, HR = 0.21, p = 0.003) than patients with an unfavorable gene signature. This is the first study to validate a gene-expression profile predictive of response to CT in mCRC patients. Larger and prospective confirmatory studies are required, however, in order to successfully provide oncologists with adequate tools to optimize treatment selection in routine clinical practice.     

Intravital imaging reveals p53-dependent cancer cell death induced by phototherapy via calcium signaling

One challenge in biology is signal transduction monitoring in a physiological context. Intravital imaging techniques are revolutionizing our understanding of tumor and host cell behaviors in the tumor environment. However, these deep tissue imaging techniques have not yet been adopted to investigate the second messenger calcium (Ca²⁺). In the present study, we established conditions that allow the in vivo detection of Ca²⁺ signaling in three-dimensional tumor masses in mouse models. By combining intravital imaging and a skinfold chamber technique, we determined the ability of photodynamic cancer therapy to induce an increase in intracellular Ca²⁺ concentrations and, consequently, an increase in cell death in a p53-dependent pathway.     

CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion

Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based cohort of 96 patient biopsies and TCGA dataset to evaluate the clinical significance of CD151 and α3β1 integrin. Functional and signaling analyses were also conducted to understand how these molecules promote the aggressiveness of glioblastoma at molecular and cellular levels. Results from our analyses showed that CD151 and α3 integrin were significantly elevated in glioblastomas at both protein and mRNA levels, and exhibited strong inverse correlation with patient survival (p < 0.006). These adhesion molecules also formed tight protein complexes and synergized with EGF/EGFR to accelerate tumor cell motility and invasion. Furthermore, disruption of such complexes enhanced the survival of tumor-bearing mice in a xenograft model, and impaired activation of FAK and small GTPases. Also, knockdown- or pharmacological agent-based attenuation of EGFR, FAK or Graf (ARHGAP26)/small GTPase-mediated pathways markedly mitigated the aggressiveness of glioblastoma cells. Collectively, our findings provide clinical, molecular and cellular evidence of CD151-α3β1 integrin complexes as promising prognostic biomarkers and therapeutic targets for glioblastoma.     

Will the implementation of the 2007 National Institute for Health and Clinical Excellence (NICE) guidelines on childhood urinary tract infection (UTI) in the UK miss significant urinary tract pathology?

What's known on the subject? and What does the study add? Most centres continue to investigate children extensively after a urinary tract infection. These investigations are invasive, time consuming and expensive and despite their widespread application they have not had a significant impact on the rates of chronic renal failure secondary to infection. Despite this evidence the National Institute for Health and Clinical Excellence (NICE) guidelines generated significant controversy that abnormalities would be missed, placing children at increased risk of renal injury, thus reducing their implementation. Significant underlying abnormalities of the urinary tract will not be missed if the NICE guidelines are followed. This will reduce the unpleasant investigations that children will be subjected to and it should lead to considerable cost savings. The NICE guidelines are safe and should be widely implemented.

OBJECTIVE

• ? To investigate whether the implementation of the August 2007 National Institute for Health and Clinical Excellence (NICE) guidelines would miss significant urinary tract pathology in children with urinary tract infection (UTI).

PATIENTS AND METHODS

• ? All ultrasound (US) performed in children aged >6 months, during the year 1 August 2006 to 31 July 2007 for UTI, were retrospectively studied.
• ? Each US scan in the study population of 346 was categorised dependent on whether it was appropriate or inappropriate to have been performed under the new guidelines and whether the US scan was normal or abnormal.
• ? The records of each patient with an inappropriate abnormal US scan were re‐analysed to see if patient management was affected by the US scan.
• ? In 2011 patients with an original inappropriate abnormal US scan were re‐evaluated to identify if any had presented with further urinary pathology.

RESULTS

• ? In accordance with the NICE guidelines patients were divided by age.
• ? Children aged 0.5–3 years: 78/95 (82%) US scans were inappropriate of which 12 (15%) were abnormal and four of these had a further documented UTI. After careful assessment of the US abnormalities it was judged that only one would have benefited from the initial US scan.
• ? Children aged >3 years: 146/251 (58%) US scans were inappropriate of which 21(14%) were abnormal and six of these (29%) had a further documented UTI. After careful assessment of the US abnormalities it was judged that only three of 21 (14%) would have benefited from the initial US scan.

CONCLUSIONS

• ? The vast majority of anomalies detected on the inappropriate US scans were of little clinical significance.
• ? It is difficult to identify any patient who would have been truly disadvantaged if the US scan had not been performed after the initial UTI.
• ? The NICE guidelines are safe to follow.