Deborah A. McNamara

Multicenter evaluation of rectal cancer reimaging post neoadjuvant (MERRION) therapy.

Objective:The aim of this study was to evaluate the utility of reimaging rectal cancer post-CRT (chemoradiotherapy) with magnetic resonance (MR) imaging of the pelvis for local staging and computed tomography of thorax, abdomen, and pelvis (CT TAP) to identify distant metastases. Background:The success of neoadjuvant CRT for locally advanced rectal cancer has changed an already complex management algorithm. There is no consensus whether patients should be restaged before surgery. Methods:Data from 5 institutions with prospectively maintained databases including patients who received neoadjuvant CRT for locally advanced rectal cancer were acquired. Only patients who had been staged pre- and post-CRT with MR imaging and CT TAP were included. MR findings were correlated with histopathological stage using weighted &kgr; (kappa) statistics to test agreement, where a &kgr; value of less than 0.5 was deemed unacceptable. Results:A total of 285 patients fulfilled the criteria for the study; 84% had American Joint Committee for Cancer stage 3 disease pre-CRT, and the remainder had stage 2 disease. Fourteen patients did not proceed to surgery post-CRT—2 were observed as “complete responders,” and the remainder either had unresectable disease or were unfit for surgery. MR imaging could not predict T stage (&kgr; = 0.212) or nodal involvement (&kgr; = 0.336). Most pertinently, MR imaging was unable to detect a complete pathological response (&kgr; = 0.021), nor could it discriminate T4 disease (&kgr; = 0.445). CT TAP restaging altered management in 6.7% of patients, who had metastatic disease. Conclusions:MR reimaging using standard protocols is of limited value in determining surgical approaches; a better modality of local restaging is required.

Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy

Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors. This counterintuitive finding suggested that sole inhibition of effector BAX and BAK could not be sufficient for systems stability in nonstressed cells. Assuming a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing drugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients.

Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy

Objective Key to the clinical management of colorectal cancer is identifying tools which aid in assessing patient prognosis and determining more effective and personalised treatment strategies. We evaluated whether an experimental systems biology strategy which analyses the susceptibility of cancer cells to undergo caspase activation can be exploited to predict patient responses to 5-fluorouracil-based chemotherapy and to case-specifically identify potential alternative targeted treatments to reactivate apoptosis. Design We quantified five essential apoptosis-regulating proteins (Pro-Caspases 3 and 9, APAF-1, SMAC and XIAP) in samples of Stage II (n=13) and III (n=17) tumour and normal colonic (n=8) tissue using absolute quantitative immunoblotting and employed systems simulations of apoptosis signalling to predict the susceptibility of tumour cells to execute apoptosis. Additional systems analyses assessed the efficacy of novel apoptosis-inducing therapeutics such as XIAP antagonists, proteasome inhibitors and Pro-Caspase-3-activating compounds in restoring apoptosis execution in apoptosis-incompetent tumours. Results Comparisons of caspase activity profiles demonstrated that the likelihood of colorectal tumours to undergo apoptosis decreases with advancing disease stage. Systems-level analysis correctly predicted positive or negative outcome in 85% (p=0.004) of colorectal cancer patients receiving 5-fluorouracil based chemotherapy and significantly outperformed common uni- and multi-variate statistical approaches. Modelling of individual patient responses to novel apoptosis-inducing therapeutics revealed markedly different inter-individual responses. Conclusions Our study represents the first proof-of-concept example demonstrating the significant clinical potential of systems biology-based approaches for predicting patient outcome and responsiveness to novel targeted treatment paradigms.

GLUT‐1 expression and response to chemoradiotherapy in rectal cancer

Preoperative chemoradiotherapy is used in locally advanced rectal cancer to reduce local recurrence and improve operability, however a proportion of tumors do not undergo significant regression. Identification of predictive markers of response to chemoradiotherapy would improve patient selection and may allow response modification by targeting of specific pathways. The aim of this study was to determine whether expression of glucose transporter‐1 (GLUT‐1) and p53 in pretreatment rectal cancer biopsies was predictive of tumor response to chemoradiotherapy. Immunohistochemical staining for GLUT‐1 and p53 was performed on 69 pretreatment biopsies and compared to tumor response in the resected specimen as determined by the tumor regression grade (TRG) scoring system. GLUT‐1 expression was significantly associated with reduced response to chemoradiotherapy and increasing GLUT expression correlated with poorer response (p = 0.02). GLUT‐1 negative tumors had a 70% probability of good response (TRG3/4) compared to a 31% probability of good response in GLUT‐1 positive tumors. GLUT‐1 may be a useful predictive marker of response to chemoradiotherapy in rectal cancer.

The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer

To date, there is no uniform consensus on whether tumour regression grade (TRG) is predictive of outcome in rectal cancer. Furthermore, the lack of standardization of TRG grading is a major source of variability in published studies. The aim of this study was to evaluate the prognostic impact of TRG in a cohort of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy (CRT). In addition to the Mandard TRG, we utilized four TRG systems modified from the Mandard TRG system and applied them to the cohort to assess which TRG system is most informative.

Malignant tumours of the small intestine

Adenocarcinoma, neuroendocrine tumours, sarcomas and lymphomas are the four most common malignant tumours arising in the small intestine, although over forty different histological subtypes are described. Collectively these account for only 2% of cancers of the digestive system. The incidence of small bowel cancer has increased in recent decades with a four-fold increase in carcinoid tumours. Risk factors for small bowel tumours include coeliac disease, inflammatory bowel disease and a number of genetic abnormalities. The non-specific nature of their symptoms and the difficulty in visualising these tumours with normal endoscopic techniques often results in late diagnosis. Furthermore the paucity of literature on this topic has made it difficult to standardise management. There has however been marked improvement in imaging methods resulting in earlier diagnosis in many cases. As expected, early detection of localised, well differentiated tumours followed by surgical resection with negative margins offers the best chance of long term survival. Better adjuvant treatment, notably for gastrointestinal stromal tumours, has improved 5-year survival rates significantly. Development of surveillance guidelines for at risk populations may be a valuable way of improving early diagnosis of this challenging group of conditions.

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach

Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis. Activation of executioner caspases also has a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells as reported recently. Tissue microarrays (TMAs) consisting of tumour tissue from 93 stage II and III colon cancer patients were analysed by immunohistochemistry. Surprisingly, patients with low levels of active Caspase-3 had an increased disease-free survival time. This was particularly pronounced in patients who received 5FU-based adjuvant CT. In line with this observation, lower serum levels of active Caspase-3 were found in patients with metastasised CRC who revealed stable disease or tumour regression compared with those with disease progression. The role of Caspase-3 in treatment responses was explored further in primary human tumour explant cultures from fresh patient tumour tissue. Exposure of explant cultures to 5FU-based CT increased the percentage of cells positive for active Caspase-3 and Terminal Deoxynucleotidyl Transferase dUTP Nick end Labelling (TUNEL), but also the expression of regeneration and proliferation markers β-Catenin and Ki-67, as well as cyclooxygenase-2 (COX-2). Of note, selective inhibition of Caspase-3 with Ac-DNLD-CHO, a selective, reversible inhibitor of Caspase-3, significantly reduced the expression of proliferation markers as well as COX-2. Inhibition of COX-2 with aspirin or celecoxib did not affect Caspase-3 levels but also reduced Ki-67 and β-Catenin levels, suggesting that Caspase-3 acted via COX-2 to stimulate cell proliferation and tissue regeneration. This indicates that low levels of active Caspase-3 may represent a new predictor of CT responsiveness, and inhibition of Caspase-3, or antagonising downstream effectors of Caspase-3 paracrine signalling, such as COX-2 may improve patient outcomes following CT in advanced CRC.

Implementation and usefulness of single access laparoscopic segmental and total colectomy.

Aim  Single‐access laparoscopic surgery is a recent vogue in the field of minimally invasive colorectal surgery. While selected series have indicated feasibility, we prospectively examined its usefulness for resectional surgery in routine practice.

Endolaparoscopic removal of colonic polyps

A proportion of colonic polyps is not amenable to exclusively colonoscopic removal due to their location, size or tortuosity of the colon. A combined laparoscopic/colonoscopic polypectomy or endolaparoscopic polypectomy (ELP) is an alternative to formal segmental resection. We present our experience of ELP.

Catheter associated blood stream infections in patients receiving parenteral nutrition: a prospective study of 850 patients.

Background Data was prospectively collected on 850 consecutive patients undergoing central venous catheterisation (CVC) to receive total parenteral nutrition (TPN) in a major university teaching hospital over a 46 months period. Methods Data included information about CVC insertion and clinical outcomes, most notably, suspected catheter-related blood stream infections (CRBSI). Results The internal jugular vein was the most common site (n = 882, 68%), followed by the subclavian vein (n = 344, 24.6%) and femoral vein (n = 95, 6.5%). The CRBSI rate per 100 line feeding days was 0.93% in patients cared for in a non ICU setting versus 1.98% for ICU managed patients. The mean number of line days preceding a pyrexial spike was 13.1. CRBSI was commonest in patients with femoral lines (n = 21/95, 22.1%), especially those cared for in a non-ICU setting (29.6% versus 14.5% for those in the ICU group). Preference should be given to internal jugular or subclavian-sited CVCs in ICU and non-ICU patients to reduce the risk of CRBSI. If femoral catheterisation is unavoidable, strict attention to aseptic technique is mandatory. Conclusion The aim of this study was to investigate the rate and pattern of CRBSI and to recommend changes in protocol, technique and equipment as deemed necessary from these findings.