Juliette Sheridan

Nuclear oxidative damage correlates with poor survival in colorectal cancer

Oxidative DNA damage results from DNA adducts such as 8-oxo-7, 8 dihydro-2′-deoxyguanosine (8-oxo-dG), which is a pro-mutagenic lesion. No known association between 8-oxo-dG, disease progression and survival exists in colorectal cancer (CRC). We examined levels of 8-oxo-dG in sporadic CRC to determine its relationship with pathological stage and outcome. A total of 143 CRC patients and 105 non-cancer patients were studied. Nuclear and cytoplasmic 8-oxo-dG was assessed using immunohistochemistry. Double immunofluorescence using 8-oxo-dG and manganese superoxide dismutase (MnSOD) antibodies localised cytoplasmic 8-oxo-dG. Apoptosis was detected using TUNEL. Nuclear staining levels were similar in tumour tissue and matched normal mucosa in both epithelial (P=0.22) and stromal (P=0.85) cells. Epithelial cytoplasmic staining was greater in tumour tissue (P<0.001). Double immunofluorescence localised cytoplasmic 8-oxo-dG to mitochondria. Epithelial and stromal nuclear 8-oxo-dG decreased with local disease spread, but highest levels were found in distant disease (P<0.01). Survival was related to epithelial nuclear and stromal staining in normal mucosa (P<0.001) and tumour (P<0.01) but was unrelated to cytoplasmic staining. Normal control cells in tissue from cancer patients with high levels of 8-oxo-dG failed to undergo cell death. 8-oxo-dG may be an important biomarker of disease risk, progression and survival for CRC patients.

The effect of green tea on oxidative damage and tumour formation in Lobund-Wistar rats.

A number of epidemiological studies suggest that the consumption of green tea reduces the incidence of prostate cancer. As the major catechins present in green tea are potent antioxidants, we hypothesized that genetic and cellular damage induced by oxygen free radicals could be significantly reduced by potent antioxidants in green tea, thus reducing the cumulative genetic and cellular damage with age, and slowing or preventing tumour formation. Long-term administration of a decaffeinated green tea extract to Lobund–Wistar rats for periods up to 26 months almost halved the incidence of primary tumours in the genitourinary tract when compared with an age-matched cohort receiving just water. We observed no inhibition of DNA adduct formation or lipid peroxidation in animals consuming green tea compared with animals consuming deionized water. The decrease in tumour formation was associated with an increase in 8-hydroxy-2′deoxyguanosine and 4-hydroxynonenal content (markers of DNA adduct formation and lipid peroxidation, respectively) in the epithelium of the ventral prostate in aging animals. In addition, there was an increase in 8-hydroxy-2′deoxyguanosine expression, but no change in 4-hydroxynonenal expression in the seminal vesicles of older animals. An age-associated increase in expression of the antioxidant enzymes manganese superoxide dismutase and catalase in the epithelium of the ventral prostate of aging animals was observed. Furthermore, there was also an increase in manganese superoxide dismutase expression, but no change in catalase expression in the seminal vesicles of older animals. These data demonstrate that consumption of green tea decreases the incidence of genitourinary tract tumours in the Lobund–Wistar rat, but has no effect on age-associated DNA adduct formation and lipid peroxidation in the ventral prostate and seminal vesicles of the aging rat.

Determinants of short- and long-term survival from colorectal cancer in very elderly patients

PURPOSE Over 5100 colorectal cancers (CRCs) are diagnosed in the United Kingdom in 85 years and older age group per year but little is known of cancer progression in this group. We assessed clinical, pathological and molecular features of CRC with early and late mortality in such patients. METHODS Data were analysed in relation to early mortality and long-term survival in 90 consecutive patients with CRC aged 85 years or older in a single hospital. RESULTS Patients not undergoing operation, those with an ASA score of III or greater and those with advanced tumour stage were more likely to die within 30 days. Regression analysis showed that 30 day mortality was independently related to failure to undergo resection (odds ratio (O.R.), 10.0; 95% confidence interval [C.I.], 1.7-58.2; p=0.01) and an ASA score of III or greater (O.R. 13.0; 95% C.I., 1.4-12.6; p=0.03). All cause three and five year survival were 47% and 23% respectively for patients who are alive 30 days after diagnosis. Three and five year relative survivals were 64% and 54%, respectively. Long-term outcome was independently related to tumour stage (relative risk [R.R.], 2; 95% C.I., 1.3-3.1; p=0.001), presence of co-morbid diseases (R.R., 2.8; 95% C.I., 1.3-6.0; p=0.007) and lipid peroxidation status (R.R., 2.9; 95% C.I., 1.1-7.5; p=0.025). CONCLUSIONS An active multidisciplinary approach to the care of patients with CRC at the upper extreme of life is reasonable. It also seems sensible to individualise care based upon the extent of disease at diagnosis and the presence of co-morbid conditions. Further studies to examine the role of lipid peroxidation are warranted.

Increased non-melanoma skin cancer risk in young patients with inflammatory bowel disease on immunomodulatory therapy: a retrospective single-centre cohort study

Recent studies report an increased risk of non‐melanoma skin cancer (NMSC) in immunosuppressed patients with inflammatory bowel disease (IBD). Concurrently, paediatric IBD incidence is rising, with more patients now exposed to immunomodulators from a younger age.

Letter: vedolizumab for the management of inflammatory bowel disease in patients after liver transplantation for primary sclerosing cholangitis.

hepatocytic accumulation of iron, copper, and alpha1 antitrypsin, and Helicobacter pylori infection, in particular by strains carrying the cytotoxin-associated gene A protein product (CagA). The latter is a well-defined carcinogen, and was almost invariably found in HCC patients; mice that were experimentally infected by Helicobacter hepaticus developed chronic hepatitis and most of these mice also developed HCC. Iron accumulation due to haemoglobinopathies is widespread in Mediterranean countries, and haemochromatosis genes are present in one in eight Europeans. These pathogens are easy to detect and to treat, at a minimal cost. We believe that these measures should always be considered in HCC prevention strategies.

Ustekinumab Drug Levels in Maternal and Cord Blood in a Woman With Crohn’s Disease Treated Until 33 Weeks of Gestation

A 35-year old woman with ileocolonic, perianal, and vulval Crohns disease was treated with subcutaneous ustekinuamb [USK] throughout pregnancy. Dose intervals were shortened from 6-weekly to 4-weekly to maintain clinical remission. The last dose of USK was administered at 33 weeks of gestation, and a healthy baby boy was delivered by caesarean section at 37 weeks. Maternal trough USK levels remained stable during pregnancy. Cord blood USK levels were nearly 2-fold higher than contemporaneous maternal serum levels. To our knowledge, this is the first report of maternal and cord USK levels in a patient with Crohns disease.

Effects of Radiation on Levels of DNA Damage in Normal Non-adjacent Mucosa from Colorectal Cancer Cases

PurposeDefects in DNA repair pathways have been linked with colorectal cancer (CRC). Adjuvant radiotherapy has become commonplace in the treatment of rectal cancer however it is associated with a higher rate of second cancer formation. It is known that radiation results in DNA damage directly or indirectly by radiation-induced bystander effect (RIBE) by causing double-strand breaks (DSBs). The majority of work in RIBE has been performed in cell lines and limited studies have been in or ex vivo.MethodsThe first study aim was to examine by immunohistochemistry, levels of DSB (expression of the protein MRE11) in normal colonic tissue outside the irradiated field post neo-adjuvant radiotherapy (group 1). These levels were compared to (a) irradiated tumour tissue post neo-adjuvant radiation within the same group, (b) a CRC patient group (group 2) who had not undergone neo-adjuvant radiotherapy and (c) a non-cancer patient group (group 3). The second aim was to determine if MRE11 expression levels were related to survival or radio-sensitivity post neo-adjuvant radiotherapy.ResultsThere was a highly significant increase in MRE 11 expression in group 1 versus groups 2 and 3 (p < 0.001). There was no association between MRE11 levels and survival or radio-sensitivity.ConclusionOur findings show radiotherapy causes DSBs at significantly higher levels in normal colonic mucosa of patients post neo-adjuvant treatment which may represent RIBE. If this damage remains unrepaired, increased levels of genomic instability may contribute to the higher occurrence of second cancers in patients treated post neo-adjuvant radiotherapy.

Myocarditis associated with infliximab: a case report and review of the literature.

To the Editor: Infliximab is a recombinant immunoglobulin G1 kappa chimeric monoclonal antibody that specifically and potently binds to and neutralizes the soluble tumor necrosis factor alpha (TNF-a) homotrimer and its membrane-bound precursor. It has been shown to be effective in the management of Crohn’s disease (CD) and, more lately, ulcerative colitis (UC). The safety profile of infliximab continues to evolve. The most commonly reported adverse event associated with its use is an increased risk of infections. There are also concerns around the use of these biological agents relating to reports of hematological and lymphoproliferative malignancies. Cardiac toxicity has been well reported with infliximab. Infliximab has been shown to adversely affect the clinical condition of patients with moderate to severe chronic heart failure. Kwon et al reported on infliximab inducing new-onset heart failure in six patients treated with infliximab under the age of 50, with no discernible risk factor. We report on the case of a previously fit, young male patient who presented with myocarditis 10 days after his first infliximab infusion. D.D. is a 21-year-old Irish male who presented to the emergency department for the first time with a 2-month history of diarrhea. Subsequent investigations (including stool cultures, plain film radiology, and colonoscopy with biopsies) confirmed that his symptoms were attributable to acute severe UC. He was treated with intravenous hydrocortisone (100 mg, 6-hourly) and rectal 5-aminosalicylate (Mesalazine, 4 g od) but failed to make any improvement by 72 hours. A decision was therefore made to proceed to salvage treatment in the form of infliximab. Chest x-ray and tuberculin skin test were performed as a standard precaution prior to administration, both of which were normal. Infliximab was subsequently administered (at a dose of 5 mg/kg intravenously). He made a rapid improvement and was discharged home a few days later on reducing dose oral corticosteroids with an appointment to return for his second infusion. He represented 10 days later feeling unwell. He described being intermittently feverish and had developed a rash on his legs, shoulders, and neck. A mild derangement of his liver function tests was noted (alanine aminotransferase 39 IU/L, range 0–35 IU/L; alkaline phosphatase 132 IU/L, range 42–121 IU/L). The remainder of his laboratory indices were unremarkable. His diarrhea had not recurred. He was treated empirically with oral antibiotics and antivirals because of a concern of opportunistic infection and discharged home. He returned to the emergency department 2 days later with worsening fevers, fatigue, and vomiting and was admitted urgently. His temperature was 38.2 C, with a tachycardia of 120 bpm. He was anemic, with a hemoglobin of 11.4 g/dL (range 13–17.5 g/dL). Further investigations revealed an elevated Creactive protein (CRP) of 286 mg/L (range 0–10 mg/L). His chest x-ray was normal. A flexible sigmoidoscopy was performed and confirmed significant mucosal healing. A computed tomography (CT) scan demonstrated the presence of colitis in remission but no other source of intraabdominal sepsis. His colitis was felt to be responding to treatment at this stage. Over the next 48 hours he developed significant sinus tachycardia and chest pain. ECG revealed anterolateral ST-T changes. A subsequent troponin I was elevated at 2.87 lg/L (range 0– 0.06 lg/L) and so he was treated with beta-blockade and antiplatelet agents. An echocardiogram showed severe left ventricular dysfunction with an ejection fraction of 30% and akinetic anteroseptal walls, supporting a diagnosis of focal segmental myocarditis, with a secondary dilated cardiomyopathy. A repeat chest x-ray and subsequent CT pulmonary angiogram revealed cardiomegaly along with diffuse interstitial infiltrates consistent with pulmonary edema. In order to further identify a cause for his cardiac decompensation, a cardiac magnetic resonance imaging (MRI) was obtained. This again showed a dilated and poorly functioning left ventricle with pleural effusions and pulmonary infiltrates bibasally. There was subtle wall enhancement in the septum which was felt to be consistent with myocarditis. There was no evidence of acute or recent myocardial infarction. A full viral and immune profile failed to identify a cause for his myocarditis. However, he was noted to be weakly positive for pANCA. He was treated with supportive care and received beta-blockers, ACE inhibitors, and diuretics. An episode of atrial fibrillation was treated with amiodarone, and he subsequently reverted to sinus rhythm. He made a gradual improvement while in the coronary care unit and was subsequently discharged home. His colitis remained quiescent on a reducing dose of oral corticosteroids. Myocarditis, an inflammatory disease of the myocardium, can be produced by a variety of different disorders. Infections (especially viruses) are a particularly common cause, but also implicated are systemic conditions (such as sarcoidosis, collagen-vascular disorders, and rarely CD). Hypersensitivity reactions to drugs are also an important potential etiological factor. Hypersensitivity myocarditis is usually characterized by acute rash, fever, abnormal liver function, and nonspecific ECG abnormalities. It may present with rapidly progressive heart Copyright VC 2010 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21546 Published online 25 October 2010 inWiley Online Library (wileyonlinelibrary.com).

Editorial: gut selective immunosuppression—is it a double edged sword?

The systematic review by Bye et al., which combines safety data from the original vedolizumab (VDZ) registration studies with post-marketing prospective cohorts, confirms the overall encouraging safety profile of vedolizumab. Vedolizumab inhibits migration of a4b7 positive cells into the gut mucosa by blocking their interaction with endothelial cells expressing MAdCAM-1 which is preferentially expressed in the gut. Systemic immune responses are preserved after treatment with vedolizumab. The benefits of gut selective immunosuppression vs systemic immunosuppression are clear in certain groups. This review confirms that vedolizumab may be a safer biological agent in inflammatory bowel disease (IBD) patients pre-disposed to infection (although with the caveat that uncertainty remains about risk of surgical site infections and of enteric infections). Another recent systematic review and meta-analysis has added support, reporting that anti-TNF treatment, but not antiintegrin therapy, was associated with a greater infection risk than placebo in the treatment of ulcerative colitis (UC). However, neither class of drug was associated with a significantly increased risk of infection over placebo in the treatment of Crohn’s disease (CD) The recognition that the immune system declines with age, also known as immunosenescence, resulting in higher incidence of infections and neoplasia supports the use of vedolizumab and gut selective immunosuppression in older patients and possibly also those with a history of cancer. Based on their systematic review, the authors highlight areas where further evidence of safety is required (eg, pregnancy) and others particular potential safety signals (See Figure 1). In addition to surgical site and enteric infections, one additional potential safety concern also merits future close attention. 6/18 cancers reported in the 2830 VDZ exposed patients were gastrointestinal (GI) malignancies. In the open labelled extension phase of the GEMINI studies, it was recently reported that treatment with vedolizumab resulted in combined endoscopic and histological remission in 5/24 (CD) and 11/34 (UC) patients, respectively. However, this study also reported dysplasia in 10% of the patients studied. There is at least a theoretical concern that the mechanism of action of vedolizumab may interfere with tumour immunosurveillance in the gut. In the GEMINI mucosal healing study, all patients with dysplasia had previously been on anti-TNF agents with a mean disease duration of 10.8 years. (range: 2-18) putting many of them in “at risk” groups due to disease duration and severity. The St. Marks group has recently reported low grade dysplasia (LGD) rates of 11.3% in their patients with long-standing UC under surveillance. This figure whilst numerically similar represents approximately a decade more of surveillance than the cohort described in the GEMINI mucosal healing study. With improved dysplasia detection methods such as chromoendoscopy, a 10% LGD rate may reflect an outcome of the disease rather than the treatment. Nonetheless, these findings emphasise the need for particularly close scrutiny of the rates of gastro-intestinal dysplasia and cancer, particularly in high-risk groups such as the PSCIBD population, to enhance our understanding of the any potential downsides of gut selective immunosuppression.

Clinical and Pathological Factors Associated with Colorectal Cancer at the Upper Extreme of Life

from the hospital infection control nurse that the patient had trichinosis. Immediately thoughts of pork, eosinophilia, muscle biopsies, other residents who may have eaten the same food, questions of incubation, our food services director, our kitchen, our meat distributors, the department of health, and the news media ran through my head. Luckily, seconds later I realized that a urinalysis and 2 g of metronidazole do not diagnose or treat trichinosis but rather trichomonas. The resident, fully alert and oriented, reported no sexual activity in years and no gynecology evaluation. Chlamydia and gonorrhea studies were determined to be negative. The patient remains asymptomatic of vaginal discharge and muscle pains. Guess what? Further investigation reveals she keeps kosher.