Evaluation of the accuracy of serum MMP-9 as a test for colorectal cancer in a primary care population

Background  

Bowel cancer is common and is a major cause of death. Meta-analysis of randomised controlled trials estimates that screening for colorectal cancer using faecal occult blood (FOB) test reduces mortality from colorectal cancer by 16%. However, FOB testing has a low positive predictive value, with associated unnecessary cost, risk and anxiety from subsequent investigation, and is unacceptable to a proportion of the target population. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP-9) have been found to be associated with colorectal cancer, and this can be measured from a blood sample. Serum MMP-9 is potentially an accurate, low risk and cost-effective population screening tool. This study aims to evaluate the accuracy of serum MMP-9 as a test for colorectal cancer in a primary care population.     

Assessing the value of matrix metalloproteinase 9 (MMP9) in improving the appropriateness of referrals for colorectal cancer

Background:

A blood test may be an effective means of improving the appropriateness of referrals for symptomatic patients referred to specialist colorectal clinics. We evaluated the accuracy of a serum matrix metalloproteinase (MMP9) test in indicating colorectal cancer or its precursor conditions in a symptomatic population.

Methods:

Patients aged over 18, referred urgently or routinely to secondary care following primary care presentation with colorectal symptoms completed a questionnaire and provided a blood sample for serum MMP9 estimation. Univariate analysis and logistic regression modelling investigated the association between presenting symptoms, MMP9 measurements and the diagnostic outcome of patient investigations, in order to derive the combination of factors which best predicted a high risk of malignancy.

Results:

Data were analysed for 1002 patients. Forty-seven cases of neoplasia were identified. Age, male gender, absence of anal pain, diabetes, blood in stools, urgent referral, previous bowel polyps and previous bowel cancer were significantly associated with neoplasia. Matrix metalloproteinase 9 measurements were not found to be associated with significant colorectal pathology.

Conclusion:

This study, despite robust sampling protocols, showed no clear association between MMP9 and colorectal neoplasia. Matrix metalloproteinase 9 therefore appears to have little value as a tool to aid referral decisions in the symptomatic population.     

MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients

Background:

Upregulation of the matrix metalloproteinases MMP-2 and MMP-9 in various cancers has been associated with worse survival of the patients.

Methods:

We assessed MMP-2 and MMP-9 levels in normal colorectal mucosa from colorectal cancer patients in relation to the course of the disease.

Results:

A high protein expression of MMP-2 as well as MMP-9 in normal mucosa was found to be correlated with worse 5-year survival. The combination of both parameters was an even stronger prognostic factor. These protein levels were found not to be related to the corresponding single nucleotide polymorphisms of MMP-2 (−1306C>T) and MMP-9 (−1562C>T). Multivariate analyses indicated that the MMP-2 and MMP-9 levels in normal mucosa are prognostic for survival, independent of TNM classification.

Conclusion:

MMP-2 and MMP-9 levels in normal mucosa are indicative of the course of disease in colorectal cancer patients.     

Prognostic Significance of Matrix Metalloproteinase-9 (MMP-9) in Stage II Colorectal Carcinoma

Background

Approximately 30% of all colorectal cancer patients are diagnosed with stage II disease. Adjuvant therapy is not widely recommended. However, it is well-established that a subgroup of patients with stage II is at high risk for recurrence within their life time and should be considered for adjuvant chemotherapy. The present work was designed to assess the value of matrix metalloproteinase-9 (MMP-9) as a predictor of disease outcome in a series of 202 stage II colorectal cancer (CRC) patients with long-term follow-up.

Methods

The present study comprises a series of 202 patients who underwent bowel resection for stage II CRC at Turku University Hospital. Archival paraffin-embedded CRC tissue samples were used to prepare tissue microarray blocks for immunohistochemical staining with MMP-9 antibody.

Results

Forty-eight percent of all CRC samples were positive for MMP-9. There was no significant correlation between MMP-9 expression and age, depth of invasion, and lymph node status. However, MMP-9 expression was significantly related to histological grade (p?=?0.03) and location of the tumor (p?=?0.01), therefore, being lower in high-grade tumors and most intense in carcinomas of the descending colon and rectum. Tumors with high MMP-9 expression showed a higher recurrence rate than tumors with low expression (p?=?0.02). MMP-9 negative tumors had a more favorable disease-free survival (DFS) than those expressing MMP-9 (p?=?0.03). The same was true with disease-specific survival (DSS; p?=?0.02) as well, high expression of MMP-9 being associated with shorter survival rates. In multivariate (Cox) survival analysis, MMP-9 expression proved to be an independent predictor of DFS, but not DSS, which was predicted by age and sex only.

Conclusion

Quantification of MMP-9 expression seems to provide valuable prognostic information in stage II CRC, particularly, in selecting the patients at high risk for recurrent disease who might benefit from adjuvant therapy.     

Thrombosis of abdominal aorta during cisplatin-based chemotherapy of testicular seminoma - a case report

Background

Bowel cancer is common and a major cause of death. The NHS is currently rolling out a national bowel cancer screening programme that aims to cover the entire population by 2010. The programme will be based on the Faecal Occult Blood test (FOBt) that reduces mortality from colon cancer by 16%. However, FOB testing has a relatively low positive predictive value, with associated unnecessary cost, risk and anxiety from subsequent investigation, and is unacceptable to a proportion of the target population. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP9) have been found to be associated with colorectal cancer, and this can be measured from a blood sample. MMP9 has potential for detecting those at risk of having colorectal cancer. The aim of this study is to assess whether MMP9 estimation enhances the predictive value of a positive FOBt.

Methods and design

FOBt positive people aged 60–69 years attending the Wolverhampton NHS Bowel Cancer Screening Unit and providing consent for colonoscopy will be recruited. Participants will provide a blood sample prior to colonoscopy and permission for collection of the clinical outcome from screening unit records. Multivariate logistic regression analyses will determine the independent factors (patient and disease related, MMP9) associated with the prediction of neoplasia.

Discussion

Colorectal cancer is a major cause of morbidity and mortality. Pilot studies have confirmed the feasibility of the national cancer screening programme that is based on FOBt. However, the test has high false positive rates. MMP9 has significant potential as a marker for both adenomas and cancers. This study is to examine whether using MMP9 as an adjunct to FOBt improves the accuracy of screening and reduces the number of false positive tests that cause anxiety and require invasive and potentially harmful investigation.     

Is “pelvic radiation disease” always the cause of bowel symptoms following prostate cancer intensity-modulated radiotherapy?

Background

Pelvic radiation disease (PRD) also widely known as “radiation proctopathy” is a well recognised late side-effect following conventional prostate radiotherapy. However, endoscopic evaluation and/or specialist referral for new or persistent post-prostate radiotherapy bowel symptoms is not routine and serious diagnoses may potentially be missed. Here we report a policy of endoscopic evaluation of bowel symptoms persisting >90 days post radiotherapy for prostate cancer.

Methods and materials

A consecutive series of 102 patients who had radical prostate intensity-modulated radiotherapy (IMRT)/image-guided radiotherapy (IGRT) and who had new or ongoing bowel symptoms or positive faecal occult blood tests (FOBT) on follow up visits more than three months after treatment, were referred for endoscopic examination. All but one (99%) had full colonoscopic investigation.

Results

Endoscopic findings included gastric/colonic/rectal polyps (56%), diverticular disease (49%), haemorrhoids (38%), radiation proctopathy (29%), gastritis/oesophagitis (8%) and rarer diagnoses, including bowel cancer which was found in 3%. Only four patients (4%) had radiation proctopathy without associated pathology and 65 patients (63%) had more than one diagnosis. If flexible sigmoidoscopy alone were used, 36.6% of patients and 46.6% patients with polyp(s) would have had their diagnoses missed.

Conclusions

Our study has shown that bowel symptoms following prostate IMRT/IGRT are due to numerous diagnoses other than PRD, including malignancy. Routine referral pathways should be developed for endoscopic evaluation/specialist review for patients with new or persistent bowel symptoms (or positive FOBT) following prostate radiotherapy. This recommendation should be considered for incorporation into national guidelines.     

Radiation-induced bowel injury: the impact of radiotherapy on survivorship after treatment for gynaecological cancers

Background:

The number of women surviving cancer who live with symptoms of bowel toxicity affecting their quality of life continues to rise. In this retrospective study, we sought to describe and analyse the presenting clinical features in our cohort, and evaluate possible predictors of severity and chronicity in women with radiation-induced bowel injury after treatment for cervical and endometrial cancers.

Methods:

Review of records of 541 women treated within the North London Gynaecological Cancer Network between 2003 and 2010 with radiotherapy with or without chemotherapy for cervical and endometrial cancer identified 152 women who reported significant new bowel symptoms after pelvic radiation.

Results:

Factor analysis showed that the 14 most common and important presenting symptoms could be ‘clustered'' into 3 groups with predictive significance for chronicity and severity of disease. Median follow-up for all patients was 60 months. Univariate analysis showed increasing age, smoking, extended field radiation, cervical cancer treatment and the need for surgical intervention to be significant predictors for severity of ongoing disease at last follow-up. On multivariate analysis, only age, cancer type (cervix) and symptom combinations/‘cluster'' of (bloating, flatulence, urgency, rectal bleeding and per-rectal mucus) were found to be significant predictors of disease severity. Fifteen (19%) women in the cervical cancer group had radiation-induced bowel injury requiring surgical intervention compared with five (6.7%) in the endometrial cancer group.

Conclusion:

Women with cervical cancer are younger and appear to suffer more severe symptoms of late bowel toxicity, whereas women treated for endometrial cancer suffer milder more chronic disease. The impact of radiation-induced bowel injury and the effect on cancer survivorship warrants further research into investigation of predictors of severe late toxicity. There is a need for prospective trials to aid early diagnosis, while identifying the underlying patho-physiological process of the bowel injury.     

A randomised controlled trial of a cognitive behavioural intervention for women who have menopausal symptoms following breast cancer treatment (MENOS 1): Trial protocol

Background  

This trial aims to evaluate the effectiveness of a group cognitive behavioural intervention to alleviate menopausal symptoms (hot flushes and night sweats) in women who have had breast cancer treatment. Hot flushes and night sweats are highly prevalent but challenging to treat in this population. Cognitive behaviour therapy has been found to reduce these symptoms in well women and results of an exploratory trial suggest that it might be effective for breast cancer patients. Two hypotheses are tested:     

Assessment of acute bowel function after radiotherapy for prostate cancer: Is it accurate enough?

Background and purpose

Pelvic radiotherapy for prostate cancer can be associated with bowel toxicity, which may have a significant impact on quality of life. Our aim was to assess the adequacy of the tools currently used to assess bowel symptoms after radiotherapy, including physician and patient reported outcomes. This sub-study on acute toxicity was part of a prospective trial assessing long-term bowel dysfunction.

Materials and methods

Between February 2013 and July 2015, 75 patients with prostate cancer who received radiotherapy completed the LENT/SOMA and the EPIC questionnaires baseline and 2 weeks after the treatment. The Bristol stool scale and two additional questions on faecal urgency were added. Physicians assessed toxicity using Common Terminology Criteria for Adverse Events v.4.0. Agreement between patients and clinicians was assessed using the Cohen’s κ coefficient.

Results

Acute toxicity during radiotherapy was very low. The pattern of overall bowel bother was similar before and after treatment. Faecal urgency significantly increased after radiotherapy compared to baseline but was only detected by the additional questions and not by the physicians or the patient-reported outcomes (PRO) questionnaires. Correlation between physician and PRO was poor for most symptoms.

Conclusion

Bowel symptoms such as urgency may remain undetected by usual tools to assess toxicity after radiotherapy. Assessment of bowel toxicity should be reappraised in order to identify those patients who may have symptoms with an impact on their quality of life.

     

Activity and expression of urokinase-type plasminogen activator and matrix metalloproteinases in human colorectal cancer

Background  

Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (uPA) are involved in colorectal cancer invasion and metastasis. There is still debate whether the activity of MMP-2 and MMP-9 differs between tumors located in the colon and rectum. We designed this study to determine any differences in the expression of MMP-2, MMP-9 and uPA system between colon and rectal cancer tissues.     

Development of a cancer of the large bowel following radiotherapy for cancer of the uterine cervix

Eight patients with a colorectal cancer, following radiotherapy for a cervical cancer have been analyzed. A total of 9 lesions in the large bowel were found. Four were located in the rectum. The average interval between radiation and the diagnosis of a second tumor was 9 years and 6 months. Four patients had had a post-irradiation interval of more than 10 years. In 7 resected specimens, histologic alterations were seen, such as atrophy or the erosion of the mucosal layer around the tumor. Radiotherapy may have contributed to the development of the colorectal cancer in some of these patients. Thus, attention should be paid to monitoring patients who have received radiotherapy for a cervical cancer, since the development of a colorectal cancer after pelvic radiotherapy may occur.     

Factors affecting attitudes toward colorectal cancer screening in the primary care population

Background:

Colorectal cancer (CRC) is a major cause of death in the United Kingdom. Regular screening could significantly reduce CRC-related morbidity and mortality. However, screening programmes in the United Kingdom have to date seen uptake rates of less than 60%. Attitudes towards screening are the primary factors determining patient uptake.

Methods:

A questionnaire was sent to people aged 50–69 years who were registered with general practices in the West Midlands. A total of 11 355 people (53%) completed the questionnaire. Multivariable logistic regression analyses were performed to identify those factors (gender, age, ethnicity, deprivation, number of symptoms, and their duration) that most strongly contributed to negative/positive attitudes in the primary care population.

Results:

Fourteen percent of respondents had a negative attitude towards screening. Men, older people, and those with Indian ethnic backgrounds were more likely to have negative attitudes toward screening, whereas people with Black-Caribbean ethnic background, people with multiple symptoms and those reporting abdominal pain, bleeding, and tiredness were more likely to have a positive attitude.

Conclusion:

Culturally relevant screening strategies should aim to increase knowledge of the symptoms and signs related to bowel cancer among South Asian ethnic groups in the United Kingdom. It is also important to find ways to increase the acceptability of screening among asymptomatic patients.     

Clinical significance of Neutrophil gelatinase-associated lipocalin(NGAL) expression in primary rectal cancer

Background  

Emerging evidence has demonstrated that Neutrophil gelatinase-associated lipocalin (NGAL) is up-regulated in multiple malignancies, including oesophagus cancer, and plays a critical role in tumorigenesis and progression. However, till now, little is known about the role of NGAL in human rectal cancer. Its association with clinicopathologic characteristics and expression of MMP-9, one of its target genes, has not been reported systematically in rectal cancer. Therefore, to further determine the potential involvement of NGAL in rectal cancer, we have evaluated the expression level of NGAL mRNA by real time RT-PCR, and further elucidated the correlation of NGAL mRNA expression with clinicopathologic features and MMP-9 in rectal cancer.     

Determining the levels of matrix metalloproteinase-9 in portal and peripheral blood is useful for predicting liver metastasis of colorectal cancer

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is one of the MMPs that play an important role in cancer invasion and metastasis. Increased levels of MMP-9 in tumor tissue have been found to correlate with advanced stages of colorectal cancer. However, the clinical significance of determining the levels of MMP-9 in blood samples from patients with colorectal cancer has not yet been clarified. The purpose of this study was to clarify the relationship between the clinicopathological variables of colorectal cancer and MMP-9 levels of drainage (portal) or peripheral venous blood and to examine whether this assay would be useful for predicting liver metastasis. METHODS: Blood samples were obtained from peripheral and drainage veins of 102 patients with colorectal cancer during surgery and the plasma levels of MMP-9 were determined by a one-step sandwich enzyme immunoassay. RESULTS: The levels of portal MMP-9 were significantly higher than those of peripheral blood (P < 0.01, n = 102). The levels of MMP-9 in peripheral venous blood did not correlate with any of the 12 clinicopathological variables examined, while the levels of MMP-9 in portal blood correlated with macroscopic type of the primary tumor (P = 0.02), Dukes' stage (P = 0.03), liver metastasis (P < 0.01) and lymph node metastasis (P = 0.02). By setting the cutoff ratio of portal to peripheral MMP-9 levels at 1.6 in patients with curative resection (n = 73), elevated ratios predicted subsequent emergence of liver metastases with 77.8% sensitivity, 81.3% specificity and 80.8% accuracy. CONCLUSION: The results suggest that synchronous determination of the levels of MMP-9 in portal and peripheral blood would be useful for selecting colorectal cancer patients at high risk of hepatic recurrence.     

Risk factors for delay in symptomatic presentation: a survey of cancer patients

Background:

Delay in symptomatic presentation leading to advanced stage at diagnosis may contribute to poor cancer survival. To inform public health approaches to promoting early symptomatic presentation, we aimed to identify risk factors for delay in presentation across several cancers.

Methods:

We surveyed 2371 patients with 15 cancers about nature and duration of symptoms using a postal questionnaire. We calculated relative risks for delay in presentation (time from symptom onset to first presentation >3 months) by cancer, symptoms leading to diagnosis and reasons for putting off going to the doctor, controlling for age, sex and deprivation group.

Results:

Among 1999 cancer patients reporting symptoms, 21% delayed presentation for >3 months. Delay was associated with greater socioeconomic deprivation but not age or sex. Patients with prostate (44%) and rectal cancer (37%) were most likely to delay and patients with breast cancer least likely to delay (8%). Urinary difficulties, change of bowel habit, systemic symptoms (fatigue, weight loss and loss of appetite) and skin symptoms were all common and associated with delay. Overall, patients with bleeding symptoms were no more likely to delay presentation than patients who did not have bleeding symptoms. However, within the group of patients with bleeding symptoms, there were significant differences in risk of delay by source of bleeding: 35% of patients with rectal bleeding delayed presentation, but only 9% of patients with urinary bleeding. A lump was a common symptom but not associated with delay in presentation. Twenty-eight percent had not recognised their symptoms as serious and this was associated with a doubling in risk of delay. Embarrassment, worry about what the doctor might find, being too busy to go to the doctor and worry about wasting the doctor''s time were also strong risk factors for delay, but were much less commonly reported (<6%).

Interpretation:

Approaches to promote early presentation should aim to increase awareness of the significance of cancer symptoms and should be designed to work for people of the lowest socioeconomic status. In particular, awareness that rectal bleeding is a possible symptom of cancer should be raised.     

Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies

Background:

A majority of patients with pancreatic malignancies, including both pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (pNETs), present with advanced disease due to a lack of specific symptoms and current diagnostic limitations, making this disease extremely difficult to detect. Our goal was to determine whether urinary matrix metalloproteases (uMMPs) and/or their endogenous inhibitors, urinary tissue inhibitor of metalloproteases (uTIMPs), could be detected in the urine of patients with pancreatic malignancies and whether they may serve as independent predictors of disease status.

Methods:

Retrospective analyses of urine samples (n=139) from PDAC and pNET patients as well as age- and sex-matched controls were conducted. Urinary MMP-2 and uTIMP-1 levels were determined using ELISA and zymography. Biomarker expression in tumour and normal pancreatic tissues was analysed via immunohistochemistry (IHC).

Results:

Multivariable logistic regression analyses indicated that, when controlling for age and sex, uMMP-2 (P<0.0001) and uTIMP-1 (P<0.0001) but not uMMP-9, were significant independent predictors for distinguishing between PDAC patients and healthy controls. Our data also indicated that uMMP-2 was an independent predictor of the presence of pNET. In addition, uTIMP-1 levels could differentiate the two cancer groups, PDAC and pNET, respectively. Immunohistochemistry analysis confirmed that MMP-2 and TIMP-1 protein expression is significantly upregulated in PDAC tissue compared with the normal pancreas.

Conclusions:

Taken together, our results suggest that the detection of uMMP-2 and uTIMP-1 may have diagnostic value in the detection of pancreatic malignancies and that uTIMP-1 may be useful in distinguishing between pancreatic adenocarcinoma and neuroendocrine tumours.