National screening for colorectal cancer is associated with stage shift to earlier diagnosis.

BACKGROUND: Australia's National Bowel Cancer Screening Program consists of an immunohistochemical faecal occult blood test, targeting adults aged 50-74. Existing literature supports the principle of early detection of colorectal cancer (CRC) via national screening, but little is known about the association between colonoscopy or polypectomy rates and CRC stage over time. The aim of this study is to identify the longitudinal change to colonoscopy and polypectomy rates, and any stage shift associated with this screening program. METHODS: A retrospective data-linkage study was performed using the Australian national health database (Medicare) to obtain colonoscopy and polypectomy rates between 1998 and 2017. A second prospective database of CRC resection specimens was analysed for this period. The cohort was divided based on time intervals related to the National Bowel Cancer Screening Program: pre-commencement 1998-2006 (Period A), immediately post-commencement 2007-2011 (Period B), and subsequent years 2012-2017 (Period C). Linear regression was used to test relation between annualized predictor and response variables. RESULTS: Annual colonoscopy rates doubled, and polypectomy rates tripled during the study (P < 0.001). Annual colonoscopy rate correlated to a lower T-stage (P = 0.038) and lower N-stage (P = 0.026), and there was a 7% increase in early CRC (stage I-II) in Period C (P < 0.001). Across the study period there was also a significant increase in right-sided tumours, and concurrent MMR deficiency and BRAF mutation. CONCLUSION: Polypectomy and colonoscopy rates increased after the introduction of the National Bowel Cancer screening program. There was a clinically significant shift to earlier CRC stage which manifested 5 years after its implementation.

Demographics and risk factors that influence the prevalence of depression in patients attending cardiac rehabilitation.

Depression has been associated with adverse outcomes in patients with cardiac disease. Data on its prevalence and the factors influencing it are limited in the cardiac rehabilitation program (CRP) setting. To elucidate the prevalence of and the factors that influence depression in patients attending CRP. Patients attending the CRP from 2003 to 2016 were included in the study. All patients had a Beck Depression Inventory-II (BDI-II) performed prior to commencement in CRP and were followed longitudinally. The BDI-II for the 4989 patients were as follows: 0 to 13 (normal) = 3623 (72%); 14 to 19 (mild depression) = 982 (20%); 20 to 28 (moderate depression) = 299 (6%); 29 to 63 (severe depression) = 85 (2%). The BDI-II (mean ± SEM) for males (mean age: 60.8 ± 0.1 years) and females (mean age: 63.4 ± 0.3 years, P < .001) were 7.0 ±â€…0.1 and 8.5 ±â€…0.2 (P < .001), respectively. Elevated BDI-II scores (14-63) were more common in type 1 (41.1%) and type 2 (30.5%) diabetics than nondiabetics (25.7%). Similarly, elevated scores were more common in smokers (36.1%) than never-smokers (24.7%). The BDI-II scores for Caucasians, South Asians, and East Asians were 7.3 ±â€…0.1, 8.0 ±â€…0.3, and 7.0 ±â€…0.3 respectively (P = .01 for CA vs SA by 1-way ANOVA and least significant difference test). The prevalence of depression is high in patients attending CRP affecting 28% of the population. BDI-II is a simple validated screening tool that can be applied to patients attending CRP. Diabetics, current smokers, and South Asians all had a higher prevalence of depression.

ALK and ROS1 overexpression is very rare in colorectal adenocarcinoma.

Crizotinib, a small molecule tyrosine kinase inhibitor, has shown tremendous promise in the treatment of lung adenocarcinomas harboring either ALK or ROS1 rearrangements. Recently, small studies of colorectal carcinomas (CRCs) have suggested an incidence of EML4-ALK translocations of 0.4% to 2.4% and FIG-ROS1 translocations of 0.8%. In lung cancer, screening immunohistochemical staining for ALK and ROS1 has been validated as highly sensitive for these translocations, but this has not been investigated in CRC. We therefore sought to investigate the incidence of ALK and ROS1 overexpression as detected by immunohistochemical staining in a large cohort of CRCs. Of the 1889 CRCs, only 1 case (0.05%) demonstrated diffuse strong positive staining for ALK, whereas 14 (0.7%) showed weak nonspecific staining; the remainder were negative. The 1 positive case was confirmed to harbor an ALK rearrangement by fluorescent in situ hybridization (FISH), whereas the 14 tumors with weak staining were FISH-negative. The ALK positive case demonstrated positive expression in all dysplastic and malignant cells indicating that the translocation was an early clonal event. No cases were positive for ROS1 by immunohistochemical staining, although 2 cases did show some nonspecific staining and were shown to be negative for ROS1 translocation by FISH. We conclude that although diffuse strong positive staining for ALK is likely to be highly specific for ALK rearrangement in CRC, both ALK and ROS1 immunohistochemical staining are very low-yield tests and difficult to justify in the routine clinical setting.

Restoring TGFbeta function in microsatellite unstable (MSI-H) colorectal cancer reduces tumourigenicity but increases metastasis formation.

BACKGROUND: TGFbeta is an important cell growth regulator which may have a role in metastasis formation. Microsatellite unstable (MSI-H) colon cancer serves as a unique model to demonstrate this as most MSI-H colon cancers have a mutation in the transforming growth factor beta receptor II (TGFbetaRII) gene and a low metastatic rate. AIMS: To demonstrate an increase in invasion and metastasis in a MSI-H colorectal cancer cell line with a known mutation in TGFbetaRII. MATERIALS AND METHODS: By restoring the wild-type TGFbetaRII gene in the KM12C MSI-H colorectal carcinoma cell line with a known mutation in TGFbetaRII, we have demonstrated that both invasion and metastasis in this cell line was significantly increased. A mouse metastatic model have shown that liver metastases were increased in mice inoculated with cells containing a wild-type TGFbetaRII gene (42% for the transfected group compared with 15% for the control group; p = 0.0379), despite a reduction in the size of primary tumours. CONCLUSIONS: This study highlights an important mechanism which may contribute to the low metastatic rate of MSI-H colon cancers and demonstrates the importance of TGFbeta signalling in metastasis formation. Previous studies involving breast cancer cell lines have shown that blocking TGFbeta signalling results in a reduction in metastasis formation. This study is the first study to use a cell line with a low metastatic rate and TGFbetaRII mutations to demonstrate that restoring TGFbeta signalling increases the metastatic rate.

Liver iron concentration and fibrosis in a cohort of transfusion-dependent patients on long-term desferrioxamine therapy.

Secondary iron overload is associated with significant mortality and morbidity. Although new, less invasive techniques are becoming available, the most acceptable and readily accessible way to assess iron overload is to measure hepatic iron by liver biopsy. In this study, we report on serial liver biopsies (at least 2) in a cohort of transfusion-dependent patients (49) on long-term desferrioxamine treatment. There was no significant change in liver iron concentrations (LIC) even in the medication-compliant patients, although there was an upward trend (not statistically significant) in the poorly compliant patients. Fibrosis was present in both HCV RNA-positive and -negative patients, but was more common in positive patients and there was also a significant relationship between fibrosis and hepatic iron concentration. Liver iron levels appear to be maintained in patients who are compliant to desferrioxamine treatment, but overall there is little evidence of significant improvement in liver iron in these patients and in the group as a whole.