The SARS-CoV-2 pandemic had a sudden, dramatic impact on healthcare. In Italy, since the beginning of the pandemic, colorectal cancer (CRC) screening programs have been forcefully suspended. We aimed ...to evaluate whether screening procedure delays can affect the outcomes of CRC screening.
We built a procedural model considering delays in the time to colonoscopy and estimating the effect on mortality due to up-stage migration of patients. The number of expected CRC cases was computed by using the data of the Italian screened population. Estimates of the effects of delay to colonoscopy on CRC stage, and of stage on mortality were assessed by a meta-analytic approach.
With a delay of 0-3 months, 74% of CRC is expected to be stage I-II, while with a delay of 4-6 months there would be a 2%-increase for stage I-II and a concomitant decrease for stage III-IV (P = .068). Compared to baseline (0-3 months), moderate (7-12 months) and long (> 12 months) delays would lead to a significant increase in advanced CRC (from 26% to 29% and 33%, respectively; P = .008 and P < .001, respectively). We estimated a significant increase in the total number of deaths (+12.0%) when moving from a 0-3-months to a >12-month delay (P = .005), and a significant change in mortality distribution by stage when comparing the baseline with the >12-months (P < .001).
Screening delays beyond 4-6 months would significantly increase advanced CRC cases, and also mortality if lasting beyond 12 months. Our data highlight the need to reorganize efforts against high-impact diseases such as CRC, considering possible future waves of SARS-CoV-2 or other pandemics.
Iron Metabolism in Cancer Progression Forciniti, Stefania; Greco, Luana; Grizzi, Fabio ...
International journal of molecular sciences,
03/2020, Letnik:
21, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Iron is indispensable for cell metabolism of both normal and cancer cells. In the latter, several disruptions of its metabolism occur at the steps of tumor initiation, progression and metastasis. ...Noticeably, cancer cells require a large amount of iron, and exhibit a strong dependence on it for their proliferation. Numerous iron metabolism-related proteins and signaling pathways are altered by iron in malignancies, displaying the pivotal role of iron in cancer. Iron homeostasis is regulated at several levels, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Mutations in
gene alter iron homeostasis leading to hereditary hemochromatosis and to an increased cancer risk because the accumulation of iron induces oxidative DNA damage and free radical activity. Additionally, the iron capability to modulate immune responses is pivotal in cancer progression. Macrophages show an iron release phenotype and potentially deliver iron to cancer cells, resulting in tumor promotion. Overall, alterations in iron metabolism are among the metabolic and immunological hallmarks of cancer, and further studies are required to dissect how perturbations of this element relate to tumor development and progression.
GPR120 (encoded by FFAR4 gene) is a receptor for long chain fatty acids, activated by ω-3 Polyunsaturated Fatty Acids (PUFAs), and expressed in many cell types. Its role in the context of colorectal ...cancer (CRC) is still puzzling with many controversial evidences. Here, we explored the involvement of epithelial GPR120 in the CRC development. Both in vitro and in vivo experiments were conducted to mimic the conditional deletion of the receptor from gut epithelium. Intestinal permeability and integrity of mucus layer were assessed by using Evans blue dye and immunofluorescence for MUC-2 protein, respectively. Microbiota composition, presence of lipid mediators and short chain fatty acids were analyzed in the stools of conditional GPR120 and wild type (WT) mice. Incidence and grade of tumors were evaluated in all groups of mice before and after colitis-associated cancer. Finally, GPR120 expression was analyzed in 9 human normal tissues, 9 adenomas, and 17 primary adenocarcinomas. Our work for the first time highlights the role of the receptor in the progression of colorectal cancer. We observed that the loss of epithelial GPR120 in the gut results into increased intestinal permeability, microbiota translocation and dysbiosis, which turns into hyperproliferation of epithelial cells, likely through the activation of β -catenin signaling. Therefore, the loss of GPR120 represents an early event of CRC, but avoid its progression as invasive cancer. these results demonstrate that the epithelial GPR120 receptor is essential to maintain the mucosal barrier integrity and to prevent CRC developing. Therefore, our data pave the way to GPR120 as an useful marker for the phenotypic characterization of CRC lesions and as new potential target for CRC prevention.
Summary Background The density of tumour-infiltrating lymphocytes (TIL) has been proposed as an independent predictor of outcome in patients with colorectal cancer. However, the relative roles of TIL ...density, nodal status, and microsatellite instability (MSI) in predicting tumour progression to metachronous metastasis remain to be elucidated. The aim of this study was to assess the relationship between the density of CD3+ TIL and the postsurgical occurrence of distant-organ metastases in a large series of patients with deeply invading and MSI-typed colorectal cancer. Methods Per cent areas of immunoreactivity due to CD3+ TIL at the invasive margin of the tumour (CD3+ TILIM ) were measured by computer-assisted image analysis in 286 tissue specimens from pT3 or pT4 MSI-tested colorectal cancer. Tissue samples were taken from consecutive patients who underwent resection at the IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy, from January, 1997, to November, 2004, for colorectal cancer with no evidence of metastasis at diagnosis. Occurrence of metachronous metastasis, disease-specific survival (DSS), and disease-free survival (DFS), were assessed retrospectively in relation to per cent immunoreactivity. Findings CD3+ TILIM density was higher in MSI colorectal cancer than in mismatch repair-system-proficient tumours (6·53% vs 2·19%; p<0·0001). At Cox analysis, higher CD3+ TILIM densities, colonic site, and absence of nodal involvement were significantly associated with a lower risk of metachronous metastasis, but only the interaction between CD3+ TILIM density and N-stage was significant on multivariate analysis (p=0·002). On separate analysis of node-negative colorectal cancer, increasing percentage of CD3+ immunoreactive area progressively reduced the risk of metachronous metastasis (<1%, reference; 1–5%, HR 0·28, 95% CI 0·10–0·81, p=0·02; >5%, 0·06, 0·01–0·48, p=0·008). Conversely, no significant association was seen between CD3+ immunoreactive area and risk of metachronous metastasis in node-positive colorectal cancer. Accordingly, CD3+ TILIM density was associated with a better DSS (p=0·01) and DFS (p=0·006) only in patients with node-negative colorectal cancer. In primary tumours that had progressed to metachronous metastasis, stage III tumours had higher CD3+ TILIM densities than stage II tumours (p=0·0004). Interpretation Metachronous metastases are unlikely to arise from node-negative colorectal cancers with a high-density CD3+ TILIM , whereas high densities of CD3+ TILIM are not associated with the absence of postsurgical metastasis in patients with node-positive colorectal cancer. Our data suggest that densities of CD3+ TILIM cannot be used as an independent predictor of clinical outcome in patients with stage III colorectal cancer and, at least for now, the tumour-node-metastasis classification should remain the preferred prognostic system. Our findings are consistent with a relationship between nodal involvement and tumour immunoevasion. Funding MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca), Target Project Oncologia 2006, and Alleanza Contro il Cancro.
AIM: To determine the efficacy of calcium supplementation in reducing the recurrence of colorectal adenomas.METHODS: We conducted a systematic review and meta-analysis of published studies. We ...searched Pub Med, Scopus, the Cochrane Library, the WHO International Clinical Trials Registry Platform, and the Clinical Trials.gov website, through December 2015. Randomized, placebo-controlled trials assessing supplemental calcium intake for the prevention of recurrence of adenomas were eligible for inclusion. Two reviewers independently selected studies based on predefined criteria, extracted data and outcomes(recurrence of colorectal adenomas, and advanced or "high-risk" adenomas), and rated each trial’s riskof-bias. Between-study heterogeneity was assessed, and pooled risk ratio(RR) estimates with their 95% confidence intervals(95%CI) were calculated using fixed- and random-effects models. To express the treatment effect in clinical terms, we calculated the number needed to treat(NNT) to prevent one adenoma recurrence. We also assessed the quality of evidence using GRADE.RESULTS: Four randomized, placebo-controlled trials met the eligibility criteria and were included. Daily doses of elemental calcium ranged from 1200 to 2000 mg, while the duration of treatment and follow-up of participants ranged from 36 to 60 mo. Synthesis of intention-to-treat data, for participants who had undergone follow-up colonoscopies, indicated a modest protective effect of calcium in prevention of adenomas(fixed-effects, RR = 0.89, 95%CI: 0.82-0.96; randomeffects, RR = 0.87, 95%CI: 0.77-0.98; high quality of evidence). The NNT was 20(95%CI: 12-61) to prevent one colorectal adenoma recurrence within a period of 3 to 5 years. On the other hand, the association between calcium treatment and advanced adenomas did not reach statistical significance(fixed-effects, RR = 0.92, 95%CI: 0.75-1.13; random-effects, RR = 0.92, 95%CI: 0.71-1.18; moderate quality of evidence). CONCLUSION: Our results suggest a modest chemopreventive effect of calcium supplements against recurrent colorectal adenomas over a period of 36 to 60 mo. Further research is warranted.
Inflammation and coagulation play crucial roles in the pathogenesis of multiple chronic inflammatory disorders. Growing evidence highlights a tight mutual network in which inflammation, coagulation, ...and fibrinolysis play closely related roles. Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), are chronic inflammatory conditions, characterized by a hypercoagulable state and prothrombotic conditions, and accompanied by abnormalities in coagulation. From a pathophysiological point of view, cells and molecules classically implicated in the physiological process of coagulation have now been shown to behave abnormally in IBD and possibly to also play an active role in disease pathogenesis and/or disease progression. This paper reviews studies performed on the coagulation profile and risk factors for thrombosis in IBD. In particular, an overview is provided of the epidemiology, clinical features, and etiology of thromboembolic complications in IBD. Furthermore, we review hemostatic abnormalities in IBD, as well as the cell types involved in such processes. Finally, we highlight the coagulation system as a dynamic participant in the multifaceted process of chronic intestinal inflammation. Overall, an overview is provided that the coagulation system represents an important, though previously underestimated, component of IBD pathogenesis, and may be a possible target for therapeutic intervention.
Introduction
Symptom association is important to distinguish non-erosive reflux disease NERD; abnormal oesophageal acid exposure time (AET) and/or positive symptom association from functional ...heartburn (FH; normal AET and negative symptom association). Asymptomatic patients during reflux monitoring are challenging as symptom association cannot be assessed.
Aim
To evaluate whether impedance-pH reflux patterns are useful to differentiate NERD from FH.
Methods
Endoscopy-negative reflux patients underwent impedance-pH off-therapy. Oesophageal AET, characteristics of reflux episodes and symptom association probability (SAP) were measured. Twenty patients asymptomatic during the first test repeated a second examination.
Results
Of 329 patients, 130 (40%) were pH-POS, 120 (36%) pH-NEG/SAP+ (hypersensitive oesophagus = HO) and 79 (24%) pH-NEG/SAP− (FH). Total and acid reflux episodes were significantly higher (
p
< 0.01) in pH-POS compared to pH-NEG/SAP+, pH-NEG/SAP− and healthy volunteers (HVs). Patients pH-NEG/SAP+ had a significantly increased number of weakly acidic reflux episodes compared to pH-POS, pH-NEG/SAP− and HVs (
p
< 0.01). The rate of proximal reflux episodes in pH-POS (50%) and pH-NEG/SAP+ (47%) was higher (
p
< 0.01) than in pH-NEG/SAP− (33%) and HVs (33%). Measuring AET, number of reflux episodes and percentage of proximal reflux events permits to identify FH in 70% of cases and HO in 80% of cases who repeated the examination.
Conclusion
In patients with normal AET and SAP+, increased number of weakly acidic reflux and higher rate of proximal reflux are the main discriminant features. There is large overlap between FH and HVs. These differences can be of help in diagnosing patients with normal oesophageal acid exposure who fail to have symptoms during MII-pH testing.
Background and aims:
Bowel damage BD will develop in the majority of Crohn’s disease CD patients. Recently, the Lémann Index LI was developed to measure BD.
Methods:
This was a prospective ...single-center cohort study. All included patients underwent full evaluation for bowel damage before starting anti-TNF therapy and every year thereafter. BD at baseline and during follow-up was measured using the LI. We assessed the impact of anti-TNF therapy on BD. We also assessed the sensitivity to change of the LI and the relationship between BD progression and disease outcomes, including the need for surgery.
Results:
Thirty CD patients were enrolled 13 on infliximab, 17 on adalimumab. Median baseline LI was 9.1 range, 1.6–34.1. Median follow up was 32.5 months range, 10–64.
By a ROC curve analysis, a LI >4.8 defined CD subjects with BD. Any change >0.3 in the LI was related to BD change AUC 0.98. During follow-up, 83% of subjects had BD regression and 17% had BD progression. Anti-TNF therapy significantly reduced LI at 12 months p=0.007. Subjects with BD progression were more likely to undergo major abdominal surgery through the follow-up period HR 0.19, p=0.005.
Conclusion:
The LI has good sensitivity to change. Anti-TNFs agents are able to reverse BD in some CD patients. BD progression as measured by the LI may be predictive of major abdominal surgery in these patients.
EUS-guided biopsy sampling is the method of choice for obtaining pancreatic tissue. Next-generation sequencing (NGS) has been applied to EUS-guided biopsy sampling and may classify patients based on ...specific molecular profiles. Our study aimed to compare side-by-side the diagnostic yield achievable by genetic identification of somatic mutations detected with NGS versus histologic and cytologic typing in locally advanced pancreatic carcinoma (LAPC) in samples acquired under EUS guidance.
We conducted a prospective comparative pilot study at Humanitas Research Hospital. The study included 33 patients referred for LAPC who underwent EUS-guided tissue acquisition using a 22-gauge Franseen needle. Material was obtained for both pathologic diagnosis and DNA extraction and targeted NGS analysis with the AmpliSeq Comprehensive Panel v3 (Illumina Inc, San Diego, Calif, USA). Twenty-one genes were prioritized for somatic mutation detection.
The final diagnosis was pancreatic ductal adenocarcinoma (PDAC) in all patients (100%). A macroscopic core was obtained in 30 patients (91%). In 3 lesions no cores adequate for histologic analysis were obtained, but cytologic analysis revealed tumoral cells from PDAC. DNA was extracted from 32 of 33 samples (97%), most of which (27/32) carried at least 2 clearly pathogenic mutations in different genes. Detection of K-ras mutation allowed for molecular diagnosis of PDAC in most of the patients (30/32).
In our study we demonstrated that proper tissue specimens obtained under EUS guidance allowed DNA sample extraction and subsequent NGS analysis in 97% of cases. These results support the potential role of NGS as a complementary diagnostic test to be implemented in association with standard diagnostic modalities. (Clinical trial registration number: NCT03578939.)
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