Aliment Pharmacol Ther 31, 1104–1111
Summary
Background Intestinal‐type gastric cancer (GC) still ranks among the high‐incidence, highly lethal malignancies. Atrophic gastritis is the cancerization ...field in which GC develops. The current histological reporting formats for gastritis do not include any (atrophy‐based) ranking of GC risk.
Aim To test the gastritis OLGA‐staging (Operative Link for Gastritis Assessment) in prognosticating neoplastic progression.
Methods Ninety‐three Italian patients were followed up for more than 12 years (range: 144–204 months). Clinical examinations, pepsinogen serology, endoscopy and histology (also assessing Helicobacter pylori status) were performed both at enrolment (T1) and at the end of the follow‐up (T2).
Results All invasive or intra‐epithelial gastric neoplasia were consistently associated with high‐risk (III/IV) OLGA stages. There was a significant inverse correlation between the mean pepsinogen ratio and the OLGA stage (test for trend; P < 0.001). OLGA‐staging at T1 predicted both the OLGA stage (Kaplan–Maier log‐rank test, P = 0.001) and the neoplasia at T2 (Kaplan–Maier log‐rank test, P = 0.001).
Conclusions This long‐term follow‐up study provides the first evidence that gastritis OLGA‐staging conveys relevant information on the clinico‐pathological outcome of gastritis and therefore for patient management. According to OLGA‐staging and H. pylori‐status, gastritis patients could be confidently stratified and managed according to their different cancer risks.
The prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data ...on immune microenvironment are very limited.
We retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated.
The analysis included 66 stage I–III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I–III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval CI: 0.16–0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17–0.81, p: 0.013) for multivariate analysis.
Immune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I–III SCLCs and warrants further investigation.
•The study depicts distribution of PD-L1 expression in small-cell lung cancer (SCLC) according to stage.•The study characterises tumour-infiltrating lymphocytes (TILs) in SCLC.•Independent positive prognostic impact of FOXP3-TILs is shown in stage I–III SCLCs.
The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic ...factor in different types of malignancies. However, the tumor–node–metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer.
Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders.
Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42–2.16, P < 0.0001, I2 = 60%; HR = 1.69, 95% CI 1.32–2.17, P < 0.0001, I2 = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65–2.61, P < 0.0001, I2 = 47%; HR = 2.31, 95% CI 1.54–3.44, P < 0.0001, I2 = 48%).
Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.
The term liquid biopsy (LB) refers to the use of various biological fluids as a surrogate for neoplastic tissue to achieve information for diagnostic, prognostic and predictive purposes. In the ...current clinical practice, LB is used for the identification of driver mutations in circulating tumor DNA derived from both tumor tissue and circulating neoplastic cells. As suggested by a growing body of evidence, however, there are several clinical settings where biological samples other than tissue could be used in the routine practice to identify potentially predictive biomarkers of either response or resistance to targeted treatments. New applications are emerging as useful clinical tools, and other blood derivatives, such as circulating tumor cells, circulating tumor RNA, microRNAs, platelets, extracellular vesicles, as well as other biofluids such as urine and cerebrospinal fluid, may be adopted in the near future. Despite the evident advantages compared with tissue biopsy, LB still presents some limitations due to both biological and technological issues. In this context, the absence of harmonized procedures corresponds to an unmet clinical need, ultimately affecting the rapid implementation of LB in clinical practice. In this position paper, based on experts’ opinions, the AIOM–SIAPEC-IAP–SIBIOC–SIF Italian Scientific Societies critically discuss the most relevant technical issues of LB, the current and emerging evidences, with the aim to optimizing the applications of LB in the clinical setting.
•In the current clinical practice LB is used for the identification of driver mutations in circulating tumor DNA (ctDNA).•New applications in tumors other than non-small-cell lung cancer (NSCLC) are emerging as useful clinical tools.•Other blood derivatives, together with other biofluids, are an active field of research and may be adopted in the near future.•Despite the evident advantages, liquid biopsy still presents limitations due to both biological and technological issues.•Standardization of the procedures needs to be addressed to ensure widespread implementation in clinical practice.
Mismatch repair (MMR) testing on all new cases of colorectal cancer (CRC) has customarily been preferably performed on surgical specimens, as more tissue is available; however, new clinical trials ...for the use of immune checkpoint inhibitors in the neoadjuvant setting require MMR testing on biopsy samples. This study aims at identifying advantages, disadvantages and any potential pitfalls in MMR evaluation on biopsy tissue and how to cope with them. The study is prospective-retrospective, recruiting 141 biopsies (86 proficient (p)MMR and 55 deficient (d)MMR) and 97 paired surgical specimens (48 pMMR; 49 dMMR). In biopsy specimens, a high number of indeterminate stains was observed, in particular for MLH1 (31 cases, 56.4%). The main reasons were a punctate nuclear expression of MLH1, relatively weak MLH1 nuclear expression compared to internal controls, or both (making MLH1 loss difficult to interpret), which was solved by reducing primary incubation times for MLH1. A mean of ≥ 5 biopsies had adequate immunostains, compared to ≤ 3 biopsies in inadequate cases. Conversely, surgical specimens rarely suffered from indeterminate reactions, while weaker staining intensity (
p
< 0.007) for MLH1 and PMS2 and increased patchiness grade (
p
< 0.0001) were seen. Central artefacts were almost exclusive to surgical specimens. MMR status classification was possible in 92/97 matched biopsy/resection specimen cases, and all of these were concordant (47 pMMR and 45 dMMR). Evaluation of MMR status on CRC biopsy samples is feasible, if pitfalls in interpretation are known, making laboratory-specific appropriate staining protocols fundamental for high-quality diagnoses.
Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies with an overall 5-year survival rate of <5%. Despite significant advances in treatment of the disease during ...the past decade, the median survival rate (∼6 months) has hardly improved, warranting the need to identify novel targets for therapeutic approaches.
Quantitative real time PCR, western blot analyses and immunohistochemical staining of tissue microarrays were used to analyse the expression of TTK gene in primary PDAC tissues and cell lines. To inhibit TTK kinase expression in a variety of pancreatic cancer cell lines, RNA interference was used. Functional roles of this kinase in the context of PDAC were studied using cell proliferation, viability and anchorage-independent growth assays. Western blotting, fluorescence-activated cell sorting analyses and fluorescence microscopy were used to gain mechanistic insight into the functional effects.
We show that the dual specificity kinase TTK (also known as Mps1), is strongly overexpressed in human PDAC. Functionally, cell proliferation was significantly attenuated following TTK knockdown, whereas apoptosis and necrosis rates were significantly increased. In addition, anchorage-independent growth, a hallmark of malignant transformation and metastatic potential, was strongly impaired in the absence of TTK gene function. Interestingly, immortalised normal pancreatic hTERT-HPNE cells were not affected by loss of TTK function. Mechanistically, these effects in cancer cells were associated with increased formation of micronuclei, suggesting that loss of TTK function in pancreatic cancer cells results in chromosomal instability and mitotic catastrophe. Taken together, our data show that TTK function is critical for growth and proliferation of pancreatic cancer cells, thus establishing this kinase as an interesting new target for novel therapeutic approaches in combating this malignancy.
Summary
Background
Among Western populations, the declining incidence of Helicobacter pylori infection coincides with a growing clinical impact of autoimmune gastritis.
Aims
To describe the ...histological phenotype of autoimmune gastritis, also to test the prognostic impact of OLGA staging in the autoimmune setting.
Methods
A single‐institutional series (spanning the years 2003–2011) of 562 consecutive patients (M:F ratio: 1:3.7; mean age = 57.6 ± 14.4 years) with serologically confirmed autoimmune gastritis underwent histology review and OLGA staging.
Results
Helicobacter pylori infection was ascertained histologically in 44/562 cases (7.8%). Forty six biopsy sets (8.2%) featured OLGA stages III–IV; they included all four cases of incidental epithelial neoplasia (three intraepithelial and one invasive; three of these four cases had concomitant H. pylori infection). There were 230 (40.9%) and 139 (24.7%) cases, respectively, of linear and micro‐nodular enterochromaffin‐like cell hyperplasia; 19 (3.4%) type I carcinoids were detected. The series included 116 patients who underwent repeated endoscopy/biopsy sampling (mean time elapsing between the two procedures = 54 months; range 24–108). Paired histology showed a significant (P = 0.009) trend towards a stage progression the stage increased in 25/116 cases (22%); it remained unchanged in 87/116 cases (75%).
Conclusions
In autoimmune gastritis, the cancer risk is restricted to high‐risk gastritis stages (III–IV), and is associated mainly with concomitant H. pylori infection. OLGA staging consistently depicts the time‐dependent organic progression of the autoimmune disease and provides key information for secondary gastric cancer prevention strategies.
Extra-nodal extension of nodal metastasis emerged as an important prognostic parameter for colorectal cancer, and future research/trial should consider colon and rectum cancer as only one entity to ...better investingate this issue.
Microsatellite instability (MSI) is a hypermutable phenotype that usually arises from either a germline mutation in components of the mismatch repair (MMR) machinery (i.e. hMLH1, MSH2, MSH6 and PMS2) ...in patients with Lynch syndrome (LS) or somatic hypermethylation of the hMLH1 promoter in sporadic carcinomas. In all colorectal cancers (CRC) is possible to identify the MMR deficiency through protein expression by immunoistochemistry (IHC). Recently, the predictive role of MMR deficiency in reduced chemotherapy benefit and the introduction of universal screening for Lynch syndrome suggest to include MMR testing into routine clinical practice. In this scenario is mandatory to update the minimal requirements for MMR IHC standardization and evaluation. According to international guidelines, these are the GIPAD and AIFEG suggestions for MMR IHC testing.
Introduction
Induction of tryptophan (TRP) catabolism is an adaptation mechanism to restrict excessive acute immune response in tissues. In the tumour microenvironment, TRP catabolism’s dysregulation ...plays an important role in local antitumour immune response suppression.
Aim
We investigated changes in the plasma concentrations of TRP and its metabolites in a cohort of colorectal cancer (CRC) patients at different tumour stages and in subjects at risk of developing CRC. TRP metabolites were assessed along kynurenine and serotonin pathways, and the activity of involved enzymes and their tissue expression were monitored.
Method
Plasmatic levels of tryptophan metabolites were quantified in 80 patients’ plasma samples by means of High-Pressure Liquid Chromatography coupled to UltraViolet/Fluorescence Detectors (HPLC-UV/FD), after a simple dilution step. Tissue
IDO1
gene expression during to the adenoma-carcinoma sequence and samples were obtained from formalin-fixed and paraffin-embedded (FFPE) normal colon and tumour tissues from a subset of patients (n = 21).
Results
Altered TRP concentrations were detected in plasma samples concomitant to pre-cancerous lesion and persisted during the adenoma-carcinoma transition. Moreover, the anatomical site of cancer lesions (colon or rectum) strongly influences the TRP metabolic profiles. Colon cancer patients exhibited increased TRP catabolism with respect to those affected by rectal cancer, suggesting that TRP’s metabolism alterations play an important role in the onset and progression of colon cancer, but not in those of rectal cancer.
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