Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide ...disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.
Despite major improvements concerning its diagnosis and treatment,pancreatic ductal adenocarcinoma(PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology,as interface ...discipline between basic and clinical medicine,has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition,by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC,a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC.This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results.Finally,recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response.The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.
Oncogene-Induced DNA Damage Model for Cancer Development Halazonetis, Thanos D; Gorgoulis, Vassilis G; Bartek, Jiri
Science (American Association for the Advancement of Science),
03/2008, Letnik:
319, Številka:
5868
Journal Article
Recenzirano
Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with ...cell proliferation. Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. In addition, in precancerous lesions, these DNA DSBs activate p53, which, by inducing apoptosis or senescence, raises a barrier to tumor progression. Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.
DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, ...all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.
The purpose of this clinical practice update expert review is to define the key principles in the diagnosis and management of low-grade dysplasia (LGD) in Barrett’s esophagus patients.
The best ...practices outlined in this review are based on relevant publications, including systematic reviews and expert opinion (when applicable).
Practice Advice 1: The extent of Barrett’s esophagus should be defined using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and visible lesions (nodularity, ulceration) when present.
Practice Advice 2: Given the significant interobserver variability among pathologists, the diagnosis of Barrett’s esophagus with LGD should be confirmed by an expert gastrointestinal pathologist (defined as a pathologist with a special interest in Barrett’s esophagus–related neoplasia who is recognized as an expert in this field by his/her peers).
Practice Advice 3: Expert pathologists should report audits of their diagnosed cases of LGD, such as the frequency of LGD diagnosed among surveillance patients and/or the difference in incidence of neoplastic progression among patients diagnosed with LGD vs nondysplastic Barrett’s esophagus.
Practice Advice 4: Patients in whom the diagnosis of LGD is downgraded to nondysplastic Barrett’s esophagus should be managed as nondysplastic Barrett’s esophagus.
Practice Advice 5: In Barrett’s esophagus patients with confirmed LGD (based on expert gastrointestinal pathology review), repeat upper endoscopy using high-definition/high-resolution white-light endoscopy should be performed under maximal acid suppression (twice daily dosing of proton pump inhibitor therapy) in 8–12 weeks.
Practice Advice 6: Under ideal circumstances, surveillance biopsies should not be performed in the presence of active inflammation (erosive esophagitis, Los Angeles grade C and D). Pathologists should be informed if biopsies are obtained in the setting of erosive esophagitis and if pathology findings suggest LGD, or if no biopsies are obtained, surveillance biopsies should be repeated after the anti-reflux regimen has been further intensified.
Practice Advice 7: Surveillance biopsies should be performed in a four-quadrant fashion every 1–2 cm with target biopsies obtained from visible lesions taken first.
Practice Advice 8: Patients with a confirmed histologic diagnosis of LGD should be referred to an endoscopist with expertise in managing Barrett’s esophagus–related neoplasia practicing at centers equipped with high-definition endoscopy and capable of performing endoscopic resection and ablation.
Practice Advice 9: Endoscopic resection should be performed in Barrett’s esophagus patients with LGD with endoscopically visible abnormalities (no matter how subtle) in order to accurately assess the grade of dysplasia.
Practice Advice 10: In patients with confirmed Barrett’s esophagus with LGD by expert GI pathology review that persists on a second endoscopy, despite intensification of acid-suppressive therapy, risks and benefits of management options of endoscopic eradication therapy (specifically adverse events associated with endoscopic resection and ablation), and ongoing surveillance should be discussed and documented.
Practice Advice 11: Endoscopic eradication therapy should be considered in patients with confirmed and persistent LGD with the goal of achieving complete eradication of intestinal metaplasia.
Practice Advice 12: Patients with LGD undergoing surveillance rather than endoscopic eradication therapy should undergo surveillance every 6 months times 2, then annually unless there is reversion to nondysplastic Barrett’s esophagus. Biopsies should be obtained in 4-quadrants every 1–2 cm and of any visible lesions.
Practice Advice 13: In patients with Barrett’s esophagus–related LGD undergoing ablative therapy, radiofrequency ablation should be used.
Practice Advice 14: Patients completing endoscopic eradication therapy should be enrolled in an endoscopic surveillance program. Patients who have achieved complete eradication of intestinal metaplasia should undergo surveillance every year for 2 years and then every 3 years thereafter to detect recurrent intestinal metaplasia and dysplasia. Patients who have not achieved complete eradication of intestinal metaplasia should undergo surveillance every 6 months for 1 year after the last endoscopy, then annually for 2 years, then every 3 years thereafter.
Practice Advice 15: Following endoscopic eradication therapy, the biopsy protocol of obtaining biopsies in 4 quadrants every 2 cm throughout the length of the original Barrett’s esophagus segment and any visible columnar mucosa is suggested.
Practice Advice 16: Endoscopists performing endoscopic eradication therapy should report audits of their rates of complete eradication of dysplasia and intestinal metaplasia and adverse events in clinical practice.
Sessile serrated polyps (SSPs) could account for a substantial proportion of colorectal cancers. We aimed to increase clarity on SSP prevalence and clinical features.
We performed a systematic review ...of MEDLINE, Web of Science, Embase, and Cochrane databases for original studies published in English since 2000. We included studies of different populations (United States general or similar), interventions (colonoscopy, autopsy), comparisons (world regions, alternative polyp definitions, adenoma), outcomes (prevalence, clinical features), and study designs (cross-sectional). Random-effects regression was used for meta-analysis where possible.
We identified 74 relevant colonoscopy studies. SSP prevalence varied by world region, from 2.6% in Asia (95% confidence interval CI, 0–5.9) to 10.5% in Australia (95% CI, 2.8–18.2). Prevalence values did not differ significantly between the United States and Europe (P = .51); the pooled prevalence was 4.6% (95% CI, 3.4–5.8), and SSPs accounted for 9.4% of polyps with malignant potential (95% CI, 6.6–12.3). The mean prevalence was higher when assessed through high-performance examinations (9.1%; 95% CI, 4.0–14.2; P = .04) and with an alternative definition of clinically relevant serrated polyps (12.3%; 95% CI, 9.3–15.4; P < .001). Increases in prevalence with age were not statistically significant, and prevalence did not differ significantly by sex. Compared with adenomas, a higher proportion of SSPs were solitary (69.0%; 95% CI, 45.9–92.1; P = .08), with diameters of 10 mm or more (19.3%; 95% CI, 12.4–26.2; P = .13) and were proximal (71.5%; 95% CI, 63.5–79.5; P = .008). The mean ages for detection of SSP without dysplasia, with any or low-grade dysplasia, and with high-grade dysplasia were 60.8 years, 65.6 years, and 70.2 years, respectively. The range for proportions of SSPs with dysplasia was 3.7%–42.9% across studies, possibly reflecting different study populations.
In a systematic review, we found that SSPs are relatively uncommon compared with adenoma. More research is needed on appropriate diagnostic criteria, variations in detection, and long-term risk.
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High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (⩾CIN3 (cervical intraepithelial neoplasia grade ...3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking.
We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for ⩾CIN3 detection in hrHPV-positive women (n=450,18-66 years).
Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with ⩾CIN3 (Spearman's ρ 0.697, P<0.001). The performance of FAM19A4 methylation analysis and/or HPV16/18 genotyping did not differ significantly between sample types. In women ⩾30 years, ⩾CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75-1.05). In women <30 years, ⩾CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55-1.21). In both groups, ⩾CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes.
FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for ⩾CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples.
Recent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years
. We assess whether these genomic signals can be used for early detection and pre-emptive cancer ...treatment using the neoplastic precursor lesion Barrett's esophagus as an exemplar
. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett's esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low-cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high-risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.
The objective of this study is to explore the clinicopathological characteristics of gastric cancer and precancerous conditions in patients with primary gastric lymphoma.
We analyzed 474 cases of ...primary gastric lymphoma, mainly DLBCL and MALT, from three clinical centres retrospectively, and compared the clinicopathological parameters of primary gastric lymphoma patients complicated with gastric cancer, precancerous conditions, or with no complications.
A total of 5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer, including metachronous gastric adenocarcinoma (3.2%) and synchronous gastric adenocarcinoma (1.9%). Of the patients with gastric lymphoma, 14.6% had precancerous conditions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%). Primary gastric lymphoma patients with an ulcerative type (p = 0.009) and Lugano classification stage IIE + IV (p < 0.001) lymphoma had a higher risk of complicating with gastric cancers or precancerous conditions. The rate of infection of Helicobacter pylori (Hp) was 68.4% in patients with primary gastric lymphoma, which was higher in patients with MALT lymphoma (p < 0.001), Lugano classification stage I + II (p < 0.001), and patients complicated with precancerous conditions and gastric cancer (p < 0.001), especially gastric cancer of the intestinal type (p = 0.04). Gastric cancer (95.8%) and precancerous conditions (91.3%) occurred mostly in Hp-infected primary gastric lymphoma patients, with a minor subset of Hp-eradicated patients. Primary gastric lymphoma patients had a higher detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population.
Patients with primary gastric lymphoma have a high risk of developing gastric cancer and precancerous conditions, and this risk may be related to Helicobacter pylori infection. Follow-up of primary gastric lymphoma provides an opportunity for the detection of early gastric cancer.
Key messages
5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer.
14.6% of the patients with gastric lymphoma had premalignant lesions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%).
Primary gastric lymphoma patients complicating with gastric cancer had a higher infection rate of Helicobacter pylori (100.0%), a detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population.
Respiratory epithelial cell death by influenza virus infection is responsible for the induction of inflammatory responses, but the exact cell death mechanism is not understood. Here we showed that ...influenza virus infection induces apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced only in malignant tumor cells infected with influenza virus. In human precancerous respiratory epithelial cells (PL16T), the number of apoptotic cells increased at early phases of infection, but pyroptotic cells were observed at late phases of infection. These findings suggest that apoptosis is induced at early phases of infection but the cell death pathway is shifted to pyroptosis at late phases of infection. We also found that the type I interferon (IFN)-mediated JAK-STAT signaling pathway promotes the switch from apoptosis to pyroptosis by inhibiting apoptosis possibly through the induced expression of the
anti-apoptotic gene. Further, the inhibition of JAK-STAT signaling repressed pyroptosis but enhanced apoptosis in infected PL16T cells. Collectively, we propose that type I IFN signaling pathway triggers pyroptosis but not apoptosis in the respiratory epithelial cells in a mutually exclusive manner to initiate proinflammatory responses against influenza virus infection.
Respiratory epithelium functions as a sensor of infectious agents to initiate inflammatory responses along with cell death. However, the exact cell death mechanism responsible for inflammatory responses by influenza virus infection is still unclear. We showed that influenza virus infection induced apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced at early phases of infection, but the cell death pathway was shifted to pyroptosis at late phases of infection under the regulation of type I IFN signaling to promote proinflammatory cytokine production. Taken together, our results indicate that the type I IFN signaling pathway plays an important role to induce pyroptosis but represses apoptosis in the respiratory epithelial cells to initiate proinflammatory responses against influenza virus infection.
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