Endoscopic advances in the management of gastric cancer and premalignant gastric conditions

Gastric cancer is the fifth most common cancer and in 2018,it was the third most common cause of cancer-related deaths worldwide.Endoscopic advances continue to be made for the diagnosis and management of both early gastric cancer and premalignant gastric conditions.In this review,we discuss the epidemiology and risk factors of gastric cancer and emphasize the differences in early vs latestage gastric cancer outcomes.We then discuss endoscopic advances in the diagnosis of early gastric cancer and premalignant gastric lesions.This includes the implementation of different imaging modalities such as narrow-band imaging,chromoendoscopy,confocal laser endomicroscopy,and other experimental techniques.We also discuss the use of endoscopic ultrasound in the diagnosis and staging of early gastric cancer.We then discuss the endoscopic advances made in the treatment of these conditions,including endoscopic mucosal resection,endoscopic submucosal dissection,and hybrid techniques such as laparoscopic endoscopic cooperative surgery.Finally,we comment on the current suggested recommendations for surveillance of both gastric cancer and its premalignant conditions.

Barretts 组织变形的诊断和管理: 什么是新的

Barrett’s esophagus(BE) is a complication of gastroesophageal reflux disease,and a premalignant lesion for esophageal adenocarcinoma(EAC).Observational studies suggest that endoscopic surveillance is associated with the detection of dysplasia and EAC at an early stage along with improved survival,but controversies still remain.The management of patients with BE involves endoscopic surveillance,preventive and clinical measures for cancer,and endoscopic and surgical approaches to treatment.Deciding upon the most appropriate treatment is a challenge.This study presents the results and the effectiveness of these practices.

Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions

Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis,due largely to late diagnosis.The importance of the interaction between Helicobacter pylori(H.pylori)infection,the main risk factor,and host-related genetic factors has been studied intensively in recent years.The genetic predisposition for non-hereditary gastric cancer is difficult to assess,as neither the real prevalence of premalignant gastric lesions in various populations nor the environmental risk factors for cancer progression are clearly defined.For non-cardiac intestinal-type cancer,identifying the factors that modulate the progression from inflammation toward cancer is crucial in order to develop preventive strategies.The role of cytokines and their gene variants has been questioned in regard to non-self-limiting H.pylori gastritis and its evolution to gastric atrophy and intestinal metaplasia;the literature now includes various and non-conclusive results on this topic.The influence of the majority of cytokine single nucleotide polymorphisms has been investigated for gastric cancer but not for preneoplastic gastric lesions.Among the investigated gene variants onlyIL10T-819C,IL-8-251,IL-18RAP917997,IL-22 rs1179251,IL1-B-511,IL1-B-3954,IL4R-398 and IL1RN were identified as predictors for premalignant gastric lesions risk.One of the most important limiting factors is the inhomogeneity of the studies(e.g.,the lack of data on concomitant H.pylori infection,methods used to assess preneoplastic lesions,and source population).Testing the modifying effect of H.pylori infection upon the relationship between cytokine gene variants and premalignant gastric lesions,or even testing the interaction between H.pylori and cytokine gene variants in multivariable models adjusted for potential covariates,could increase generalizability of results.

Narrow-band imaging with magnifying endoscopy for the evaluation of gastrointestinal lesions

Narrow band imaging(NBI) endoscopy is an optical image enhancing technology that allows a detailed inspection of vascular and mucosal patterns, providing the ability to predict histology during real-time endoscopy. By combining NBI with magnification endoscopy(NBI-ME), the accurate assessment of lesions in the gastrointestinal tract can be achieved, as well as the early detection of neoplasia by emphasizing neovascularization. Promising results of the method in the diagnosis of premalignant and malignant lesions of gastrointestinal tract have been reported in clinical studies. The usefulness of NBI-ME as an adjunct to endoscopic therapy in clinical practice, the potential to improve diagnostic accuracy, surveillance strategies and cost-saving strategies based on this method are summarized in this review. Various classification systems of mucosal and vascular patterns used to differentiate preneoplastic and neoplastic lesions have been reviewed. We concluded that the clinical applicability of NBI-ME has increased, but standardization of endoscopic criteria and classification systems, validation in randomized multicenter trials and training programs to improve the diagnostic performance are all needed before the widespread acceptance of the method in routine practice. However, published data regarding the usefulness of NBI endoscopy are relevant in order to recommend the method as a reliable tool in diagnostic and therapy, even for less experienced endoscopists.

Role of the Chinese Herbal Medicine Xianhuayin on the Reversal of Premalignant Mucosal Lesions in the Golden Hamster Buccal Pouch

Aim To investigate the role of the Chinese herbal medicine Xianhuayin on the reversal of 7,12-dimethylbenz[a]anthracene （DMBA）-induced premalignant mucosal lesions in the oral buccal pouch of golden hamsters. Methodology The animals were randomly divided into a non-diseased control group （n=5） and an experimental group including 50 animals in which the buccal mucosa had been painted with DMBA （0.5% in acetone） to generate an oral mucosa premalignant lesion. Animals in the experi- mental group were further divided into Xianhuayin-treated group （n=30）, untreated prem＇alignant lesion group （n=10） and normal saline （NS）-treated group （n=10）. The cheek （buccal） pouch mucosa of the golden hamsters in each group was observed with light and electron microscopy eight weeks after intragastric administration with NS or Xianhuayin. Results In the non-diseased control group, the buccal mucosa was keratinized and stratified squamous epithelium under a light microscope. In the untreated premalignant lesion group, variable degrees of epithelial dysplasia was observed. The irregular epithelial mucosa gradually became distinct in the Xianhuayin-treated group. Scanning electronic microscopic （SEM） analysis showed that surface of the cells exhibited honeycomb structures in the hamster of untreated- group. The cells were morphologically irregular, overlapped and loosened in the untreated premalignant lesion group. Most of the cell surface exhibited honeycomb structure in the Xianhuayin-treated group. Transmission electronic micro- scopic （TEM） analysis showed that buccal mucosal epithelial cells were morphologically regular in the non-diseased control group. Desmosomes and tonofibrils were reduced and the nucleus was morphologically irregular in the untreated premalignant lesion group. In the Xianhuayin-treated group, the widening intercellular gap was gradually reduced, desmosomes and the cells becoming morphologically regular. No significant difference was observed between the hamsters in NS-treated group and those in the untreated premalignant lesion group. Significant therapeutic efficacy was observed in the group receiving Xianhuayin. Conclusion Xianhuayin is effective in the reversal of DMBA-induced premalignant lesions in the buccal pouch of golden hamsters.

Lack of estrogen receptors expression in malignant and pre-malignant colorectal lesions in Egyptian patients

Background: incidence of Colorectal cancer (CRC) is increasing globally. In Egypt, CRC ranks the sixth most common cancer in males and the fifth in females. Aim: To assess the expression of estrogen receptors (alpha and beta) in pre-malignant (adenomatous polyps and IBD), malignant colorectal lesions and normal colonic mucosa in group of Egyptian patients. Methods: This prospective study was done on 45 patients presenting with colonic symptoms, patients were divided into four groups;15 CRC patients, 10 patients with adenomatous polyps, 10 IBD patients and 10 patients in the control group. Patients subjected to: Stool analysis, FOBT, CBC, CEA, Abdominal ultrasound & colonoscopy and biopsy (number = 80), Pathological, immunohistochemistry and RT- PCR quantification of ERα and ERβ were done. Results: Mean age: 39.2 (12 - 73), gender: M/F: 28/17. Bleeding per rectum was the commonest presentation;29/45 (64.4%). CEA was significantly elevated in the CRC group compared with other studied groups (1692 mg/L vs. 4.0, 4.0 and 4.4 mg/L). Ultrasonography of the studied patients showed that metastatic CRC: 3/15 (20%);Colonic wall thickening: 5/15 (33.3%), 1/10 showed colonic polypoidal lesions in adenomatous polyps groups, in IBD group: 4/10 (40%) showed colonic and ileocecal thicknening. All the studied patients showed negative results for estrogen receptors (alpha and beta) by the use of immunohistochemistry staining and RT-PCR technique. Conclusion: Role of estrogen receptors in the colonic mucosa, precancerous and colorectal cancer is doubtful, contradictory results with some literature data could be due to racial and genetic difference in the studied population.

Precancerous lesions of oral mucosa

Precancerous lesions of oral mucosa, known as potentially malignant disorders in recent years, are consists of a group of diseases, which should be diagnosed in the early stage. Oral leukoplakia, oral submucous fibrosis, and oral erythroplakia are the most common oral mucosal diseases that have a very high malignant transformation rate. Oral lichen planus is one of the potentially malignant disorders that may be seen in six different subtypes including papular, reticular, plaquelike, atrophic, erosive, and bullous type, clinically. Atrophic and erosive subtypes have the greater increased malignant transformation risk compared to another subtypes. Although there are various etiological studies, the etiology of almost all these diseases is not fully understood. Geographically, etiologic factors may vary.The most frequently reported possible factors are tobacco use, alcohol drinking, chewing of betel quid containing areca nut, and solar rays. Early diagnosis is very important and can be lifesaving, because in late stages, they may be progressed to severe dysplasia and even carcinoma in situ and/or squamous cell carcinoma. For most diseases, treatment results are not satisfactory in spite of miscellaneous therapies. While at the forefront of surgical intervention, topical and systemic treatment alternatives such as corticosteroids, calcineurin inhibitors, and retinoids are widely used.

Detection and Identification of Human Papiliomavirus in Vulvar Intraepithelial Neoplasia

Objective： To evaluate the rate and types of human papillomavirus infection in vulvar intraepithelial neoplasia. Methods： We detected and identified HPV in 40 VIN cases with 67 lesions using PCR based reverse line blot hybridization and DNA sequencing. Among the 40 patients, 13 were diagnosed as VIN Ⅲ, 11 as VIN Ⅱ, and 16 as VIN Ⅰ. 31 patients had multifocal disease. First a fragment of 150 bp was amplified from the L1 region of HPV with GPS/GP6 primers. If the result was negative, a short fragment of 65 bp was amplified also from the LI region with SPFI/SPF2 primers. Results： Using general primer GPS/GP6, the positive rate was 52.2% （35167）. Using a short PCR fragment （SPF PCR）, the positive rate of the rest 32 lesions was 81.2% （26132）. The total positive rate was 91.0% （61/67）. 90% of the HPV types found in VIN were high risk types. All 35 GP PCR products were analyzed by sequencing. The gene types of 31 mono-infection lesions were in accordance with the reverse line blot results, while sequence results of the 4 multi-infection samples could not be analyzed. The SPF PCR products were also sequenced, 24 of the 26 SPF PCR products could be analyzed and 2 samples failed. 80.6% （25/31） cases with multifocal VIN displayed the identical type of HPV, suggesting monoclonality in different lesions from the same patient. Conclusion： The high risk type of HPV is associated with vulvar intraepithelial neoplasia and may be necessary for development of HPV-associated invasive vulvar carcinoma.

EXPRESSION OF p16,CYCLIN D1 AND RB PROTEIN IN GASTRIC CARCINOMA AND PREMALIGNANT LESIONS

Objective: To investigate the expression of p16, cyclin D1 and Rb protein in gastric carcinoma and premalignant lesions including dysplastic gastric mucosa and intestinal metaplasia gastric mucosa. Methods: Using SP immunohistochemical methods, the expression of pl6, cyclin D1 and Rb proteins was detected in 10 specimens of normal gastric mucosa, 15 specimens of dysplastic gastric mucosa, 15 specimens of intestinal metaplasia gastric mucosa, 30 specimens of gastric carcinoma. The clinical characteristics of the 30 patients with gastric carcinoma were analysed to explore the relationship between the parameter detected and biological action of gastric cancer. Results: Expression of p16 protein was detected in 90% of normal gastric mucosa, 86.67% of dysplastic gastric mucosa, 86.67% of intestinal metaplasia gastric mucosa, 36.67% of gastric carcinoma. The positive rate of p16 protein expression in gastric carcinoma is significantly lower than that in normal gastric mucosa and gastric premalignant lesions mucosa (P<0.01). Expression of cyclin D1 protein was detected in 10% of normal gastric mucosa, 20% of dysplastic gastric mucosa, 20% of intestinal metaplasia gastric mucosa, 53.33% of gastric carcinoma. The positive rate of cyclin D1, protein expression in gastric carcinoma is significantly higher than that in normal gastric mucosa and gastric premalignant lesions mucosa (P<0.05). Expression of Rb protein was detected in 90% of normal gastric mucosa, 80% of dysplastic gastric mucosa, 80% of intestinal metaplasia gastric mucosa, 50% of gastric carcinoma. The positive rate of Rb protein expression in gastric carcinoma is significantly lower than that in normal gastric mucosa (P<0.05). The expression of p16, cyclin D1 gene were associated with the degree of differentiation of gastric carcinoma, lymphnodes metastasis and distant metastasis. Conclusion: p16, Cyclin D1 and Rb gene play important role in gastric carcinoma genesis. The expression of p16, cyclin D1 and Rb gene have some value to the diagnosis at earlier stage of gastric cancer. Detection of expression of p16, cyclin D1 gene would be helpful to judge the prognosis of gastric cancer.

Determination of telomerase activity and its clinical significance in gastric cancer and premalignant lesions

In order to explore the role of telomerase activity (TA) in the development and progression of gastric cancer (GC) and if TA can be used as an indicator for the early diagnosis of GC, TA in 176 specimens of gastric mucosa of 57 cases of chronic atrophic gastritis (CAG), 18 intestinal metaplasia (IM), 8 dysplasia (Dys), 65 GC obtained through operation or endoscopy was determined with PCR-based TRAP assay. Meanwhile, operative specimens of GC were analyzed with serial dilution. It was found that TA was detected in 24. 6% of CGA, 38. 9% of IM, 37.5% of Dys and 92.3% of GC, but not detected in 28 cases of normal tissues. TA detection was not related to patients’ sex, tumor location, size, depth of invasion, differentiation, lymph node metastasis and clinicalstage. Telomerase activity in premalignant lesions indicates that it plays a crucial role in the development and progression of GC. Thus the determination of telomerase activity is helpful to predict the progress of premalignant changes and to diagnose early GC.

Circulating immune parameters-based nomogram for predicting malignancy in laryngeal neoplasm

BACKGROUND Malignancy prediction remains important to preoperative diagnosis and postoperative follow-up in laryngeal neoplasm.AIM To evaluate the circulating immune population and develop a nomogram for prediction of malignancy in patients with laryngeal neoplasm.METHODS A primary cohort of 156 patients was divided into laryngeal benign lesion,premalignant lesion and malignant lesion groups.Peripheral blood from patients was measured by blood routine test and flow cytometry.A nomogram was developed and applied to a validation cohort containing 55 consecutive patients.RESULTS Age,gender and seven circulating immune parameters exhibited significant differences between laryngeal benign lesion and premalignant lesion.The nomogram incorporated predictors,including gender,age,smoke index,proportions of monocytes,CD8+T cells,CD4+T cells,B cells and CD4/CD8+T cell ratio.It showed good discrimination between laryngeal premalignant lesion and malignant lesion,with a C-index of 0.844 for the primary cohort.Application of this nomogram in the validation cohort(C-index,0.804)still had good discrimination and good calibration.Decision curve analysis revealed that the nomogram was clinically useful.CONCLUSION This novel nomogram,incorporating both clinical risk factors and circulating immune parameters,could be appropriately applied in preoperative individualized prediction of malignancy in patients with laryngeal neoplasm.

P^（53） PROTEIN OVEREXPRESSION IN PREMALIGNANT AND MALIGNANT LESIONS OF ORAL MUCOSA：IMMUNOHISTOCHEMICAL OBSERVATION

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CYTOMORPHOMETRIC ANALYSIS DURING CANCERATION OF NASOPHARYNEAL EPITHELIUM

Cellular morphology was quantitatively analysed by using the point-counting technique In 76 specimens inciuding 18 normal nasopharyngeal epithelia, 16 simple hyperplasia and metaplasia, 18 dysplasia and 24 untreated nasopharyngeal carcinoma (NPC). Altogether 19 morphometric parameters of the cell were measured and calculated. THe results showed that with malignant transformation of nasopharyngeal epithelium, the great majority of the cellular morphometric parameters gradually increased in numerical values while no marked difference was shown between normal nasopharyngeal epithelium and simple hyperplasia or metaplasia in terms of cytomorphometric characteristics. Most of the parameters in dysplasla changed significantly as compared with those in other three groups. Cytomorphometric analysis seems to give strong support to the concept that dysplasla is among the transition stages of disease process between normal nasopharyngeal epithelium and NPC. 19 parameters were processed with multivarite analysis and the discriminatory functions were established with entrance of six parameters. When replaced with the cytomorphometric data obtained from all the 76 cases the discriminatory functions gave a result in accordance with 91 percent of those provided by histopathology.

Effect of Impaired Lung Function on the Development and Progression of Endobronchial Premalignant Lesions

Background: Chronic obstructive pulmonary disease (COPD) and presence of endobronchial premalignant lesions (EPL) are individual risk factors for lung cancer (LC). However, effect of impaired lung function (ILF) on the natural history of EPL has not been explored. Patients and Methods: This study included 217 high-risk participants from a hospital-based LC surveillance cohort who underwent pulmonary function testing followed by bronchoscopy with endobronchial biopsies. Baseline histopathology diagnoses included 91 cases (41.9%) with squamous metaplasia (SM), 25 (11.5%) with squamous dysplasia (SD), 1 (0.5%) with in-situ carcinoma and 5 (2.3%) with invasive LC. Follow-up biopsies were obtained for 69 patients, and 16 (23.2%) patients demonstrated progression to a higher grade lesion. Regression models were used to evaluate the relationship between ILF and EPL. All the models were adjusted for age, gender and tobacco smoking. Results: Patients with FEV1% of <50% had 4.5 times greater risk of being diagnosed with an EPL [95% confidence interval: 1.93-10.80] and 8-fold greater risk of SD, compared to patients with FEV1% ≥80. COPD was associated with 2.7 and 4.8 times greater risk of SM and SD, respectively. The mean time to progression to a higher-grade lesion was shorter in COPD patients compared to patients without COPD (27 versus 50 months, p = 0.02). Conclusion: Our results indicate that ILF may be a predictor of prevalence and progression of EPLs among patients at high risk of LC. Therefore, spirometry can be a complementary pre-screening tool for identifying patients with EPL who need more intense LC surveillance.

Actinic Cheilitis: Clinical Characteristics Observed in 75 Patients and a Summary of the Literature of This Often Neglected Premalignant Disorder

Actinic cheilitis can progress to squamous cell carcinoma in 20% of cases. The purpose of this study was to identify the clinical characteristics of 75 patients with actinic cheilitis and to summarise the current literature concerning actinic cheilitis. A total of 75 patients were evaluated over a 3-year period. The medical history, physical examination results and images were collected from each patient. Demographic data were collected and analysed. To review the literature, the relevant data were collected from scientific journals in the last 30 years. The mean age of the patients was 56 years old;42 patients (56%) were female, and 66 patients (88%) were white. Nineteen (25.3%) patients reported at least one symptom, including pain, burning and itching. Sixty-five (86.7%) patients presented actinic cheilitis only in the lower lip. All of the patients reported sun exposure, and 44 (58.6%) patients were exposed for more than 10 years. The main clinical aspects investigated and analysed included dryness (100%), flaking (72%) and white lesions (57.3%). Lip assessment is extremely important in medical and dental care. From the 15 lesions assessed in the presence of actinic cheilitis, the most common clinical characteristics observed were dryness, flaking and white lesions. It is imperative to know the clinical aspects that may be encountered in actinic cheilitis in order to achieve early diagnosis, thus avoiding lip squamous cell carcinoma transformation.

Screening for Oral Cancer 2018

In Hungary, the incidence and mortality from oral cancer is so high, that in the past decades it has attracted international attention. The mortality rates are the highest in Europe. As risk factors, smoking and alcohol drinking have a multiplicative role;in addition, a number of dental factors also play a role. Premalignant conditions and lesions are well known. They should be targeted for early detection and early treatment. The screening tool is simple: inspection and palpation. The physician-patient encounters provide opportunity for screening. This paper looks for the answer to the long debated question: who is responsible for oral screening?

Inflammation as a Mediator of Microbiome Dysbiosis-Associated DNA Methylation Changes in Gastric Premalignant Lesions

Evidence for the influence of chronic inflammation induced by microbial dysbiosis on aberrant DNA methylation supports a plausible connexion between disordered microbiota and precancerous lesions of gastric cancer(PLGC).Here,a comprehensive study including multi-omics data was performed to estimate the relationships amongst the gastric microbiome,inflammatory proteins and DNA methylation alterations and their roles in PLGC development.The results demonstrated that gastric dysbacteriosis increased the risk of PLGC and DNA methylation alterations in related tumour suppressor genes.Seven inflammatory biomarkers were identified for antrum and corpus tissues,respectively,amongst which the expression levels of several biomarkers were significantly correlated with the microbial dysbiosis index(MDI)and methylation status of specific tumour suppressor genes.Notably,mediation analysis revealed that microbial dysbiosis partially contributed to DNA methylation changes in the stomach via the inflammatory cytokines C-C motif chemokine 20(CCL20)and tumour necrosis factor receptor superfamily member 9(TNFRSF9).Overall,these results may provide new insights into the mechanisms that might link the gastric microbiome to PLGC.

Establishment of novel rat models for premalignant breast disease

Background Breast cancer has become one of the most common malignant tumors among females over the past several years.Breast carcinogenesis is a continuous process,which is featured by the normal epithelium progressing to premalignant lesions and then to invasive breast cancer （IBC）.Targeting premalignant lesions is an effective strategy to prevent breast cancer.The establishment of animal models is critical to study the mechanisms of breast carcinogenesis,which will facilitate research on breast cancer prevention and drug behaviors.In this study,we established a feasible chemically-induced rat model of premalignant breast cancer.Methods Following the administration of the drugs （carcinogen,estrogen,and progestogen） to Sprague-Dawley （SD） rats,tumors or suspicious tumors were identified by palpation or ultrasound imaging,and were surgically excised for pathological evaluation.A series of four consecutive steps were carried out in order to determine the carcinogen：7,12-dimethylbenzaanthracene （DMBA） or 1-methyl-1-nitrosourea,the route of carcinogen administration,the administration period of estrogen and progestogen,and the DMBA dosage.Results Stable premalignant lesions can be induced in SD rats on administration of DMBA （15 mg/kg,administered three times） followed by administration of female hormones 5-day cycle.Results were confirmed by ultrasound and palpation.Conclusion Under the premise of drug dose and cycle,DMBA combined with estrogen and progestogen can be used as a SD rat model for breast premalignant lesions.

A comprehensive update:gastrointestinal microflora,gastric cancer and gastric premalignant condition,and intervention by traditional Chinese medicine

With the recent upsurge of studies in the field of microbiology,we have learned more about the complexity of the gastrointestinal microecosystem.More than 30 genera and 1000 species of gastrointestinal microflora have been found.The structure of the normal microflora is relatively stable,and is in an interdependent and restricted dynamic equilibrium with the body.In recent years,studies have shown that there is a potential relationship between gastrointestinal microflora imbalance and gastric cancer(GC)and precancerous lesions.So,restoring the balance of gastrointestinal microflora is of great significance.Moreover,intervention in gastric premalignant condition(GPC),also known as precancerous lesion of gastric cancer(PLGC),has been the focus of current clinical studies.The holistic view of traditional Chinese medicine(TCM)is consistent with the microecology concept,and oral TCM can play a two-way regulatory role directly with the microflora in the digestive tract,restoring the homeostasis of gastrointestinal microflora to prevent canceration.However,large gaps in knowledge remain to be addressed.This review aims to provide new ideas and a reference for clinical practice.