Missed diagnosis of early gastric cancer or high-grade intraepithelial neoplasia

AIM: To investigate the causes of missed diagnosis of early gastric cancer (EGC) or high-grade intraepithelial neoplasia (HGIN) in Chongqing, China. METHODS: The present study summarizes 103 cases of EGC/HGIN detected by esophagogastroduodenos-copy (EGD) and pathological analysis from January 2010 to December 2011. Dimethyl silicone oil was administrated orally 15 min before the EGD procedures. The stomach was cleaned by repeated washing with saline when the gastroscope entered the stomach cavity. Suspected EGC lesions were subject to conventional biopsy sampling and pathological examinations. The correlation between lesion locations, endoscopic morphology of cancerous sites, training level of the examiners, pathological biopsies, and missed diagnosis was analyzed. RESULTS: Twenty-three cases were missed among the 103 cases (22.23%) of EGC/HGIN. The rate of missed EGC in the gastroesophageal junction (8/19, 42.1%) was significantly higher than at other sites (15/84, 17.86%) (χ2 = 5.253, P = 0.022). In contrast, the rate of missed EGC in the lower stomach body (2/14, 14.29%) was lower than at other sites (21/89,23.6%), but there were no significant differences (χ2 = 0.289, P = 0.591). The rate of missed EGC in the gastric antrum (5/33, 15.15%) was lower than at other sites (18/70, 25.71%), but there were no significant differences (χ2 = 1.443, P = 0.230). Endoscopists from less prestigious hospitals were more prone to not diagnosing EGC than those from more prestigious hospitals (χ2 = 4.261, P = 0.039). When the number of biopsies was < 4, the rate of missed diagnosis was higher (20/23, 89.96%) than for when there were > 4 biopsies (3/23, 13.04%) (P < 0.001). In addition, there was no significant difference in the rate of missed diagnosis in patients with 1-3 biopsy specimens (χ2 = 0.141, P = 0.932). CONCLUSION: Endoscopists should have a clear understanding of the anatomical characteristics of the esophagus/stomach, and endoscopic identification of early lesions increases with the number of biopsies.

High-grade pancreatic intraepithelial neoplasia diagnosed based on changes in magnetic resonance cholangiopancreatography findings:A case report

BACKGROUND High-grade pancreatic intraepithelial neoplasia(PanIN)exhibits no mass and is not detected by any examination modalities.However,it can be diagnosed by pancreatic juice cytology from indirect findings.Most previous cases were diagnosed based on findings of a focal stricture of the main pancreatic duct(MPD)and caudal MPD dilatation and subsequent pancreatic juice cytology using endoscopic retrograde cholangiopancreatography(ERCP).We experienced a case of high-grade PanIN with an unclear MPD over a 20-mm range,but without caudal MPD dilatation on magnetic resonance cholangiopancreatography(MRCP).CASE SUMMARY A 60-year-old female patient underwent computed tomography for a follow-up of uterine cancer post-excision,which revealed pancreatic cysts.MRCP revealed an unclear MPD of the pancreatic body at a 20-mm length without caudal MPD dilatation.Thus,course observation was performed.After 24 mo,MRCP revealed an increased caudal MPD caliber and a larger pancreatic cyst.We performed ERCP and detected atypical cells suspected of adenocarcinoma by serial pancreatic juice aspiration cytology examination.We performed a distal pancreatectomy and obtained a histopathological diagnosis of high-grade PanIN.Pancreatic parenchyma invasion was not observed,and curative resection was achieved.CONCLUSION High-grade Pan-IN may cause MPD narrowing in a long range without caudal MPD dilatation.

Adverse Pregnancy Outcomes Following Cryotherapy, Thermal Ablation and Loop Electrosurgical Excision Procedure for Cervical Intraepithelial Neoplasia Treatment: A Pilot Study among Zambian Women

Background: Cervical Intraepithelial neoplasia treatments have become essential interventions to manage cervical lesions. Majority of the recipients of these treatments are women within the reproductive age group, who according to literature may be at risk of adverse pregnancy outcomes. This pilot study is part of a study investigating adverse pregnancy outcomes among women who received Cryotherapy, Thermal ablation and Loop Electrosurgical Excision Procedure compared to the untreated women in Zambia. Materials and Methods: This descriptive study analyzed records of 886 (n = 443 treated and n = 443 untreated) women aged 15 - 49 years. The women were either screened with Visual Inspection with Acetic Acid or treated for Cervical Intraepithelial neoplasia at the Adult Infectious Disease Centre between January 2010 and December 2020. Women meeting the criteria were identified using the Visual Inspection with Acetic Acid screening records and telephone interviews to obtain the adverse pregnancy outcome experienced. Data were analysed using STATA version 16 to determine the prevalence and obtain frequency distribution of outcomes of interest. Univariate and multivariable binary logistic regression estimated odds of adverse pregnancy outcomes across the three treatments. Results: The respondents were aged 15 to 49 years. Adverse pregnancy outcomes were observed to be more prevalent in the treatment group (18.5%) compared to the untreated group (5.4%). Normal pregnancy outcomes were lower in the treated (46.3%;n = 443) than the untreated (53.7%;n = 443). The treated group accounted for the majority of abortions (85.2%), prolonged labour (85.7%) and low birth weight (80%), whereas, the untreated accounted for the majority of still births (72.7%). Women treated with cryotherapy (aOR = 2.43, 95% CI = 1.32 - 4.49, p = 0.004), thermal ablation (aOR = 6.37, 95% CI = 0.99 - 41.2, p = 0.052) and Loop Electrosurgical Excision Procedure (aOR = 9.67, 95% CI = 2.17 - 43.1, p = 0.003) had two-, six- and ten-times higher odds of adverse pregnancy outcomes respectively, relative to women who required no treatment. Conclusion: Adverse pregnancy outcomes are prevalent among women who have received treatment in Zambia. The findings indicate that treating Cervical Intraepithelial Neoplasia has been linked to higher chances of experiencing abortion, delivering low birth weight babies and enduring prolonged labor that may result in a caesarean section delivery. Cervical neoplasia treatments, particularly Loop Electrosurgical Excision Procedure, are associated with significantly increased odds of adverse pregnancy outcomes. It is essential to include information about prior Cervical Intraepithelial neoplasia treatment outcomes in obstetric care.

High-grade pancreatic intraepithelial lesions： prevalence and implications in pancreatic neoplasia

BACKGROUND： High-grade pancreatic intraepithelial neoplasia（Pan IN-3）, a precursor of pancreatic ductal adenocarcinoma（PDAC）, is not universally detected in resected pancreatic neoplasms. We sought to determine the prevalence and prognostic relevance of Pan IN-3 lesions in primary surgical resections of PDACs and intraductal papillary mucinous neoplasms（IPMNs）.METHODS： A retrospective review of a tertiary care center pathology database（1/2000-6/2014） was performed. Demographics, imaging, pathology, disease-recurrence, and survival data were reviewed.RESULTS： A total of 458 patients who underwent primary pancreatic resection were included. “Pan IN-3” lesions were found in 74（16.2%） patients who either had PDAC（n=67） or main duct（MD）-IPMN（n=7）. Among IPMN-MDs, Pan IN-3 lesions were exclusively found in those with pathological evidence of chronic pancreatitis. For PDACs, the median overall survival（OS） for pancreata with Pan IN-3 lesions was significantly better than those without（OS 1.12 years, interquartile range [IQR] 0.72, 2.05 years vs OS 0.86 years, IQR 0.64,1.60 years respectively; P=0.04）. Multivariate Cox regression analysis demonstrated that the presence of Pan IN-3 lesions was associated with a reduced risk of death（HR=0.43; 95% CI： 0.23-0.82; P=0.01）.CONCLUSIONS： Following primary resection of pancreatic adenocarcinoma, the lower survival observed in patients without Pan IN-3 lesions might suggest a state of complete or accelerated transformation. Further investigations are necessary to validate these findings that might impact disease prognosis and management.

Efficacy and Tolerability of Thermocoagulation Treatment of High-Grade Cervical Intraepithelial Neoplasia

Purpose: Cervical cancer is still one of the main causes of cancer and mortality in women, especially in low- and middle-income countries, although it is a completely preventable disease through the detection and treatment of pre-cancer lesions. We evaluated the efficacy and tolerability of thermocoagulation treatment of high-grade cervical intraepithelial neoplasia (CIN 2 and 3). Methods: We evaluated 115 women with high-grade cervical intraepithelial neoplasia, 54 with CIN 2 and 61 with CIN 3, confirmed by biopsy and without previous treatment, from January 2016 to December 2018, undergoing thermocoagulation treatment at the Lower Genital Tract Pathology and Colposcopy Service of the Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. Results: The mean age was 33.11 years (SD = 9.83) for CIN 2 and 35.28 years (SD = 7.97) for CIN 3 patients. Treatment efficacy was 90.8% in CIN 2 and 94.9% in CIN 3 cases. Pain was the main symptom reported at the time of treatment, occurring more frequently in the CIN 3 group (49.1% versus 27.8% in the CIN 2 group). As the more important long-term complication, there were 3 cases of pelvic inflammatory disease in CIN 2 (5.6%) and 3 in CIN 3 group (5.0%). The percentage of residual lesion was very low in both groups, 5 in CIN 2 group (9.2%) and 2 in CIN 3 group (3.4%). Conclusion: Thermocoagulation is an effective method for the treatment of cervical pre-cancer lesions (CIN 2 and CIN 3), with a low risk of adverse events and complications.

Distribution of High-Risk Human Papillomavirus Genotypes among Women with Colposcopic Diagnosis of Cervical Intraepithelial Neoplasia in Bangladesh

Background: The incidence of cervical cancer is high in Bangladesh and there is a high prevalence of preinvasive lower genital tract disease among women of reproductive age. Persistent high-risk Human Papilloma Virus (HPV) infection is the main underlying cause of cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN). Objective: The aim of the study was to identify the subtypes of high-risk HPV infection among women with the colposcopic diagnosis of cervical intraepithelial neoplasia in Bangladesh. Methods: This cross-sectional observational study was conducted in the colposcopy clinic of Dhaka Medical College Hospital over a six-month period. A total of 100 participants were enrolled. Married women, between 30 - 60 years of age with colposcopically diagnosed cervical intra epithelial neoplasia were enrolled. Women with chronic illness, pregnancy, and women unable to consent were excluded from this study. After counselling, colposcopically directed punch biopsies were taken from each CIN case concurrently with high-risk HPV testing by polymerase chain reaction (PCR). Results: The mean age of the patients was 38.69 (SD ±7.76) years. CIN 1 was diagnosed in 57% of participants, while 24% had CIN II and 19% had CIN III lesions. High-risk HPV was present in 52 patients. HPV 16 was the most common identified in 28 (53.84%) and HPV 18 was the second most common with 20 (38.46%) either singly or in combination with other high-risk subtypes. The other HPV strains, HPV 31, 33, 35, 52, 56 and 58, were also detected either as mono or co-infections. Out of the 52 HPV positive cases, 29 (55.8%) had mono infection and 23 (44.2%) had co-infection with several subtypes. The highest incidence (50%) of oncogenic HPV infections was present among women aged 35 - 45 years. Risk factors associated with HPV positive cases were high parity (P 0.05), early age at marriage (P = 0.754) and early age of first child. Conclusion: This study identified a high prevalence of HPV 16 and 18 genotypes. HPV vaccination with the current 9-valent HPV vaccine, which contains HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Will be an effective public health measure to eradicate cervical cancer in Bangladesh.

Prevalence of HPV Infection And Cervical Intraepithelial Neoplasia And Attitudes towards HPV Vaccination among Chinese Women Aged 18-25 in Jiangsu Province

Objective：Few data are available on the epidemiology of HPV and cervical cancer among Chinese women younger than 25 years old.This study aimed to estimate the HPV infection rate and the prevalence of cervical intraepithelial neoplasia（CIN） in women aged 18-25,as well as their knowledge of and attitudes towards HPV vaccination.Methods：A population-based cervical cancer screening study was conducted on women aged 18-25 in Jiangsu province in 2008.Participants provided socio-demographic,reproductive and behavioral information and completed a survey about their knowledge of and attitudes towards HPV vaccination.Women then underwent a gynecologic exam to provide two cervical exfoliated cell samples for high risk HPV DNA testing and liquid-based cytology（LBC） as well as visual inspection with acetic acid（VIA）.Women testing positive for any test were referred to colposcopy and biopsy.The gold standard for diagnosis of cervical lesions was directed or random biopsies.Results：Within the sample of 316 women,3.4% of them were diagnosed with CIN grade 2 or worse lesions and 17.1% were found to be positive for HPV DNA.Among these young women,extra-marital sexual behavior of them（OR=2.0,95%CI：1.1-3.8） or their husbands（OR=2.6,95%：1.4-4.7） were associated with an increased risk of HPV positivity.Although overall HPV awareness was low,after a brief educational intervention,98.4% reported they would electively receive HPV vaccination and would also recommend that their daughters be vaccinated.However,most urban and rural women reported their ideal maximum out-of-pocket contribution for HPV vaccination to be less than 500 RMB and 50-100 RMB,respectively.Conclusion：Our study indicates cervical disease burden is relatively high among sampled Chinese women aged 18-25.Appropriate educational interventions for female adolescents and strategies to subsidize vaccine costs are definitely needed to ensure the effectiveness of vaccination campaigns in China.

Treatment strategy for gastric non-invasive intraepithelial neoplasia diagnosed by endoscopic biopsy

Treatment strategies,whether as follow-up or"total incisional biopsy"for gastric noninvasive intraepithelial neoplasia diagnosed by examination of an endoscopic forceps biopsy specimen,are controversial due to problems associated with the diagnostic accuracy of endoscopic forceps biopsy and questions about the safety and efficacy of endoscopic treatment.Based on the histological findings of the biopsy specimen,it is difficult to differentiate between reactive or regenerative changes,inflammation and neoplastic changes,intraepithelial and invasive tumors.Therefore,gastric neoplasia diagnosed as noninvasive intraepithelial often develop into invasive carcinoma during follow-up.Recent advances in endoscopic modalities and treatment devices,such as image-enhanced endoscopy and highfrequency generators,may make endoscopic treatment,such as endoscopic submucosal dissection(ESD),a therapeutic option for gastric intraepithelial neoplasia,including low-grade neoplasms.Future studies are required to evaluate whether ESD is a valid strategy for gastric intraepithelial neoplasm with regard to safety and cost effectiveness.

Pancreatic intraepithelial neoplasia arising from an ectopic pancreas in the small bowel

BACKGROUND： Ectopic pancreatic tissue is relatively uncommon, and is characterized as pancreatic tissue with no contact with the normal pancreas, and with its own ductal system and blood supply. It is usually asymptomatic, and can be incidentally diagnosed by conventional imaging studies. METHOD： A 69-year-old woman with a prior history of bilateral breast carcinoma presented with ectopic pancreatic intraepithelial neoplasia （PanIN） that was identified incidentally in the small bowel during an oncological resection of a synchronous primary pancreatic adenocarcinoma, and renal cell carcinoma. RESULTS： The patient underwent subtotal pancreatectomy with splenectomy, regional lymphadenectomy, radical left nephrectomy, and small bowel resection with primary anastomosis of ectopic PanlN-2. She had an uneventful hospitalization and was discharged home on postoperative day 7. CONCLUSIONS： The occurrence of ectopic PanIN is extremely unusual with only few cases previously reported in the literature. The need for negative margins after surgical resection of ectopic PanIN lesions remains controversial.

Clinical Observation of rhIL-2 Combined with Zhenqi Fuzheng and BaofuKang Suppository in the Treatment of Cervical Intraepithelial Neoplasia II with HPV Infection

Objective: To investigate the clinical effects of recombinant human interleukin-2 (rhIL-2) combined with Zhenqi Fuzheng and Baofukang on cervical intraepithelial neoplasia II (CINII) combined with human papilloma virus infection. Methods: There were 593 patients diagnosed with CINII with HPV infection, including 296 in the control group and 297 in the experimental group. The control group was given only Zhenqi Fuzheng oral and Baofukang suppository vaginal medicine. The experimental group was treated with rhIL-2 injection in addition to Zhenqi Fuzheng oral and Baofukang suppository vaginal medicine which is treated for 3 months. After 3 months, Thinprep cytologic test (TCT), human papilloma virus (HPV) quantitative examination and colposcopy biopsy were reviewed. Results: After 3 months of treatment, the negative conversion rate and total effective rate of HPV in the control group were 58.11% and 70.95% respectively, and the negative conversion rate and total effective rate of the experimental group were 79.46% and 90.57% respectively. There was significant difference between the two groups (p = 0.000). The curative rate of cervical lesions was significantly higher in the test group than in the control group, 89.56%, 68.91%, respectively. The statistical difference between the two groups is significant (p = 0.000). Conclusion: It has an essential clinical value that HPV infection patients and cervical intraepithelial neoplasia II associated with HPV infection patients are treated by rhIL-2 combined with Zhenqifuzheng and Baofukang, which is safe, effective, non-invasive, reusable advantages. However, the long-term efficacy and side effects need to be further studied.

Proteomic analysis of pancreatic intraepithelial neoplasia and pancreatic carcinoma in rat models

AIM:To detect the proteomic variabilities of pancreatic intraepithelial neoplasia(PanIN)and pancreatic carcinoma(PC)induced by 7,12-dimethylbenzanthracene(DMBA) in rat models and to identify potential biomarkers.METHODS:Sixty adult male Sprague Dawley rats were randomized into three groups.The rats had DMBA implanted into their pancreas for one(n=20)or two months(n=20)or assigned to the normal group(n =20).The rats were killed after one or two months,and were evaluated histopathologically.Three tissue samples from each group of rats with either normal pancreas,PanIN(PanIN-2)or PC were examined by 2D-DIGE.The different expression spot features were analyzed by matrix-assisted laser desorption/ionizationtime of flight/time of flight(MALDI-TOF/TOF)tandem mass spectrometry.The expression of enolase 1,a differentially expressed protein,was identified by immu-nohistochemistry.RESULTS:There was significant difference in the proportions of neoplastic changes between the 1-and 2-mogroups(P=0.0488).There was an increase in the frequency of adenocarcinomas in the 2-mo group compared with the 1-mo group(P=0.0309).No neoplastic changes were observed in any of the animals in the normal group.Enolase 1,pancreatic ELA3B,necdin,Hbp23,CHD3,hnRNP A2/B1,Rap80,and Gnb2l1 were up-regulated in the PanIN and PC tissues,and CEL,TPT1,NME2,PCK2,an unnamed protein product,and glycine C-acetyltransferase were down-regulated in the PanIN and PC tissues.The immunohistochemical results showed that enolase 1 expression was up-regulated in the pancreatic cancer tissues of rats and humans.CONCLUSION:The pancreatic protein expression changes induced by DMBA suggest potential molecular targets for the early diagnosis and treatment of PC.

Clinical efficacy and prognostic risk factors of endoscopic radiofrequency ablation for gastric low-grade intraepithelial neoplasia

BACKGROUND The use of radiofrequency ablation(RFA)has been reported in the treatment of gastric low-grade intraepithelial neoplasia(LGIN).However,its efficacy and prognostic risk factors have not been well analyzed.AIM To explore the efficacy and prognostic risk factors of RFA for gastric LGIN in a large,long-term follow-up clinical study.METHODS The clinical data of 271 consecutive cases from 198 patients who received RFA for treatment of gastric LGIN at the Chinese PLA General Hospital from October 2014 to October 2020 were reviewed in this retrospective study.Data on operative parameters,complications,and follow-up outcomes including curative rates were recorded and analyzed.RESULTS The curative rates of endoscopic RFA for gastric LGIN at 3 mo,6 mo,and 1-5 years after the operation were 93.3%,92.8%,91.5%,90.3%,88.5%,85.7%,and 83.3%,respectively.Multivariate analyses revealed that Helicobacter pylori(H.pylori)infection and disease duration>1 year had a significant effect on the curative rate(P<0.001 and P=0.013,respectively).None of patients had bleeding,perforation,infection,or other serious complications after RFA,and the main discomfort was postoperative abdominal pain.CONCLUSION RFA was safe and effective for gastric LGIN during long-term follow-up.H.pylori infection and disease course>1 year may be the main risk factors for relapse of LGIN after RFA.

Diagnosis of gastric intraepithelial neoplasia by narrow-band imaging and confocal laser endomicroscopy

AIM:To evaluate the diagnosis of different differentiated gastric intraepithelial neoplasia (IN) by magnifica-tion endoscopy combined with narrow-band imaging (ME-NBI) and confocal laser endomicroscopy (CLE). METHODS:Eligible patients with suspected gastric IN lesions previously diagnosed by endoscopy in secondary hospitals and scheduled for further diagnosis and tratment were recruited for this study. Excluded from the study were patients who had liver cirrhosis, impaired renal function, acute gastrointestinal (GI) bleeding, coagulopathy, esophageal varices, jaundice, and GI post-surgery. Also excluded were those who were pregnant, breastfeeding, were younger than 18 years old, or were unable to provide informed consent. All patients had all mucus and bile cleared from their stom-achs. They then received upper GI endoscopy. When a mucosal lesion is found during observation with whitelight imaging, the lesion is visualized using maximal magnification, employing gradual movement of the tip of the endoscope to bring the image into focus. Saved images are analyzed. Confocal images were evaluated by two endoscopists (Huang J and Li MY), who were familiar with CLE, blinded to the related information about the lesions, and asked to classify each lesion as either a low grade dysplasia (LGD) or high grade dysplasia (HGD) according to given criteria. The results were compared with the final histopathologic diagnosis. ME-NBI images were evaluated by two endoscopists (Lu ZS and Ling-Hu EQ) who were familiar with NBI, blinded to the related information about the lesions and CLE images, and were asked to classify each lesion as a LGD or HGD according to the "microvascular pattern and surface pattern" classification system. The results were compared with the final histopathologic diagnosis. RESULTS: The study included 32 pathology-proven low grade gastric IN and 26 pathology-proven high grade gastric IN that were detected with any of the modalities. CLE and ME-NBI enabled clear visualization of the vascular microsurface patterns and microvascular structures of the gastric mucosa. The accuracy of the CLE and the ME-NBI diagnosis was 88% (95% CI:78%-98%) and 81% (95% CI: 69%-93%), respectively. The kappa coefficient of agreement between the histopathology and the in vivo CLE imaging was 0.755; between the histopathology and the in vivo CLE imaging was 0.615. McNemar's test (binomial distribution used) indicated that the agreement was significant (P < 0.05). When patients were diagnosed by MENBI with CLE, the overall accuracy of the diagnosis was 86.21% (95% CI:73%-96%), and the kappa coefficient of agreement was 0.713, according to McNemar's test (P < 0.05). CONCLUSION:Higher diagnostic accuracy, sensitivityand specificity of CLE over ME-NBI indicate the feasibility of these two techniques for the efficacious diagnostic classification of gastric IN.

Mutations in the p16 gene in DMBA-induced pancreatic intraepithelial neoplasia and pancreatic cancer in rats

BACKGROUND：7,12-dimethylbenzanthracene（DMBA）-induced pancreatic intraepithelial neoplasia（PanIN）and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer.However,this model has not been characterized genetically,and in particular,the major genetic alterations in the p16 gene are unknown.METHODS： Lesions of PanlN and pancreatic cancer were induced with DMBA implantation in 40 rats, and control pancreatic tissue was obtained from 10 age-matched rats without exposure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozy- gous deletions and point mutations of the pl6 （exons 1 and 2） gene were detected by PCR amplification and direct sequencing. RESULTS： DMBA implantation in the 40 rats induced 26 Pan- INs and 9 carcinomas. The overall frequency of p 16 alterations in the pancreatic tissue of these rats was 42.86% （15/35）, and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% （8/26） of the rats with PanIN and 77.78% （7/9） of the rats with carcinoma （P〈0.05）. The increasing incidence of p16 alterations was detected in 20.00% （1/5） of PanIN-1, 28.57% （2/7） of PanIN-2 and 35.71% （5/14） of PanIN-3 lesions. CONCLUSION： Our findings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.

The Prevalence of High Grade Cervical Intraepithelial Neoplasia (CIN) in a Primary Human Papillomavirus (HPV) Cervical Screening Programme Population with HPV Positive and Cytology Negative Smear Results

High-risk HPV is found in 99.7% of cervical cancers. The causative role of HPV in cervical cancer has led to the inclusion of HPV testing as part of cervical screening. A pilot of HPV testing as primary screening was commenced in 2013 at six pilot sites in England. North Cumbria Integrated Care (NCIC) NHS Foundation Trust took part in the pilot, in which women with an HPV-positive/cytology-negative result were recalled at 12 months. Women with HPV type 16/18 found at initial screening and persisting at 12 months in spite of negative cytology were referred to Colposcopy services at 12 months. Women with smear positive for hrHPV other than 16/18 types were recalled twice at 12 and 24 months before referral to colposcopy. Persistent hrHPV positive/cytology negative smear at 12 and 24 months initiated a colposcopy referral. Objective: To assess the prevalence of high grade CIN and invasive cancer in patients referred to colposcopy services at NCIC NHS Foundation Trust with hrHPV positive/cytology negative smears. Method: The study was conducted at NCIC NHS Foundation Trust between January 2015 and December 2017. Data was collected retrospectively from the colposcopy data base (INFOFLEX). All patients with HPV positive/cytology negative smears seen in colposcopy clinic during the study period were included. Patients with high grade CIN, cervical glandular intraepithelial neoplasia (CGIN) or invasive cancer were recorded. Results: 763 women were included in the study. A total of 50 (6.6%) women had high grade CIN, CGIN or invasive cancer. 40 of these 50 women (80%) were treated by large loop excision of the transformation zone (LLETZ). Conclusion: HPV primary screening is more effective than cytology-based screening. A high grade HPV positive result with negative cytology, persisting for one year in type 16/18 and for two years in other high-risk HPV types, warrants referral for colposcopy, as 6.6% of women in this study had high grade or invasive pathology.

High-dose dietary zinc promotes prostate intraepithelial neoplasia in a murine tumor induction mode

To evaluate the role of high-dose dietary zinc in the process of prostate malignancy,60 Sprague-Dawley rats were randomly divided into four groups：tumor induction with carcinogen and hormone （group 1）,oral zinc administration without tumor induction （group 2）,oral zinc administration with tumor induction （group 3） and a control without zinc administration or tumor induction （group 4）. Zinc was supplied orally in the form of zinc sulfate heptahydrate dissolved in drinking water to groups 2 and 3 for 20 weeks. Although the serum level of zinc measured at 20 weeks was maintained similarly in each group （P = 0.082）,intraprostatic zinc concentrations were statistically different. Group 1 prostates contained the least amount of zinc in both the dorsolateral and ventral lobes at levels of 36.3 and 4.8 μg g^-1,respectively. However,in group 3,zinc levels increased in both lobes to 59.3 and 12.1 μg g^-1,respectively,comparable with that of group 4 （54.5±14.6 and 14.1±2.4 μg g^-1）. In spite of these increases in zinc concentration,the prevalence of prostate intraepithelial neoplasm was rather increased in group 3 （53.3% and 46.7%） compared with group 1 （33.3% and 33.3%） in both dorsolateral and ventral prostate lobes. Although prostate intraepithelial neoplasm did not develop in any prostate in group 4,zinc administration did induce prostate intraepithelial neoplasm in group 2 （46.7% and 40.0%）. Thus,although high dietary zinc increased intraprostatic zinc concentrations,it promoted,instead of preventing,prostate intraepithelial neoplasm in a murine prostate malignancy induction model.

Anal intraepithelial neoplasia: A review of diagnosis and management

Anal intraepithelial neoplasia(AIN) is a premalignant lesion of the anal mucosa that is a precursor to anal cancer. Although anal cancer is relatively uncommon, rates of this malignancy are steadily rising in the United States, and among certain high risk populations the incidence of anal cancer may exceed that of colon cancer. Risk factors for AIN and anal cancer consist of clinical factors and behaviors that are associated with the acquisition and persistence of human papilloma virus(HPV) infection. The strongest HPV-associated risk factors are HIV infection, receptive anal intercourse, and high risk sexual behavior. A history of HPVmediated genital cancer, which suggests infection with an oncogenic HPV strain, is another risk factor for AIN/anal cancer. Because progression of AIN to anal cancer is known to occur in some individuals over several years, screening for AIN and early anal cancer, as well as treatment of advanced AIN lesions, is reasonable in certain high-risk populations. Although randomized controlled trials evaluating screening and treatment outcomes are lacking, experts support routine screening for AIN in high risk populations. Screening is performed using anal cytological exams, similar to those performed in cervical cancer screening programs, along with direct tissue evaluation and biopsy via high resolution anoscopy. AIN can be treated using topical therapies such as imiquimod, 5-flurouracil, and trichloroacetic acid, as well as ablative therapies such as electrocautery and laser therapy. Reductions in AIN and anal cancer rates have been shown in studies where high-risk populations were vaccinated against the oncogenic strains of HPV. Currently, the CDC recommends both high-risk and average-risk populations be vaccinated against HPV infection using the quadrivalent or nonavalent vaccines. It is important for clinicians to be familiar with AIN and the role of HPV vaccination, particularly in high risk populations.

RELATIONSHIP BETWEEN CYCLIN G1 AND HUMAN PAPILLOMA VIRUS INFECTION IN CERVICAL INTRAEPITHELIAL NEOPLASIA AND CERVICAL CARCINOMA

Objective To evaluate the overexpression of cyclin G1 in cervical intraepithelial neoplasia (CIN) and cervical carcinoma, and the correlation between cyclin G1 and high-risk human papilloma virus (HPV) infection. Methods All of the specimens were obtained from the Department of Pathology of China-Japan Friendship Hospital from January 2000 to August 2004.We detected the expression of cyclin G1 with immunohistochemistry, HPV16/18 infection with in situ hybridization, and high-risk HPV infection with Hybrid capture system II (HC-II) in normal group (25 cases), CIN I (48 cases), CIN II (56 cases), CIN III (54 cases), and invasive cervical squamous-cell carcinoma (SCC, 31 cases). Results The positive rates of cyclin G1 expression in CIN(77.85%)and SCC cervical tissues (87.10%) were significantly higher than normal (8.00%, P<0.01), and the intensities of cyclin G1 expression in CIN(40.60%)and SCC cervical tissues (61.51%) were significantly higher than normal (2.72%, P<0.05). The positive rates and intensities of cyclin G1 expression increased gradually with the grade of cervical lesions. High-risk HPV infection rates were higher in CIN and SCC than normal groups (P<0.05). There was a positive correlation between cyclin G1 expression and high-risk HPV infection detected with HC-II (Kendall’s tau-b=0.316, 0.269, 0.352, and 0.474 in CIN I, CINII, CIN III, and SCC, respectively, P<0.05). Conclusions Cyclin G1 is overexpressed in CIN and SCC. Cyclin G1 may be a biomarker for detecting CIN and SCC. Cyclin G1 may play an important role in the oncogenesis of CIN and SCC by high-risk HPV infection.

Multiple therapeutic and preventive effects of 3,3'-diindolylmethane on cancers including prostate cancer and high grade prostatic intraepithelial neoplasia

Cruciferous vegetables belong to the plant family that has flowers with four equal-sized petals in the pattern of a crucifer cross.These vegetables are an abundant source of dietary phytochemicals,including glucosinolates and their hydrolysis products such as indole-3-carbinol（I3C） and 3,3＇-diindolylmethane（DIM）.By 2013,the total number of natural glucosinolates that have been documented is estimated to be 132.Recently,cruciferous vegetable intake has garnered great interest for its multiple health benefits such as anticancer,antiviral infections,human sex hormone regulation,and its therapeutic and preventive effects on prostate cancer and high grade prostatic intraepithelial neoplasia（HGPIN）.DIM is a hydrolysis product of glucosinolates and has been used in various trials.This review is to provide an insight into the latest developments of DIM in treating or preventing both prostate cancer and HGPIN.