Clinicopathologic factors and molecular markers related to lymph node metastasis in early gastric cancer

AIM: To analyze predictive factors for lymph node metastasis in early gastric cancer.METHODS: We analyzed 1104 patients with early gastric cancer(EGC) who underwent a gastrectomy with lymph-node dissection from May 2003 through July 2011. The clinicopathologic factors and molecular markers were assessed as predictors for lymph node metastasis. Molecular markers such as microsatellite instability, human mut L homolog 1, p53, epidermal growth factor receptor(EGFR) and human epidermal growth factor receptor 2(HER2) were included. The χ2 test and logistic regression analysis were used to determine clinicopathologic parameters.RESULTS: Lymph node metastasis was observed in 104(9.4%) of 1104 patients. Among 104 cases of lymph node positive patients, 24 patients(3.8%) were mucosal cancers and 80 patients(16.7%) were submucosal. According to histologic evaluation, the number of lymph node metastasis found was 4(1.7%) for well differentiated tubular adenocarcinoma, 45(11.3%) for moderately differentiated tubular adenocarcinoma, 36(14.8%) for poorly differentiated tubular adenocarcinoma, and 19(8.4%) for signet ring cell carcinoma. Of 690 EGC cases, 77 cases(11.2%) showed EGFR overexpression. HER2 overexpression was present in 110 cases(27.1%) of 406 EGC patients. With multivariate analysis, female gender(OR = 2.281, P = 0.009), presence of lymphovascular invasion(OR = 10.950, P < 0.0001), diameter(≥ 20 mm, OR = 3.173, P = 0.01), and EGFR overexpression(OR = 2.185, P = 0.044) were independent risk factors for lymph node involvement.CONCLUSION: Female gender, tumor size, lymphovascular invasion and EGFR overexpression were predictive risk factors for lymph node metastasis in EGC.

Sex-and gender-specific disparities in colorectal cancer risk

Colorectal cancer is one of the most common causes of cancer morbidity both in men and in women.However,females over 65 years old show higher mortality and lower 5-year survival rate of colorectal cancer compared to their age-matched male counterparts.The objective of this review is to suggest gender-based innovations to improve colorectal cancer outcomes in females.Women have a higher risk of developing right-sided(proximal) colon cancer than men,which is associated with more aggressive form of neoplasia compared to left-sided(distal) colon cancer.Despite differences in tumor location between women and men,most of scientific researchers do not consider sex specificity for study design and interpretation.Also,colorectal cancer screening guidelines do not distinguish females from male,which may explain the higher frequency of more advanced neoplasia when tumors are first detected and false negative results in colonoscopy in females.Moreover,socio-cultural barriers within females are present to delay screening and diagnosis.Few studies,among studies that included both men and women,have reported sex-specific estimates of dietary risk factors which are crucial to establish cancer prevention guidelines despite sex-and genderassociated differences in nutrient metabolism and dietary practices.Furthermore,anti-cancer drug use for colorectal cancer treatment can cause toxicity to the reproductive system,and gender-specific recurrence and survival rates are reported.Therefore,by understanding sex-and gender-related biological and socio-cultural differences in colorectal cancer risk,gender-specific strategies for screening,treatment and prevention protocols can be established to reduce the mortality and improve the quality of life.

Characteristics of gastric cancer in peptic ulcer patients with Helicobacter pylori infection

AIM:To evaluate the incidence and clinical characteristics of gastric cancer(GC) in peptic ulcer patients with Helicobacter pylori(H.pylori) infection.METHODS:Between January 2003 and December 2013, the medical records of patients diagnosed with GC were retrospectively reviewed.Those with previous gastric ulcer(GU) and H.pylori infection were assigned to the Hp GU-GC group(n = 86) and those with previous duodenal ulcer(DU) disease and H.pylori infection were assigned to the Hp DUGC group(n = 35).The incidence rates of GC in the Hp GU-GC and Hp DU-GC groups were analyzed.Data on demographics(age, gender, peptic ulcer complications and cancer treatment), GC clinical characteristics [location, pathological diagnosis, differentiation, T stage, Lauren's classification, atrophy of surrounding mucosa and intestinal metaplasia(IM)], outcome of eradication therapy for H.pylori infection, esophagogastroduodenoscopy number and the duration until GC onset were reviewed.Univariate and multivariate analyses were performed to identify factors influencing GC development.The relative risk of GC was evaluated using a Cox proportional hazards model.RESULTS:The incidence rates of GC were 3.60%(86/2387) in the Hp GU-GC group and 1.66%(35/2098) in the Hp DU-GC group.The annual incidence was 0.41% in the Hp GU-GC group and 0.11% in the Hp DUGC group.The rates of moderate-to-severe atrophy of the surrounding mucosa and IM were higher in the Hp GU-GC group than in the Hp DU-GC group(86% vs 34.3%, respectively, and 61.6% vs 14.3%, respectively, P < 0.05).In the univariate analysis, atrophy of surrounding mucosa, IM and eradication therapy for H.pylori infection were significantly associated with the development of GC(P < 0.05).There was no significant difference in the prognosis of GC patients between the Hp GU-GC and Hp DU-GC groups(P = 0.347).The relative risk of GC development in the Hp GUGC group compared to that of the Hp DU-GC group,after correction for age and gender,was 1.71(95%CI:1.09-2.70;P=0.02).CONCLUSION:GU patients with H.pylori infection had higher GC incidence rates and relative risks.Atrophy of surrounding mucosa,IM and eradication therapy were associated with GC.

New approaches to gastric cancer staging:Beyond endoscopic ultrasound,computed tomography and positron emission tomography

Currently, there is no single gold standard modality for staging of gastric cancer and several methods have been used complementarily in the each clinical situation. To make up for the shortcomings of conventional modalities such as endoscopic ultrasound, computed tomography and 18F-fluoro-2-deoxyglucose positron emission tomography, numerous attempts with new approaches have been made for gastric cancer staging. For T staging, magnifying endoscopy with narrow-band was evaluated to differentiate mucosal cancer from submucosal cancer. Single/double contrast-enhanced ultrasound and diffusion-weighted magnetic resonance imaging were also tried to improve diagnostic accuracy of gastric cancer. For intraoperative staging with sentinel node mapping, indocyanine green infrared and fluorescence imaging was introduced. In addition, to detect micrometastasis, real-time reverse transcription-polymerase chain reaction system with multiple markers was studied. Staging laparoscopy using 5-aminolevulinic acid-mediated photodynamic diagnosis and percutaneous diagnostic peritoneal lavage were also evaluated. However, most studies reporting new staging methods is preliminary and further studies for validation in clinical practice are needed. In this mini-review, we discuss new progress in gastric cancer staging. Especially, we focus on new diagnostic approach to gastric cancer staging beyond the conventional modalities and briefly review the remarkable clinical results of the studies published over the past three years.

Clinicopathologic and molecular features associated with patient age in gastric cancer

AIM: To compare characteristics and prognosis of gastric cancer based on age.METHODS: A retrospective study was conducted on clinical and molecular data from patients(n =1658) with confirmed cases of gastric cancer in Seoul National University Bundang Hospital(Seoul, South Korea) from 2003 to 2010 after exclusion of patients diagnosed with lymphoma, gastrointestinal stromal tumor, and metastatic cancer in the stomach. DNA was isolated from tumor and adjacent normal tissue,and a set of five markers was amplified by polymerase chain reaction to assess microsatellite instability(MSI). MSI was categorized as high, low, or stable if ≥ 2, 1, or 0 markers, respectively, had changed.Immunohistochemistry was performed on tissue sections to detect levels of expression of p53, human epidermal growth factor receptor(HER)-2, and epidermal growth factor receptor. Statistical analysis of clinical and molecular data was performed to assess prognosis based on the stratification of patients by age(≤ 45 and> 45 years).RESULTS: Among the 1658 gastric cancer patients, the number of patients with an age ≤ 45 years was 202(12.2%; 38.9 ± 0.4 years) and the number of patients> 45 years was 1456(87.8%; 64.1 ± 0.3 years).Analyses revealed that females were predominant inthe younger group(P < 0.001). Gastric cancers in the younger patients exhibited more aggressive features and were at a more advanced stage than those in older patients. Precancerous lesions, such as atrophic gastritis and intestinal metaplasia, were observed less frequently in the older than in the younger group(P < 0.001). Molecular characteristics, including overexpression of p53(P < 0.001), overexpression of HER-2(P = 0.006), and MSI(P = 0.006), were less frequent in gastric cancer of younger patients. Cancer related mortality was higher in younger patients(P= 0.048), but this difference was not significant after adjusting for the stage of cancer.CONCLUSION: Gastric cancer is distinguishable between younger and older patients based on both clinicopathologic and molecular features, but stage is the most important predictor of prognosis.

Optimal initiation of Helicobacter pylori eradication in patients with peptic ulcer bleeding

AIM:To evaluate when Helicobacter pylori(H.pylori)eradication therapy(ET)should be started in patients with peptic ulcer bleeding(PUB).METHODS:Clinical data concerning adults hospitalizedwith PUB were retrospectively collected and analyzed.Age,sex,type and stage of peptic ulcer,whether endoscopic therapy was performed or not,methods of H.pylori detection,duration of hospitalization,and specialty of the attending physician were investigated.Factors influencing the confirmation of H.pylori infection prior to discharge were determined using multiple logistic regression analysis.The H.pylori eradication rates of patients who received ET during hospitalization and those who commenced ET as outpatients were compared.RESULTS:A total of 232 patients with PUB were evaluated for H.pylori infection by histology and/or rapid urease testing.Of these patients,53.7%(127/232)had confirmed results of H.pylori infection prior to discharge.In multivariate analysis,duration of hospitalization and ulcer stage were factors independently influencing whether H.pylori infection was confirmed before or after discharge.Among the patients discharged before confirmation of H.pylori infection,13.3%(14/105)were lost to follow-up.Among the patients found to be H.pylori-positive after discharge,41.4%(12/29)did not receive ET.There was no significant difference in the H.pylori eradication rate between patients who received ET during hospitalization a n d t h o s e w h o c o m m e n c e d E T a s o u t p a t i e n t s[intention-to-treat:68.8%(53/77)vs 60%(12/20),P=0.594;per-protocol:82.8%(53/64)vs 80%(12/15),P=0.723].CONCLUSION:Because many patients with PUB who were discharged before H.pylori infection status was confirmed lost an opportunity to receive ET,we should confirm H.pylori infection and start ET prior to discharge.

Two-year delay in ulcerative colitis diagnosis is associated with anti-tumor necrosis factor alpha use

BACKGROUND Ulcerative colitis(UC)is an uncommon inflammatory bowel disease(IBD).However,its incidence has recently increased in South Korea.Moreover,UC diagnoses are frequently delayed,and the relationship between diagnostic delay and UC prognosis has not been extensively studied in South Korean patients.AIM To identify meaningful diagnostic delay affecting UC prognosis and to evaluate risk factors associated with diagnostic delay in South Korean patients.METHODS Medical records of 718 patients with UC who visited the outpatient clinic of six university hospitals in South Korea were reviewed;167 cases were excluded because the first symptom date was unknown.We evaluated the relationship between the prognosis and a diagnostic delay of 3,6,12,18,and 24 mo by comparing the prognostic factors[anti-tumor necrosis factor(TNF)-αuse,admission history due to acute flare-ups,frequent admission due to flare-ups,surgery associated with UC,and the clinical remission state at the latest followup]at each diagnostic interval.RESULTS The mean diagnostic interval was 223.3±483.2 d(median,69 d;75th percentile,195 d).Among the prognostic factors,anti-TNFαuse was significantly increased after a diagnostic delay of 24 mo.Clinical risk factors predictive of a 24-mo diagnostic delay were age<60 years at diagnosis[odd ratio(OR)=14.778,95%confidence interval(CI):1.731-126.121],smoking history(OR=2.688,95%CI:1.239-5.747,P=0.012),and misdiagnosis of hemorrhoids(OR=11.066,95%CI:3.596-34.053).Anti-TNFαuse was associated with extensive UC at diagnosis(OR=3.768,95%CI:1.860-7.632)and 24-mo diagnostic delay(OR=2.599,95%CI:1.006-4.916).CONCLUSION A diagnostic delay>24 mo was associated with increased anti-TNFαuse.Age<60 years at diagnosis,smoking history,and misdiagnosis of hemorrhoids were risk factors for delayed diagnosis.

Eradication rate and histological changes after Helicobacter pylori eradication treatment in gastric cancer patients following subtotal gastrectomy

AIM: To investigate the eradication rate and histological changes after Helicobacter pylori(H. pylori) eradication treatment following subtotal gastrectomy for gastric cancer.METHODS: A total of 610 patients with H. pylori infection who had undergone surgery for either early or advanced gastric adenocarcinoma between May 2004 and December 2010 were retrospectively studied. A total of 584 patients with proven H. pylori infection after surgery for gastric cancer were enrolled in this study. Patients received a seven day standard triple regimen as first-line therapy and a 10 d bismuthcontaining quadruple regimen as second-line therapy in cases of eradication failure. The patients underwent an esophagogastroduodenoscopy(EGD) between six and 12 mo after surgery, followed by annual EGDs. A further EGD was conducted 12 mo after confirming the result of the eradication and the histological changes. A gastric biopsy specimen for histological examination and Campylobacter-like organism testing was obtained from the lesser and greater curvature of the corpus of the remnant stomach. Histological changes in the gastric mucosa were assessed using the updated Sydney system before eradication therapy and at follow-up after 12 mo.RESULTS: Eradication rates with the first-line and second-line therapies were 78.4%(458/584) and 90%(36/40), respectively, by intention-to-treat analysis and 85.3%(458/530) and 92.3%(36/39), respectively, by per-protocol analysis. The univariate and multivariate analyses revealed that Billroth Ⅱ surgery was an independent factor predictive of eradication success in the eradication success group(OR = 1.53, 95%CI: 1.41-1.65, P = 0.021). The atrophy and intestinal metaplasia(IM) scores 12 mo after eradication were significantly lower in the eradication success group than in the eradication failure group(0.25 ± 0.04 vs 0.47 ± 0.12, P = 0.023; 0.27 ± 0.04 vs 0.51 ± 0.12, P = 0.015, respectively). The atrophy and IM scores 12 mo after successful eradication were significantly lower in the Billroth Ⅱ group than in the Billroth I group(0.13 ± 0.09 vs 0.31 ± 0.12, P = 0.029; 0.32 ± 0.24 vs 0.37 ± 0.13, P = 0.034, respectively).CONCLUSION: Patients with H. pylori following subtotal gastrectomy had a similar eradication rate to patients with an intact stomach. H. pylori eradication is recommended after subtotal gastrectomy.

Fourteen- vs seven-day bismuth-based quadruple therapy for second-line Helicobacter pylori eradication

AIM: To compare the efficacy of 14- and 7-d bismuthbased quadruple therapies as second-line eradication treatment for Helicobacter pylori(H.pylori) infection.METHODS: Between 2004 and 2014,the medical records of 790 patients who had experienced failure of first-line proton pump inhibitor(PPI)-based eradication therapy and were then treated with bismuth-based quadruple therapy were retrospectively reviewed.Those who received bismuth-based quadruple therapy [PPI,bismuth,metronidazole,and tetracycline(PBMT)] for either 7 d or 14 d were assigned to a PBMT-7 group(n = 543) or a PBMT-14 group(n = 247),respectively.The eradication rates for both groups were determined by intention-to-treat(ITT) and per-protocol(PP) analyses.ITT analysis compared the treatment groups as originally allocated while the PP analysis including only those patients who had completed the treatment as originally allocated.Successful eradication therapy for H.pylori infection was defined as a negative 13C-urea breath test 4 wk after the end of eradication treatment.RESULTS: The overall ITT eradication rate was 69.1%(546/790).Final ITT eradication rates were 67.4%(366/543; 95%CI: 63.1%-71.7%) in the PBMT-7 group and 72.8%(180/247; 95%CI: 67.4%-78.2%) in the PBMT-14 group(P = 0.028).The overall PP eradication rate was 80.0%(546/682),and the final PP eradication rates were 78.2%(366/468; 95%CI: 72.1%-84.0%) in the PBMT-7 group and 84.1%(180/214; 95%CI: 76.8%-90.8%) in the PBMT-14 group(P = 0.009).The H.pylori eradication rates in the PBMT-14 group weresignificantly higher than in the PBMT-7 group according to both ITT(P = 0.028) and PP analysis(P = 0.009).Compliance was similar in both groups(PBMT-7 group: 97.9%; PBMT-14 group: 96.4%).Adverse event rates were 10.7%(51/478) and 17.1%(38/222) in the PBMT-7 and PBMT-14 groups,respectively(P = 0.487).CONCLUSION: The 14-d bismuth-based quadruple therapy is a significantly more effective second-line eradication treatment for H.pylori infection than the 7-d alternative.

Efficacy of moxifloxacin-based sequential therapy for first-line eradication of Helicobacter pylori infection in gastrointestinal disease

AIM:To evaluate the efficacy of 14-d moxifloxacinbased sequential therapy as first-line eradication treatment of Helicobacter pylori(H.pylori) infection.METHODS:From December 2013 to August 2014, 161 patients with confirmed H.pylori infection randomly received 14 d of moxifloxacin-based sequential group(MOX-ST group, n = 80) or clarithromycin-based sequential group(CLA-ST group, n = 81) therapy.H.pylori infection was defined on the basis of at least one of the following three tests:a positive 13C-urea breath test; histologic evidence of H.pylori by modified Giemsa staining; or a positive rapid urease test(CLOtest; Delta West, Bentley, Australia) by gastric mucosal biopsy.Successful eradication therapy for H.pylori infection was defined as a negative 13C-urea breath test four weeks after the end of eradication treatment.Compliance was defined as good when drug intake was at least 85%.H.pylori eradication rates, patient compliance with drug treatment, adverse event rates, and factors influencing the efficacy of eradication therapy were evaluated.RESULTS:The eradication rates by intention-to-treat analysis were 91.3%(73/80;95%CI:86.2%-95.4%)in the MOX-ST group and 71.6%(58/81;95%CI:65.8%-77.4%)in the CLA-ST group(P=0.014).The eradication rates by per-protocol analysis were 93.6%(73/78;95%CI:89.1%-98.1%)in the MOX-ST group and 75.3%(58/77;95%CI:69.4%-81.8%)in the CLAST group(P=0.022).Compliance was 100%in both groups.The adverse event rates were 12.8%(10/78)and 24.6%(19/77)in the MOX-ST and CLA-ST group,respectively(P=0.038).Most of the adverse events were mild-to-moderate in intensity;there was none serious enough to cause discontinuation of treatmentin either group.In multivariate analysis,advanced age(≥60 years)was a significant independent factor related to the eradication failure in the CLA-ST group(adjusted OR=2.13,95%CI:1.97-2.29,P=0.004),whereas there was no significance in the MOX-ST group.CONCLUSION:The 14-d moxifloxacin-based sequential therapy is effective.Moreover,it shows excellent patient compliance and safety compared to the 14-d clarithromycin-based sequential therapy.

Efficacy of moxifloxacin-based sequential and hybrid therapy for first-line Helicobacter pylori eradication

AIM: To evaluate the efficacy of moxifloxacin-based sequential therapy(MBST) versus hybrid therapy as a first-line treatment for Helicobacter pylori(H. pylori) infection.METHODS: From August 2014 to January 2015, 284 patients with confirmed H. pylori infection were randomized to receive a 14-d course of MBST(MBST group, n = 140) or hybrid(Hybrid group, n = 144) therapy. The MBST group received 20 mg rabeprazole and 1 g amoxicillin twice daily for 7 d, followed by 20 mg rabeprazole and 500 mg metronidazole twice daily, and 400 mg moxifloxacin once daily for 7 d. The Hybrid group received 20 mg rabeprazole and 1 g amoxicillin twice daily for 14 d. In addition, the Hybrid group received 500 mg metronidazole and 500 mg clarithromycin twice daily for the final 7 d. Successful eradication of H. pylori infection was defined as a negative 13C-urea breath test 4 wk after the end of treatment. Patient compliance was defined as "good" if drug intake was at least 85%. H. pylori eradication rates, patient compliance with treatment, and adverse event rates were evaluated.RESULTS: The eradication rates in the intention-totreat(ITT) analysis were 91.4%(128/140; 95%CI: 90.2%-92.9%) in the MBST group and 79.2%(114/144; 95%CI: 77.3%-80.7%) in the Hybrid group(P = 0.013). The eradication rates in the perprotocol(PP) analysis were 94.1%(128/136; 95%CI: 92.9%-95.6%) in the MBST group and 82.6%(114/138; 95%CI: 80.6%-84.1%) in the Hybrid group(P = 0.003). The H. pylori eradication rate in the MBST group was significantly higher than that of the Hybrid group for both the ITT(P = 0.013) and the PP analyses(P = 0.003). Both groups exhibited full compliance with treatment(MBST/Hybrid group: 100%/100%). The rate of adverse events was 11.8%(16/136) and 19.6%(27/138) in the MBST and Hybrid group, respectively(P = 0.019). The majority of adverse events were mild-to-moderate in intensity; none were severe enough to cause discontinuation of treatment in either group.CONCLUSION: MBST was more effective and led to fewer adverse events than hybrid therapy as a first-line treatment for H. pylori infection.

Sex-based differences in histology,staging,and prognosis among 2983 gastric cancer surgery patients

BACKGROUND Few studies have been conducted on sex differences in the incidence, pathophysiology, and prognosis of gastric cancer(GC).AIM To analyze the differences in GC characteristics according to sex in patients who underwent surgical treatment for GC.METHODS A total of 2983 patients diagnosed with gastric adenocarcinoma who received surgical treatment at the Seoul National University Bundang Hospital between 2003 and 2017 were included.Baseline clinicopathological characteristics, histologic type of GC, overall and GC-specific survival rates, and associated risk factors were analyzed.RESULTS Among the 2983 patients, 2005(67.2%) and 978(32.8%) were males and females, respectively.The average age of the female group(59.36 years) was significantly younger than that of the male group(61.66 years;P < 0.001).Cancer of the gastric body(P < 0.001) and diffuse-type histology(P < 0.001) were more common in females than in males.This trend was more prominent in females younger than 60 years of age, with a significantly higher proportion of diffuse-type cancer than in the male group.Regardless of sex, diffuse-type GC was more common in younger patients, and the proportion of intestinal-type GC increased with age.The overall survival rate was significantly higher in females(P < 0.001).However, this difference disappeared for GC-specific survival(P = 0.168), except for the poor GC-specific survival rate in advanced-stage cancer(stage Ⅲ or above) in females(P = 0.045).The risk factors for GC-related mortality were older age, upper location of GC, and diffuse-or mixed-type histology.In terms of comorbidities, more males died from diseases other than GC, including other malignancies such as lung cancer, hepatocellular carcinoma, and pancreatic cancer, and respiratory diseases such as interstitial lung disease and chronic obstructive pulmonary disease, while there were relatively more cardiovascular or cerebrovascular deaths in females.CONCLUSION Sex-based differences in GC were observed in clinicopathological features, including age at diagnosis, tumor location, histologic type, survival rate, and comorbidities.

Helicobacter pylori eradication with moxifloxacin-containing therapy following failed first-line therapies in South korea

AIM: To investigate moxifloxacin-containing triple therapy as second-line treatment for Helicobacter pylori (H. pylori) infection following failed first-line treatment.