Tumor immune response and immunotherapy in gastric cancer

Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.

Genomic Analysis of miR-21-3p and Expression Pattern with Target Gene in Olive Flounder

MicroRNAs (miRNAs) act as regulators of gene expression by binding to the 3’ untranslated region (UTR) of target genes. They perform important biological functions in the various species. Among many miRNAs, miR-21-3p is known to serve vital functions in development and apoptosis in olive flounder. Using genomic and bioinformatic tools, evolutionary conservation of miR-21-3p was examined in various species, and expression pattern was analyzed in olive flounder. Conserved sequences (5’-CAGUCG-3’) in numerous species were detected through the stem-loop structure of miR-21-3p. Thus, we analyzed target genes of miR-21-3p. Among them, 3’ UTR region of PPIL2 gene indicated the highest binding affinity with miR-21-3p based on the minimum free energy value. The PPIL2 gene showed high expression levels in testis tissue of the olive flounder, whereas miR-21-3p showed rather ubiquitous expression patterns except in testis tissue, indicating that miR-21-3p seems to control the PPIL2 gene expression in a complementary repression manner in various tissues of olive flounder. Taken together, this current study contributes to infer the target gene candidates for the miR-21-3p using bioinformatics tools. Furthermore, our data offers important information on the relationship between miR-21-3p and target gene for further functional study.

Update on the Proposal for Creating a Guideline for Cancer Registration of the Gastrointestinal Tumors (I-2)

BACKGROUND: Cancer registries play a fundamental role in cancer control and multicenter collaborative research. Recently, the need for reassessment of cancer registry criteria has arisen due to the newly released 2010 World Health Organization (WHO) classification. Accordingly, development of new coding guidelines for cancer is necessary to improve the quality of cancer registries, as well as to prevent conflicts that may arise when seeking medical insurance compensation. METHODS: With funding from the Management Center for Health Promotion, 35 members of the Gastrointestinal Pathology Study Group and the Cancer Registration Committee of the Korean Society of Pathologists (KSP) participated in a second workshop for gastrointestinal tumor registration in Korea. RESULTS: The topics of gastric epithelial tumor, colonic intramucosal carcinoma, neuroendocrine tumor (NET), gastrointestinal stromal tumor (GIST) and appendiceal mucinous tumor were discussed for new coding guidelines. A survey was then conducted among 208 members of the KSP for a consensus of the guidelines proposed in the workshop. CONCLUSIONS: Although a few issues were set aside for further discussion, such as coding for non-gastric GIST and some types of NET, the members agreed upon most of the proposed guidelines. Therefore, we suggest using the newly revised International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) coding guidelines for registering gastrointestinal tumors in Korea.

Markers for Screening Lynch Syndrome Are Reliable and Useful for Identifying the Specimen Mislabeling

BACKGROUND: During specimen processing in surgical pathology laboratories, specimen-related adverse events (SRAEs), such as mislabeling and specimen mixed-up might occur. In these situations, molecular techniques using short tandem repeat (STR) loci are required to identify the personal identity. Microsatellite instability (MSI) test is widely used for screening the hereditary non-polyposis colon cancer (Lynch syndrome) in surgical pathologies using polymorphic STR markers. We tried to evaluate the applicability of the MSI test for SRAEs. METHODS: We obtained 253 MSI test results to analyze the allele frequencies. After calibrating the estimated nucleotide lengths, we calculated the allele frequencies, a random match probability, and a likelihood ratio (LR) of three dinucleotide STR markers (D5S349, D17S250, and D2S123). RESULTS: The distribution of LR was 136.38 to 5,606,213.10. There was no case of LR10,000. Furthermore, the combined probability of identity was 9.23x10(-4) and the combined power of exclusion was 0.99908. CONCLUSIONS: Using the three STR markers that are recommended for MSI test, all the cases were positively identified in 1% range and about one-third cases showed high LR (>10,000). These results showed that MSI tests are useful to screen the personal identity in case of SRAE in pathology laboratories.

CDX1 and CDX2 Expression in Intestinal Metaplasia, Dysplasia and Gastric Cancer

Intestinal metaplasia (IM) has been regarded as a premalignant condition. However, the pathogenesis of IM is not fully understood. The aim of this study was to evaluate the role of CDX1 and CDX2 in the formation of IM and the progression to dysplasia and gastric cancer (GC). A total of 270 subjects included 90 with GC, dysplasia and age- and sex-matched controls. Real-time PCR (RT-PCR) was performed with body specimens for CDX1 and CDX2. The expression of CDX2 was significantly higher in H. pylori positive group than H. pylori negative group (P = 0.045). CDX1 and CDX2 expression increased proportional to the IM grade of the body (P < 0.001). CDX2 expression was significantly higher in incomplete type of IM than in complete type (P = 0.045). The expression of CDX1 in dysplasia group was significantly higher than in the control group (P = 0.001); in addition, CDX1 and CDX2 in cancer group was significantly higher than control group (P < 0.001, and P < 0.001, respectively). Aberrant expression of CDX1 and CDX2 correlated with H. pylori infection and grade of IM in the body. Furthermore, the results suggest that CDX1 and CDX2 play a role in the progression to GC and dysplasia.

Current Trends in the Epidemiological and Pathological Characteristics of Gastrointestinal Stromal Tumors in Korea, 2003-2004

Despite remarkable progress in understanding and treating gastrointestinal stromal tumors (GISTs) during the past two decades, the pathological characteristics of GISTs have not been made clear yet. Furthermore, concrete diagnostic criteria of malignant GISTs are still uncertain. We collected pathology reports of 1,227 GISTs from 38 hospitals in Korea between 2003 and 2004 and evaluated the efficacy of the NIH and AFIP classification schemes as well as the prognostic factors among pathologic findings. The incidence of GISTs in Korea is about 1.6 to 2.2 patients per 100,000. Extra-gastrointestinal GISTs (10.1%) are more common in Korea than in Western countries. In univariate analysis, gender, age, tumor location, size, mitosis, tumor necrosis, vascular and mucosal invasions, histologic type, CD34 and s-100 protein expression, and classifications by the NIH and AFIP criteria were found to be significantly correlated with patient's survival. However, the primary tumor location, stage and classification of the AFIP criteria were prognostically significant in predicting patient's survival in multivariate analysis. The GIST classification based on original tumor location, size, and mitosis is more efficient than the NIH criteria in predicting patient's survival, but the mechanism still needs to be clarified through future studies.

Five-years of Breast Cancer Management in a New Hospital: Analysis Using Clinical Data Warehouse / 한국유방암학회지

PURPOSE: This study is to review the initial 5-years of breast cancer management in a single hospital using the clinical data warehouse (CDW). METHODS: We reviewed the electronic medical records of 754 patients with breast cancer who were treated by a single surgeon between June 2003 and December 2007 in Seoul National University Bundang Hospital. We analyzed the epidemiological, clinical and therapeutic profiles of the breast cancer patients which were encoded and stored at the CDW. RESULTS: The mean age of the patients was 49.3 years and the peak incidence was in the fifth decade (36.6%). Symptomatic breast cancer was 74.6% and screening-detected breast cancer was 25.4%. Breast conserving surgery (BCS) was performed in 54.1% of all cases and the BCS rate increased annually. Immediate reconstruction after mastectomy was performed in 62 cases (17.7%). Sentinel lymph node (SLN) biopsy for nodal staging was performed in 501 cases (72.1%) and 160 cases (23.0%) underwent complete axillary lymph node dissection. The proportion of in situ and early stage invasive breast cancer was 85.0%. Six hundred and ninety three patients (92.5%) received more than one adjuvant therapy. Thirty one patients experienced local or systemic relapse after surgery and ipsilateral breast tumor recurrence (IBTR) occurred in 6 cases. The median follow-up period was 29.5 months. Two-year and 3-year disease-free survival rates were 95.9% and 94.4%. CONCLUSION: BCS and SLN biopsy continuously increased and immediate reconstruction after mastectomy was performed widely. Most patients received more than one adjuvant therapy. Moreover, we saved the time and human power to review the medical record by using the CDW.

Five-years of Breast Cancer Management in a New Hospital: Analysis Using Clinical Data Warehouse / 한국유방암학회지

PURPOSE: This study is to review the initial 5-years of breast cancer management in a single hospital using the clinical data warehouse (CDW). METHODS: We reviewed the electronic medical records of 754 patients with breast cancer who were treated by a single surgeon between June 2003 and December 2007 in Seoul National University Bundang Hospital. We analyzed the epidemiological, clinical and therapeutic profiles of the breast cancer patients which were encoded and stored at the CDW. RESULTS: The mean age of the patients was 49.3 years and the peak incidence was in the fifth decade (36.6%). Symptomatic breast cancer was 74.6% and screening-detected breast cancer was 25.4%. Breast conserving surgery (BCS) was performed in 54.1% of all cases and the BCS rate increased annually. Immediate reconstruction after mastectomy was performed in 62 cases (17.7%). Sentinel lymph node (SLN) biopsy for nodal staging was performed in 501 cases (72.1%) and 160 cases (23.0%) underwent complete axillary lymph node dissection. The proportion of in situ and early stage invasive breast cancer was 85.0%. Six hundred and ninety three patients (92.5%) received more than one adjuvant therapy. Thirty one patients experienced local or systemic relapse after surgery and ipsilateral breast tumor recurrence (IBTR) occurred in 6 cases. The median follow-up period was 29.5 months. Two-year and 3-year disease-free survival rates were 95.9% and 94.4%. CONCLUSION: BCS and SLN biopsy continuously increased and immediate reconstruction after mastectomy was performed widely. Most patients received more than one adjuvant therapy. Moreover, we saved the time and human power to review the medical record by using the CDW.

Adenoma of the Nipple

Adenoma of the nipple (AN) is an uncommon benign tumor of the breast. This tumor usually arises from the lactiferous ducts of the nipple. The common clinical findings are unilateral serosanguinous discharge with crust and a palpable nodule in the nipple. The symptoms and signs of AN are similar to those of Paget's disease and this confusion sometimes leads to unnecessary mastectomy. Thus performing careful clinical and histological examinations along with radiologic investigations are very important for the proper management of AN. This tumor is usually treated by total excision of the nipple. We report here on two cases of AN in two women who presented with red swelling, serosanguinous discharge and erosion of the nipple. We successfully managed them with partial excision or total excision along with reconstruction. Although AN is a relatively rare disease, surgeons should keep the diagnosis in mind for the proper management of this disease.

Hydrops Fetalis Due to Parvovirus B19 Infection: Report of Two Autopsy Cases

Hydrops fetalis (HF) is a disease characterized by generalized subcutaneous edema and cavity effusion in the fetal stage. We report here on two autopsy cases of HF that were caused by parvovirus B19 (PVB19) infection. The human PVB19 is an erythrovirus that cause diverse clinical manifestations ranging from an asymptomatic or mild presentation to more severe effects such as hydrops fetalis, and this is the only known human pathogenic parvovirus. The gestational ages of the two fetuses were 21 weeks and 23 weeks, respectively. Both fetuses were hydropic and anemic. Hepatic tissues of both fetuses demonstrated erythroblasts with eosinophilic intranuclear inclusions, the so called "lantern cells". PVB19 was confirmed by electron microscopy and immunohistochemical staining. For the diagnosis of this disease, recognition of parvovirus infection as a cause of hydrops fetalis and careful examination of red blood cells with a high-power view are required.

Pathological Analysis of 1,000 Cases of Transrectal Ultrasoundguided Systematic Prostate Biopsy: Establishment of New Sample Processing Method and Diagnostic Utility of Immunohistochemistry

BACKGROUND: We developed a new processing method for extended prostate needle biopsy, and evaluated diagnostic utility of routine immunohistochemistry in 1,000 consecutive unselected cases of transrectal ultrasound-guided systematic prostate biopsy. METHODS: Four to five biopsy cores were embedded in one paraffin block. All the biopsy cores were immunohistochemically stained with basal cell markers. RESULTS: The new sample processing method was technically perfect for making a diagnosis from extended prostate needle biopsy. Among 1,000 cases, there were 323 cases (32.3%) of adenocarcinoma, 5 cases of other malignant tumors, 9 cases of high-grade prostatic intraepithelial neoplasia without a carcinoma, and only 8 cases of atypical small acinar proliferation. Among the 323 cases of adenocarcinoma, there were 38 cases (11.8%) of microcarcinomas <0.1 cm and 101 cases (31.3%) of small adenocarcinomas <0.3 cm in length. In the needle biopsy specimens, 59 cases (18.3%) were classified as clinically insignificant carcinomas. Among them, 37 cases underwent radical prostatectomy, which turned out to be clinically significant carcinomas in 24 cases (64.9%). CONCLUSIONS: Routinely performed immunohistochemistry combined with the new sample processing method is very effective for detecting microscopic carcinoma foci as well as differentiating carcinoma from benign conditions mimicking cancer.

Undifferentiated Carcinoma Arising in a Choledochal Cyst: A Case Report

An association between choledochal cyst and carcinoma is well established. Here, we report an extremely rare case of undifferentiated carcinoma exhibiting extensive sarcomatous features arising in a choledochal cyst. The patient in our case had a radiologically confirmed choledochal cyst and anomalous pancreaticobiliary ductal union, and mild wall thickening in the cyst was observed on endoscopic retrograde cholangiopancreatography. The patient underwent common bile duct excision and cholecystectomy. In the choledochal cyst, a nodule measuring 1.5x1 cm was detected. The lesion was composed of atypical, spindle-shaped and large, round pleomorphic tumor cells simulating sarcoma. Neither glandular nor squamous differentiation was observed. These cells were immunoreactive for both vimentin and cytokeratin by immunohistochemistry. These histologic and immunohistochemical findings were consistent with undifferentiated carcinoma, spindle and giant cell type, according to the WHO classification.

Pathologic Features of Korean Prostate Adenocarcinoma: Mapping Analysis of 83 Cases

BACKGROUND :Prostatic adenocarcinoma makes up about 2% of the total cancer incidence and cancer death in Korean men, but the incidence of this malady is continuously increasing. So far, there have been only a few studies describing the pathologic characteristics of the prostatic adenocarcinoma in Korean patients. In this study, we analyzed 83 radical prostatectomy specimens by using mapping analysis to discover the clinico pathologic characteristics of Korean prostatic adenocarcinoma. METHODS: The resected prostates were serially sectioned and embedded for histologic mapping. The clinico pathologic findings, including the Gleason score, tumor size, prostate intraepithelial neoplasia (PIN) and tumor invasion to the surrounding tissues, were examined. RESULTS: The mean values were as follows: age, 64.1+/-6.6 years; serum prostate specific antigen (sPSA), 16.6+/-16.2 ng/mL; tumor volume, 22.3+/-22.4%; tumor size, 2.2+/-1.2 cm; and Gleason score, 6.9+/-0.9. The rate of high grade PIN was 79.7%. The Gleason score, tumor extent and T stage were statistically correlated (p<0.05). CONCLUSIONS: Some prognostic factors such as sPSA and the Gleason scores showed significantly lower levels compared with those of the previous studies on Korean prostate adenocarcinoma (16-36 ng/mL vs 16.6 ng/mL and 7.3-7.7 vs 6.9, respectively). Although these values are still higher than those of the western studies, this study implies that the early detection of prostate adenocarcinoma is increasing in Korea.

Immunohistochemical Characteristics of Kaposi Sarcoma and its Mimicries

BACKGROUND: The differential diagnosis of Kaposi sarcoma includes many disease that range from benign disease to malignant tumors. However, little information is available about the immunohistochemical characteristics of Kaposi sarcoma. METHODS: The expressions of 13 various proteins (HHV-8 LNA-1, Ki-67, bcl-2, p53, CD31, CD34, factor VIII, D2-40, vimentin, SMA, S-100, EMA, and c-kit) were evaluated immunohistochemically in 49 vascular tumors including 16 Kaposi sarcomas, 8 angiosarcomas, 2 hemangioendotheliomas, and 23 benign vascular tumors with using the tissue array method. RESULTS: All 16 cases of Kaposi sarcoma showed nuclear staining for HHV-8 LNA-1, whereas all the cases of angiosarcoma and benign vascular lesions were negative for HHV-8 LNA-1 (p0.05). No Kaposi sarcoma showed a bcl-2 expression, but 62.5% of the angiosarcomas and 21.7% of the benign vascular tumors had bcl-2 expressions (p=0.005). CONCLUSIONS: Immunohistochemical detection of HHV-8 LNA-1 and D2-40 are useful tools to differentiate Kaposi sarcoma from other vascular tumors.

The Development of Bronchiolitis obliterans after Mycoplasma pneumoniae Pneumonia: Relationship with Antibody Titer and X-ray Pattern / 소아알레르기및호흡기학회지

The aims of this study were to document bronchiolitis obliterans(BO), the long term pulmonary sequelae after mycoplasma pneumonia, and to evaluate the difference of development of BO according to antibody titer and X-ray pattern. Twenty five subjects who had mycoplasma pneumonia underwent high resolution CT(HRCT) 1.3 years(1.0-2.0 years) after the initial infection. Fifteen boys and 10 girls, with mean age of 6.3 years(3-15 year) at the time of the infection, were included. The clinical diagnosis of Mycoplasma pneumoniae(M. pneumoniae) pneumonia was confirmed by a fourfold or higher rise in the antibody titers between acute and convalescent phase or a single very high titers(> or = 1:640) and abnormal chest radiographs. The subjects were divided into two groups as high titer group(antibody titer 1:5120 1:20480, n=15) and low titer group(antibody titer 1:640-1:2560, n=10). Nine of 25 subjects(36.0%) demonstrated BO findings on HRCT which included mosaic perfusion in 8 of 9 subjects(88.9%), bronchiectasis in 6(66.7%), mosaic perfusion associated with bronchiectasis in 6(66.7%), bronchial wall thickening in two(22.2%), and decreased pulmonary vascularity in one(11.1%). Those findings were more commonly seen in high titer group compared to low titer group[53.3%(8/15) vs 10.0%(1/10), P<0.05] and lobar type compared to linear type[58.0%(7/12) vs 15.4% (2/13), P<0.05]. The involved areas on HRCT exactly corresponded with initially involved area on chest radiographs in 8 of 9 subjects (88.9%). The development of BO was closely related to the M. pneumoniae pneumonia and was noted significantly in individuals with high antibody titer and lobar type x-ray pattern. We suggest that it is necessary to pay attention to the development of BO after M. pneumoniae pneumonia with high antibody titer and lobar type x-ray pattern.

The Efficacy of Fetal Ultrasonography and Postnatal Abdominal Ultrasonography for the Diagnosis of Neonatal Abdominal Mass

PURPOSE: Most neonatal abdominal masses are benign in nature, but early detection and management is important to avoid the development of complications. So, we studied the causes of neonatal abdominal masses and the efficacy of ultrasonography for early detection and diagnosis. METHODS: We reviewed 36 newborn infants with abdominal masses who had been admitted to the nursery and Neonatal Intensive Cave Unit of Seoul National University Children' s Hospital from Jan. 1, 1989 to Dec. 31, 1995. RESULTS: The mean gestational age was 38 weeks and the male to female ratio was 22 : 14. All masses were benign and the most common etiology was hydronephrosis (41.7%). The following etiologies were multicystic dysplastic kidney, polycystic kidney, ovarian cyst, hemangioendothelioma, teratoma, meconium peritonitis, mesenteric cyst and intestinal duplication cyst. All except one were detected before the first 48hours, and among them, 32 cases (88.9%) detected antenatally. All patients except one who died shortly after birth, were examined by abdominal ultrasonography, and 31 of 35 masses (88.6%) had the same diagnosis of ultrasonography. Five cases had associated abnormalities in the opposite kidney and other organs. CONCLUSION: The most common etiology of neonatal abdominal masses was hydronephrosis and majority of masses originated from genitourinary system. Most abdominal masses were detected antenatally and abdominal ultrasonography was an efficient method for the diagnosis of neonatal abdominal masses.

Influence of Phototherapy on Incidence of Patent Ductus Arteriosus in Very Low Birth Weight Infants

PURPOSE: Patent ductus arteriosus (PDA) is a common disease in very low birth weight infants (VLBWI). Hemodynamically significant PDA increases the morbidity and mortality of premature infants. Based on experimental model, light inhibits the constriction of immature piglet's ductal rings. No specific mechanism adequately explains the effect of light on the relaxation of PDA. Several hypotheses, including activation of photosensitive metabolites, alterations in receptors, or alterations in prostaglandin metabolism, have been postulated. The purpose of this study was to evaluate the influence of phototherapy on incidence of PDA in VLBWI. Mehtods : Sixty-three infants with birth weights less than 1,500 gm from March 1994 to February 1996 who were admitted in NICU of Seoul National University Children's Hospital were included. Thirty-four infants from March 1995 to February 1996 were shielded with aluminium foils on left chest during phototherapy (Shield group) and twenty-nine infants from March 1994 to February 1995 were not shielded (No shield group : control group). We investigated the incidence and the perinatal risk factors of PDA. RESULTS: 1) The incidence of PDA was 18% in shield group and 41% in control group. There was statistically significant between the two groups (P<0.05). 2) There was not statistically significant between two groups with gestational age, birth weight, sex, delivery mode, etc. 3) The perinatal risk factors which were statistically significant were group and presence of respiratory distress syndrome (RDS), and use of artificial surfactant. With linear logistic regression analysis, only group (OR=8.3, 95% CI=1.17-58.69) and presence of RDS (OR=21.3, 95% CI=1.39-329.81) were proved to be related to the occurrence of PDA. CONCLUSIONS: We conclude that chest shielding during phototherapy is a simple and inexpensive method to decrease the incidence of PDA.

A case of Adenovirus Infection in the Neonate

Adenovirus is an important etiologic agent in the pediatric population with fever and respiratory disease, but in newborn period, it has been known rarely to cause illness. But, its tendency of dissemination in immunocompromized host makes the neonate a high risk group of severe adenoviral infection. A newborn girl who presented with pneumonia, pulmonary hemorrhage, hepatitis, and disseminated intravascular coagulation continued to deteriorate in spite of the antibiotic therapy and maximal ventilatory support. The autopsy revealed adenoviral infection in the lung by electron microscopy. Adenoviral infection should be also suspected when a newborn infant has pneumonia, hepatitis, neurologic symptoms, and disseminated intravascular coagulation and especially his or her bacterial culture results are negative.

Isolated Splenic Infarction in a Girl with Systemic Lupus Erythematosus

Splenic infarction is a rare disease and usually detected as a complication of SBE, atrial fibrillation, hemoglobinopathy, or myeloproliperative disorders. Although thrombotic event, such as deep vein, cerebral or renal thrombosis, is a frequent complication of SLE, there have been only a couple of cases documenting splenic infarction complicated in SLE. This is, to our knowledge, the first case report describing isolated splenic infarction in pediatric SLE. The splenic infarction was diagnosed on abdominal CT, 99mTc-RBC splenic scan, and abdominal USG, and resolved with anticoagulant therapy. And we discussed about the possibility of antiphospholipid syndrome as a cause of the infarction in this case.