[Show abstract][Hide abstract] ABSTRACT: The extent to which metastatic tumors further evolve by accumulating additional mutations is unclear and has yet to be addressed extensively using next-generation sequencing of high-grade serous ovarian cancer.
Eleven spatially separated tumor samples from the primary tumor and associated metastatic sites and two normal samples were obtained from a Stage IIIC ovarian cancer patient during cytoreductive surgery prior to chemotherapy. Whole exome sequencing and copy number analysis were performed. Omental exomes were sequenced with a high depth of coverage to thoroughly explore the variants in metastatic lesions. Somatic mutations were further validated by ultra-deep targeted sequencing to sort out false positives and false negatives. Based on the somatic mutations and copy number variation profiles, a phylogenetic tree was generated to explore the evolutionary relationship among tumor samples.
Only 6% of the somatic mutations were present in every sample of a given case with TP53 as the only known mutant gene consistently present in all samples. Two non-spatial clusters of primary tumors (cluster P1 and P2), and a cluster of metastatic regions (cluster M) were identified. The patterns of mutations indicate that cluster P1 and P2 diverged in the early phase of tumorigenesis, and that metastatic cluster M originated from the common ancestral clone of cluster P1 with few somatic mutations and copy number variations.
Although a high level of intratumor heterogeneity was evident in high-grade serous ovarian cancer, our results suggest that transcoelomic metastasis arises with little accumulation of somatic mutations and copy number alterations in this patient.
BMC Cancer 12/2015; 15(1):1077. DOI:10.1186/s12885-015-1077-4 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are currently three ongoing studies on less radical surgery in cervical cancer: ConCerv, GOG-278, and SHAPE. The aim of this study was to evaluate the performance of the criteria used in ongoing studies retrospectively and suggest a new, simplified criterion in microscopic Stage IB1 cervical cancer.
A retrospective analysis was performed in 125 Stage IB1 cervical cancer patients who had no clinically visible lesions and were allotted based on microscopic findings after conization. All patients had magnetic resonance imaging (MRI) after conization and underwent type C2 radical hysterectomy. We suggested an MRI criterion for less radical surgery candidates as patients who had no demonstrable lesions on MRI. The rates of parametrial involvement (PMI) were estimated for patients that satisfied the inclusion criteria for ongoing studies and the MRI criterion.
The rate of pathologic PMI was 5.6% (7/125) in the study population. ConCerv and GOG-278 identified 11 (8.8%) and 14 (11.2%) patients, respectively, as less radical surgery candidates, and there were no false negative cases. SHAPE and MRI criteria identified 78 (62.4%) and 74 (59.2%) patients, respectively, as less radical surgery candidates; 67 patients were identified as less radical surgery candidates by both sets of criteria. Of these 67 patients, only one had pathologic PMI with tumor emboli.
This study suggests that the criteria used in three ongoing studies and a new, simplified criterion using MRI can identify candidates for less radical surgery with acceptable false negativity in microscopic Stage IB1 disease.
BMC Cancer 12/2015; 15(1). DOI:10.1186/s12885-015-1184-2 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
We aimed to evaluate the protein and mRNA expression of fibroblast growth factor receptor 2 (FGFR2) by immunohistochemistry (IHC) and mRNA in situ hybridization (ISH), respectively, and to assess the heterogeneity of FGFR2 expression in gastric cancer (GC).
A tissue microarray containing 362 surgically resected GC tissues and 135 matched metastatic lymph nodes was evaluated using FGFR2b IHC and FGFR2 ISH. FGFR2 fluorescence ISH was also performed in 188 cases.
All FGFR2-amplified cases (5 of 188) showed FGFR2b protein and FGFR2 mRNA overexpression (p < 0.001), and FGFR2 amplification was not identified in FGFR2b IHC- and FGFR2 mRNA ISH-negative cases. Kaplan-Meier survival analysis revealed that FGFR2b protein and FGFR2 mRNA overexpression was significantly associated with a poor overall survival (p < 0.001 and p = 0.012, respectively), and multivariate analyses showed that FGFR2 mRNA overexpression was an independent biomarker of a poor overall survival. Intratumoral heterogeneity of FGFR2b protein and FGFR2 mRNA overexpression was observed in 5 of 9 (55.5%) and 18 of 21 (85.7%) cases, respectively. Discordant FGFR2b and FGFR2 expression results between primary and matched metastatic lymph nodes were observed in 5 of 9 (55.5%) and 4 of 14 (28.6%) cases, respectively.
Intratumoral heterogeneity and discordant FGFR2b expression in primary tumors and metastatic lymph nodes are common in GC.
[Show abstract][Hide abstract] ABSTRACT: Backgrounds:
Valproic acid (VPA) has been reported to have survival and neuroprotective effects in a cardiac arrest rat model. This study was designed to investigate the effect of VPA combined with therapeutic hypothermia (HT) in an asphyxial cardiac arrest rat model.
Rats were subjected to 6 minutes of asphyxial cardiac arrest. Cardiopulmonary resuscitation was performed and then the randomly allocated to 1 of 4 groups (normal saline [NS]/normothermia [NT], VPA/NT, NS/HT, and VPA/HT). Hypothermia (32.5°C ± 0.5°C, 4 hours of HT and 2 hours of rewarming) or NT (37°C ± 0.5°C for 6 hours) was applied, and VPA (300 mg/kg) or NS was administered immediately after the return of spontaneous circulation. Neurologic deficit score was measured, and a tape removal test was performed for 3 days. Histologic injury of hippocampus was evaluated.
Valproic acid significantly improved neurologic deficit score at 48 and 72 hours in the NT-treated rats and at 72 hours in the HT-treated rats (all P < .05). Although the latency and success rate were not significantly different between the VPA/NT and NS/NT groups, the VPA/HT group showed significantly lower latency and higher success rates compared to the NS/HT group (P < .05). The histologic injury score in the hippocampal CA1 sector was significantly lower in the VPA/NT group than the NS/NT group (P < .05) and showed a tendency to be decreased in the VPA/HT group compared with the NS/HT group (P = .06).
In an asphyxial cardiac arrest rat model, administration of VPA improved neurologic outcomes and added a neuroprotective effect to HT.
The American journal of emergency medicine 09/2015; DOI:10.1016/j.ajem.2015.08.036 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The AT-rich interactive domain 1A (ARID1A) gene encodes a member of the switch/sucrose nonfermentable (SWI-SNF) chromatin remodeling complex, and is considered to work as a tumor suppressor in concert with p53. We investigated the clinical significance of ARID1A protein expression in gastric cancer (GC), and examined its association with Epstein-Barr virus-associated (EBV) GC, mismatch repair (MMR) deficiency, and p53 alteration. We performed immunohistochemistry for ARID1A in 417 GC specimens using tissue microarray. EBV infection was examined using EBV-encoded small RNA in situ hybridization. Evaluation of MMR protein deficiency and p53 alteration was performed using immunohistochemistry, and microsatellite instability status was also assessed. Loss of ARID1A expression was observed in 21.1% of GC (88/417), but was not observed in gastric adenoma tissues or non-neoplastic gastric mucosa tissues. Loss of ARID1A showed positive correlations with advanced pTNM stage and tumor invasion (P=0.029 and 0.001, respectively). Overall survival was significantly influenced by the loss of ARID1A expression in wild-type p53 group (P=0.016, log-rank test). Moreover, ARID1A loss was significantly associated with EBV positivity, loss of MMR protein expression, and microsatellite instability high status (P=0.028, <0.001, and 0.011, respectively). All of the results from our cohort were verified using data from the Cancer Genome Atlas. In conclusion, loss of ARID1A is more common in advanced GC and is related to EBV positivity and MMR deficiency.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 06/2015; DOI:10.1097/PAI.0000000000000199 · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant struma ovarii is extremely rare and difficult to diagnose histologically, particularly in cases of follicular carcinoma. This case study is intended to describe three cases of follicular proliferative lesion arising in struma ovarii that we experienced. The first case was clearly malignant given the clinical picture of multiple recurrences, but there was little histological evidence of malignancy. Our second case featured architectural and cellular atypia and necrosis and was diagnosed as malignant despite the absence of vascular and stromal invasion. Our third case exhibited solid microfollicular proliferation without any definite evidence of malignancy (even the molecular data was negative); however, we could not completely exclude malignant potential after conducting a literature review. In cases such as our third case, it has been previously suggested that a diagnostic term recognizing the low-grade malignant potential, such as "proliferative stromal ovarii" or "follicular proliferative lesion arising in the stromal ovarii" would be appropriate.
[Show abstract][Hide abstract] ABSTRACT: Moyamoya disease (MMD) occurs predominantly in Korean and Japanese women. The aim of this study was to investigate clinical features and pregnancy outcomes in women with MMD.
We conducted a retrospective chart review of women with MMD who visited our Department of Obstetrics and Gynecology between January 2005 and October 2013. For all study subjects, clinical features, demographic characteristics, and perinatal outcomes were recorded.
We identified 28 pregnancies in 22 patients who had been diagnosed with MMD. The mean maternal age at delivery was 31.9±3.5 years old. The mean gestational age at delivery was 38.0±0.9 weeks. Among the 28 pregnancies, 25 (92.5%) underwent cesarean section; 19 (76.0%) of them were performed under regional anesthesia and six (24.0%) under general anesthesia. The mean newborn weight was 3233.7±348.2 g. The 5-minute Apgar score in 85% of the newborns was higher than 8, with no other apparent complications. During the puerperal period, transient ischemic attack symptom or seizure occurred in 4 cases, although patients recovered within a few days.
For pregnant women with MMD, it is important to control blood pressure and prevent hyperventilation during the intrapartum period, and the best methods of delivery and anesthesia should be considered to avoid unfavorable sequelae. Additionally, a multidisciplinary approach (i.e., neurosurgery) is necessary to constantly manage underlying diseases.
Yonsei medical journal 05/2015; 56(3):793-7. DOI:10.3349/ymj.2015.56.3.793 · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although nerve-sparing radical surgery (NSRS) is an emerging technique for reducing surgery-related dysfunctions, its efficacy is controversial in patients with cervical cancer. Thus, we performed a meta-analysis to compare clinical outcomes, and urinary, anorectal, and sexual dysfunctions between conventional radical surgery (CRS) and NSRS.
After searching PubMed, Embase, and the Cochrane Library, two randomized controlled trials, seven prospective and eleven retrospective cohort studies were included with 2,253 patients from January 2000 to February 2014. We performed crude analyses and then conducted subgroup analyses according to study design, quality of study, surgical approach, radicality, and adjustment for potential confounding factors.
Crude analyses showed decreases in blood loss, hospital stay, frequency of intraoperative complications, length of the resected vagina, duration of postoperative catheterization (DPC), urinary frequency, and abnormal sensation in NSRS, whereas there were no significant differences in other clinical parameters and dysfunctions between CRS and NSRS. In subgroup analyses, operative time was longer (standardized difference in means, 0.948; 95% confidence interval [CI], 0.642 to 1.253), while intraoperative complications were less common (odds ratio, 0.147; 95% CI, 0.035 to 0.621) in NSRS. Furthermore, subgroup analyses showed that DPC was shorter, urinary incontinence or frequency, and constipation were less frequent in NSRS without adverse effects on survival and sexual functions.
NSRS may not affect prognosis and sexual dysfunctions in patients with cervical cancer, whereas it may decrease intraoperative complications, and urinary and anorectal dysfunctions despite long operative time and short length of the resected vagina when compared with CRS.
[Show abstract][Hide abstract] ABSTRACT: Adjuvant chemoradiation following primary surgery is frequently indicated in patients with Stage IB cervical cancer. The aim of this study is to evaluate the role of an MRI-based strategy in avoiding trimodality therapy.
We retrospectively reviewed all patients with Stage IB cervical cancer treated initially with primary surgery at Seoul National University Hospital. We suggest an alternative triage strategy in which the primary treatment modality is determined based on preoperative MRI findings. Using this strategy, primary surgery is only indicated when there is no evidence of parametrial involvement (PMI) and lymph node metastasis (LNM) in the MRI results; when there is evidence of either or both of these factors, primary chemoradiation is selected. Assuming that this strategy is applied to our cohort, we evaluate how the rate of trimodality therapy is affected.
Of the 254 patients in our sample, 77 (30.3%) had at least one Category 1 risk factor (PMI, LNM, positive resection margin) upon pathologic examination. If the MRI-based strategy had been applied to our cohort, 168 patients would have undergone primary surgery and 86 would have undergone primary chemoradiation. Only 25 patients (9.8%) would have required trimodality therapy based on an indication of at least one Category 1 pathologic risk factor following radical hysterectomy.
The inclusion of MRI in the decision-making process for primary treatment modality could have reduced the number of patients requiring trimodality therapy based on the indication of a Category 1 risk factor from 30.3% to 9.8% in our cohort.
Cancer Research and Treatment 03/2015; DOI:10.4143/crt.2014.370 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whether endometriosis affects the prognosis of ovarian clear cell carcinoma (OCCC) remains controversial despite the relationship between OCCC and endometriosis. A two-center cohort study and meta-analysis were performed to investigate the effect of endometriosis on the prognosis of OCCC.
The study reviewed the clinicopathologic data of 109 patients with OCCC arising (n = 47) or not arising (n = 62) in endometriosis between 1997 and 2012 at two tertiary medical centers. Tumor response and survival were compared between the two groups. For further evaluation, PubMed, EmBase, and the Cochrane Library were searched, and a meta-analysis was conducted using 10 cohort studies published from March 1996 to May 2014, including the current cohort study.
Complete response did not differ between the patients with OCCC arising in endometriosis and those without endometriosis (77.5 vs. 87.3 %; P = 0.444). Early-stage disease and optimal debulking surgery were the only independent factors that reduced the risk of noncomplete response (adjusted odds ratios 0.203 and 0.038; 95 % confidence intervals [CIs] 0.045-0.920 and 0.006-0.226, respectively). Progression-free survival (PFS) and overall survival (OS) did not differ between the two groups. Early-stage disease and optimal debulking surgery were the only favorable factors that improved PFS (adjusted hazard ratios [HRs] 0.216 and 0.332; 95 % CIs 0.099-0.469 and 0.150-0.732, respectively) and OS (adjusted HRs 0.099 and 0.339; 95 % CIs 0.039-0.252 and 0.141-0.815, respectively). Furthermore, crude and subgroup meta-analyses showed no effect of endometriosis on PFS or OS in OCCC patients.
Endometriosis may not affect the tumor response or the prognosis of OCCC patients.
[Show abstract][Hide abstract] ABSTRACT: The inhibition of mitochondrial permeability transition pore opening during ischemia-reperfusion can ameliorate injuries. This study aimed to investigate the effects of cyclosporine A (CsA) in rats after hemorrhagic shock.
Male Sprague-Dawley rats were subjected to pressure-controlled hemorrhagic shock (mean arterial pressure, 38 ± 1 mm Hg) for 90 minutes. After the hemorrhagic shock period, rats were randomly allocated to one of three groups as follows: a control group, a CsA10 group, or a CsA50 group. CsA for the treatment groups (10 mg/kg for the CsA10 group and 50 mg/kg for the CsA50 group) or normal saline for the control group was administered via tail vein for 10 minutes, and shed blood was transfused for 15 minutes. For the survival study, animals were observed for up to 9 hours, and their survival time was recorded until death. Separate experiments were performed to examine the effect of CsA on inflammatory responses and liver injury. Rats were sacrificed at 210 minutes after the shock period, and blood and liver tissues were harvested.
Survival times were shown to be significantly longer in the CsA-treated groups (i.e., the CsA10 and CsA50 groups) than in the control group. Plasma interleukin-6 and thiobarbituric acid-reactive substances were significantly lower in the CsA50 group than in the control group and phosphorylation of Akt, GSK-3β, and Bad were significantly increased in the CsA-treated groups compared with the control group. Expressions of Bcl-2, cleaved caspase 3, and cytoplasmic cytochrome C were significantly decreased in the CsA-treated groups compared with the control group. Although histologic liver injury was not significantly different among the groups, ultrastructural changes of mitochondria were more prominent in the control group than in the CsA-treated groups.
CsA increased survival time, decreased proinflammatory cytokine and lipid peroxidation, and augmented Akt survival pathways in rats subjected to pressure-controlled hemorrhagic shock.
Journal of Trauma and Acute Care Surgery 02/2015; 78(2):370-377. DOI:10.1097/TA.0000000000000511 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endoscopic ultrasound-guided fine needle aspiration cytology (EUS-FNAC) is currently the most commonly used procedure for obtaining cytologic specimens of the pancreas. It is accurate, minimally invasive, safe and cost-effective. However, there is discrepancy between cytological and surgical diagnoses. This study was aimed at evaluating the diagnostic accuracy of EUS-FNAC of the pancreas.
We performed a retrospective review of 191 cases of pancreatic lesions initially diagnosed by EUS-FNAC with subsequent histological diagnosis between 2010 and 2012 in the Department of Pathology, Seoul National University Hospital. Cytologic and surgical diagnoses were categorized into five groups: negative, benign, atypical, malignant, and insufficient for diagnosis. Subsequently, 167 cases with satisfactory yield in both surgical and cytology specimens were statistically analyzed to determine correlations with diagnosis.
In comparison to surgical diagnoses, cytologic diagnoses were true-positive in 103 cases (61.7%), true-negative in 28 cases (16.8%), false-positive in 9 cases (5.4%), and false-negative in 27 cases (16.1%). The diagnostic accuracy was 78.4%, sensitivity was 79.2%, and specificity was 75.7%. The positive predictive value was 92.0%, and negative predictive value was 50.9%.
EUS-FNAC has high accuracy, sensitivity, specificity and positive predictive value. Overcoming the limitations of EUS-FNAC will make it a useful and reliable diagnostic tool for accurate evaluation of pancreatic lesions.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The purpose of this study is to compare the MRI features of intestinal and endocervical mucinous borderline ovarian tumors (MBOT).
Fifty seven and 17 patients with histologically proven intestinal (n = 62) and endocervical (n = 22) MBOT, respectively, underwent preoperative MRI which were reviewed by two radiologists blinded to histology. An array of MRI features and clinical factors (age, cancer antigen 125 [CA-125]) were compared between intestinal and endocervical subtypes using the t test and Chi-square test. Univariate and multivariate logistic regression analyses were performed to evaluate for significant predictors of subtype.
There was no significant difference in patient age of intestinal and endocervical MBOT (P = 0.423). CA-125 levels were higher in endocervical MBOT (P = 0.022). Regarding MR features, intestinal MBOT was larger, had more septations, more frequently demonstrated honeycomb loculi, and signal intensity discrepancy while endocervical MBOT was more frequently bilateral with papillary projections (P < 0.05). At multivariate analysis, higher CA-125 (odds ratio [OR] 1.015, P = 0.034) and the presence of papillary projections (OR 11.441, P = 0.024) were the only independent predictive factors of endocervical MBOT.
Intestinal and endocervical subtypes of MBOT demonstrated significantly different features on MRI. The presence of papillary projection was the only independent MRI feature predictive of endocervical MBOT.
[Show abstract][Hide abstract] ABSTRACT: Success factors of laparoscopic nerve-sparing radical hysterectomy (LNRH) to preserve bladder function are little known despite its widespread use. Thus, we conducted a protocol-based prospective cohort study to evaluate clinicopathologic factors for preserving autonomic nerves and its impact on duration of postoperative catheterization (DPC).
From 2012 to 2014, 30 patients with stage IB1 to IIA2 cervical cancer were recruited prospectively to undergo LNRH. All procedures were performed on the left side of the patients by one gynecologic oncologist. Extent of resection and preservation of autonomic nerves were documented in the protocol during LNRH.
All patients received laparoscopic type C1 radical hysterectomy, where extent of resection and preservation of autonomic nerves were not different between the right and left sides. Stage IB1 disease was associated with the reduced risk of injury of the left junctions between the hypogastric and the splanchnic nerves; between the splanchnic nerve and the vesical branch of the pelvic plexus (S-V junction) (adjusted odds ratios, 0.06 and 0.06; 95 % confidence intervals, 0.01-0.92 and 0.01-0.48); the right S-V junction with marginal significance (adjusted odds ratio, 0.18; 95 % confidence interval, 0.03-1.06). Furthermore, bilateral preservation of autonomic nerves decreased DPC significantly when compared with failure or unilateral preservation (median, 6 days vs. 34 days or 57 days; P < 0.05).
LNRH has a higher likelihood of its success in stage IB1 than in stage IB2 to IIA disease. Moreover, preservation of bilateral autonomic nerves reduces DPC significantly in comparison with failure or unilateral preservation.
[Show abstract][Hide abstract] ABSTRACT: We investigated MET mRNA expression status using RNA in situ hybridization (ISH) technique in primary and metastatic lesions of 535 surgically resected gastric carcinoma (GC) cases. We compared the results with those of immunohistochemistry and silver in situ hybridization, and examined the association with clinicopathologic characteristics and prognosis. Among 535 primary GCs, 391 (73.1%) were scored 0, 87 (16.3%) were scored 1, 38 (7.1%) were scored 2, 12 (2.2%) were scored 3 and 7 (1.3%) were scored 4 by RNA ISH. High MET mRNA expression (score ≥3) was associated with lymph node metastasis (P = .014), distant metastasis (P = .001), and higher TNM stage (P<.001). MET mRNA expression was correlated with protein expression (r = 0.398; P<.001) and gene copy number (r = 0.345; P<.001). The patients showing high-MET mRNA in primary or metastatic lesions had shorter overall survival than those showing low-MET mRNA (primary tumors, P = .002; metastatic lymph nodes, P<.001). The patients showing positive conversion of MET mRNA status in metastatic lymph node had shorter overall survival than those with no conversion (P = .011). Multivariate analysis demonstrated that high MET mRNA expression in metastatic lymph node was an independent prognostic factor for overall survival (P = .007). Therefore, this study suggests that MET mRNA expression assessed by RNA ISH could be useful as a potential marker to identify MET oncogene-addicted GC.
PLoS ONE 11/2014; 9(11):e111658. DOI:10.1371/journal.pone.0111658 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Diabetic patients with endometrial cancer had more lymph node metastasis than non-diabetic patients with endometrial cancer. L1 cell adhesion molecule (L1CAM) could be possibly associated with lymph node metastasis in diabetic patients with endometrial cancer via epithelial-mesenchymal transition. We aimed to investigate the association between L1CAM expression and lymph node metastasis in diabetic patients with endometrial cancer.
We conducted a matched case control study of 68 endometrial cancer patients who comprise each 34 diabetic and non-diabetic patients. L1CAM expression was evaluated by immunohistochemistry using fresh formalin-fixed paraffin-embedded tissue block of the patients. The association between L1CAM expression and pelvic lymph node metastasis was assessed according to the presence of diabetes.
Of the 68 patients, 13 (19.1%) were positive for L1CAM immunostaining. Positive rate of L1CAM expression in diabetic endometrial cancer patients was similar to that in non-diabetic endometrial cancer patients (14.7% vs. 23.5%, P = 0.355). Tumor recurred more frequently in patients with positive L1CAM expression than those with negative L1CAM expression (33.3% vs. 1.6%, P = 0.019). However, we failed to find any significant association between L1CAM expression and lymph node metastasis. Only for the diabetic patients (n = 34), patients with pelvic lymph node metastasis had more L1CAM expression than those without lymph node metastasis (50.0% vs. 3.6%, P = 0.035). Advanced stage was the only risk factor for recurrence that showed a significant association with L1CAM expression for the diabetic endometrial cancer patients (P = 0.006), as well as all the enrolled patients (P = 0.014).
L1CAM expression is associated with pelvic lymph node metastasis and advanced stage in diabetic patients with endometrial cancer.