Assessing Genetic Variants in Matched Biocompartments From Patients With Serous Ovarian Cancer.

The clinical use of molecular tumor profiling (MTP) is expanding and there is an increasing use of MTP data to manage patient care. At the University of Colorado, 18 patients were diagnosed with primary serous ovarian cancer between 9/2015 and 6/2019 and consented for banking and analysis of tumor, ascites and plasma. All 18 patients had tumor and plasma samples that were sent for MTP, and 13 of 18 patients additionally had ascites collected and sent for MTP. 50-gene panel testing and BRCA testing were performed on primary tumor. BRCA genetic variants were more likely to be identified in plasma as compared to ascites or tumor, though not statistically significant (P = 0.17). Co-occurring genetic variants between plasma and ascites were less common in comparison to co-occurring variants between tumor and plasma or tumor and ascites, though not statistically significant (P = 0.68). Variants in KDR (VEGFR2) and TP53 were most likely to be conserved across all 3 biocompartments. Mutant allele frequencies (MAF) of individual genetic variants varied across biocompartments, though tended to be highest in the tumor, followed by ascites.

High grade, advanced, serous ovarian cancer with low serum CA125 levels.

This study compares characteristics of advanced stage, high grade serous ovarian cancer, presenting with high or low serum CA125 level. This was a retrospective cohort of 118 patients with high grade serous ovarian, fallopian tube or primary peritoneal cancer, stages IIIC-IV diagnosed from January 1 1997 through January 9 2017. Patient demographics, tumour characteristics, surgical findings, chemotherapy protocols and clinical outcomes were collected. Three groups were evaluated: group A: 21 patients with CA125 serum level ≤152 U/ml, group B: 97 patients with CA125 serum level >152 U/ml, group C: 43 patients from group B with CA125 serum level >500 U/ml and <1000 U/ml. No significant difference was found between groups regarding age, stage at diagnosis, extent of residual disease or disease volume. More group A patients had surgery as primary treatment compared to groups B and C (p=.003, p=.022, respectively). CA125 level at recurrence was lower in group A as compared to the other groups (162.2 vs. 851.7 and 603.4, p=.003, p=.006). Overall survival and progression-free survival did not differ based on CA125 levels. We conclude that patients with advanced stage, high grade, serous ovarian cancer with low CA125 serum levels had the same clinical outcome as patients with higher levels.Impact StatementWhat is already known on this subject? It is known that CA125 level is a prognostic and predictive factor for epithelial ovarian cancer (EOC) outcome. It is elevated in 80% of the patients and within normal range in only 10% of women with advanced stage EOC. Various studies had addressed the patients with advanced stage serous EOC who had high serum CA125 levels at time of diagnosis. But, no study has addressed the 10% of patients with advanced stage who had low serum CA125 levels at time of diagnosis.What the results of this study add? To the best of our knowledge, this is the first study addressing patients with advanced stage EOC who had low serum CA125 levels at time of diagnosis. According to the results of this study, patients with advanced stage, high grade serous EOC presenting with low serum CA125 levels have similar clinical outcomes as do patients with high serum CA125 levels.What the implications are of these findings for clinical practice and/or further research? Further translational research is encouraged for this group of tumours to identify specific molecular markers that might lead to better understanding and treatment for the disease.

Prediction of the Probability of Malignancy in Mucinous Cystic Neoplasm of the Pancreas With Ovarian-Type Stroma: A Nationwide Multicenter Study in Japan.

OBJECTIVE: The aim of the study was to develop a formula for predicting the probability of malignancy of mucinous cystic neoplasm (MCN) of the pancreas with ovarian-type stroma. METHODS: A total of 364 patients were enrolled. A total score was calculated as the sum of the approximate integers of the odds ratios of the predictive factors identified by multivariate analysis. The relationship between the total score and pathological results was assessed. RESULTS: A total of 321 patients had benign MCN and 43 had malignant MCN. Five possible predictive factors were analyzed: 56 years or older, high serum carcinoembryonic antigen level, high carbohydrate antigen 19-9 level, tumor size of 51 mm or greater, and the presence of mural nodules. The total score was significantly higher in patients with malignant MCN (median, 24; range, 0-37) compared with benign MCN (median, 5; range, 0-33; P < 0.001). Receiver operating characteristic curve analysis demonstrated that the area under the curve was 0.86, and the sensitivity and specificity of the total score for discriminating malignant MCNs were 72% and 83%, respectively, using a cut-off value of 22. CONCLUSIONS: The current simple formula can predict the malignancy of MCN and may thus contribute to the adequate management of patients with MCN.

The diagnostic challenge of ovarian carcinoma in normal-sized ovaries: a report of two cases.

Normal-sized ovarian carcinoma syndrome (NOCS) is a rare condition characterised by malignancy identified in ovaries of normal size with abdominal metastasis. We report two cases of advanced ovarian carcinoma with ovaries of normal size. The first case was a 13-year-old adolescent with malignant ascites and bilateral normal sized multicystic ovaries detected on ultrasound. Serum cancer antigen 125 (CA 125) and lactate dehydrogenase were markedly raised. A computed tomography (CT) scan showed the presence of thick omental cake but no ovarian tumour. An ultrasound-guided biopsy of the omental cake was undertaken. A histopathological examination and immunohistochemical studies of omentum caking confirmed a diagnosis of high-grade serous carcinoma of ovarian in origin. Despite neoadjuvant chemotherapy, she deteriorated rapidly with acute renal failure and respiratory distress. She succumbed to her disease 10 weeks after diagnosis. The second case, a 69-year-old postmenopausal female presented with malignant ascites and ultrasound evaluation showed hydrometra and bilateral atrophic ovaries. CA 125 was significantly raised. A laparoscopic biopsy of the left ovary and endometrial sampling were performed. A diagnosis of synchronous primary high grade papillary serous ovarian cystadenocarcinoma and endometrial adenocarcinoma were revealed. Relapse occurred despite ongoing adjuvant chemotherapy. We concluded that a preoperative definitive diagnosis of NOCS is difficult. Strong clinical suspicion is needed when all the important causes of malignant ascites are excluded. Radiological-guided biopsy and laparoscopic biopsy are useful to achieve the diagnosis of NOCS.

Clinical Impact of KRAS and GNAS Analysis Added to CEA and Cytology in Pancreatic Cystic Fluid Obtained by EUS-FNA.

BACKGROUND: Pancreatic cysts are common incidental findings with malignant potential, raising diagnostic and treatment dilemmas. AIMS: To determine the added value of KRAS and GNAS mutation analysis on cyst classification and decision making. METHODS: We analyzed 52 frozen samples of pancreatic cystic fluid obtained by EUS-FNA between 2008 and 2014. In addition to cytology and CEA, mutations of GNAS (exons 8 and 9) and KRAS (exons 2 and 3) genes were analyzed using Sanger sequencing. RESULTS: There were 52 patients, 67% females, with a mean age of 59 ± 15 years (29-91). Cysts were classified as mucinous in 21 patients (40%) (14 low-risk, seven malignant) and non-mucinous in 31 patients (60%). After EUS-FNA, 11 patients had surgery, six had chemotherapy or palliation, one had endoscopic drainage, and 34 are on follow-up after a mean of 57 months. KRAS mutation was detected in nine and GNAS in two samples. Patients harboring cysts with KRAS mutations were older (p = 0.01), cysts were more commonly mucinous (p = 0.001) and malignant (p = 0.01). KRAS mutations were present in both low-risk and malignant mucinous lesions. For identifying mucinous lesions, CEA > 192 ng/mL performed better (AUC ROC = 93%), whereas for malignant/high-risk mucinous lesions, EUS imaging had the best accuracy (AUC ROC = 88%). After molecular analysis, a modification in cyst classification occurred in ten patients, but was correct in only two, a pseudocyst re-classified as IPMN and a malignant cyst as a non-mucinous cyst. CONCLUSIONS: In this cohort of patients with pancreatic cysts, KRAS and GNAS mutations had no significant diagnostic benefit in comparison with conventional testing.

Distinct homologous recombination gene expression profiles after neoadjuvant chemotherapy associated with clinical outcome in patients with ovarian cancer.

OBJECTIVE: The expression of homologous recombination (HR) genes in high grade ovarian cancer (HGOC) samples from debulking surgeries were correlated to outcomes in patients selected for chemotherapy treatment regimens. STUDY DESIGN: RNA was extracted from 96 fresh frozen tumor samples from debulking surgeries from chemotherapy naïve patients with HGOC (primary derived surgeries (PDS), n = 55) or following neoadjuvant chemotherapy treatment (NACT), n = 41). The samples were selected for high tumor content by a gynecological pathologist, and cancer cell content was further confirmed using a percent tumor content covariate, and mutation score covariate analysis. Gene expression analysis was performed using a tailored NanoString-based Pancancer Pathway Panel. Cox proportional hazard regression models were used to assess the associations between the expression of 19 HR genes and survival. RESULTS: In the PDS group, over-expression of six HR genes (C11orf30, NBN, FANCF, FANCC, FANCB, RAD50) was associated with improved outcome, in contrast to the NACT group where four HR genes (BRCA2, TP53, FANCB, RAD51) were associated with worse outcome. With the adding extent of debulking as a covariate, three HR genes (NBN, FANCF, RAD50), and only one HR gene (RAD51) remained significantly associated with survival in PDS and NACT groups, respectively. CONCLUSION: Distinct HR expression profiles define subgroups associated with overall outcome in patients that are exposed to neoadjuvant chemotherapy and not only chemotherapy-naïve patients.

Preoperative CA-125 Values as a Predictive Factor for the Postoperative Outcome in Primary Serous Ovarian Cancer.

BACKGROUND/AIM: The purpose of the study was to examine the preoperative CA-125 values as a predictive factor for postoperative outcome in primary serous ovarian cancer (POC) for complete tumor resection (CTR) and evaluate the preoperative CA-125 levels with other vital clinical dynamics such as ascites, lymph node involvement, diffuse peritoneal carcinomatosis, grading and staging. PATIENTS AND METHODS: A cohort of 277 POC-patients aged 18-75 years, who had undergone primary cytoreductive surgery at the Department of Gynecology & Oncological Surgery, Charité, Campus Virchow Klinikum (CVK) between 2000 und 2009 was analyzed in correlation with the preoperative CA-125 values. RESULTS: The median preoperative CA-125 value in high-grade serous POC patients was 636 U/ml (204- 2312 U/ml) compared to 284 U/ml (148.5-1,378 U/ml) in low-grade serous POC patients (p=0.016). For the survival analyses both the cut-off values 252 and 475 U/ml, with highest sum from sensitivity (79.1% and 65.9%, respectively) and specificity (41.9% and 55.1%, respectively), were used to compare the relationship between preoperative CA-125 levels and (CTR), progression-free (PFS) and overall survival (OS). There was no significant difference between PFS and OS in three different groups of patients (preoperative CA-125 levels <252 U/ml, CA 125 levels between 252-475 U/ml and >475 U/ml). CONCLUSION: Preoperative CA-125 is a poor, but statistically significant predictive factor for CTR after PCS. Preoperative CA-125 can predict neither the progression-free nor overall survival for POC patients.

Cytologic characteristics of circulating epithelioid cells in pancreatic disease.

BACKGROUND: Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin. METHODS: Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment. Blood was processed with the ScreenCell size-based filtration device. Evaluable CECs were analyzed in a blinded fashion for cytomorphologic characteristics, including cellularity; nucleoli; nuclear size, irregularity, variability, and hyperchromasia; and nuclear-to-cytoplasmic ratio. Statistical differences between variables were analyzed via the Fisher exact test. RESULTS: No CECs were identified among the 9 normal healthy controls. Of the 115 patients with CECs (positive or suspicious for), 25 had nonmalignant disease and 90 had malignancy. There were no significant differences in any of the cytologic criteria noted between groups divided by benign versus malignant, neoplastic versus nonneoplastic, or pancreatic ductal adenocarcinoma versus neuroendocrine tumor. CONCLUSIONS: CECs were observed in patients with malignant and nonmalignant pancreatic disease, but not in healthy controls. There were no morphologic differences observed between cells from different pancreatic diseases, suggesting that numerous conditions may be associated with CECs in the circulation and that care must be taken not to overinterpret cells identified by cytomorphology as indicative of circulating tumor cells of pancreatic cancer. Additional studies are required to determine the origin and clinical significance of these cells. Cancer Cytopathol 2017;125:332-340. © 2017 American Cancer Society.

A multicenter assessment of the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease at primary debulking for advanced epithelial ovarian cancer.

OBJECTIVE: To assess the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease (RD) at primary cytoreduction in advanced ovarian cancer. METHODS: A prospective, non-randomized, multicenter trial of patients who underwent primary debulking for stage III-IV epithelial ovarian cancer previously identified 9 criteria associated with suboptimal (>1cm residual) cytoreduction. This is a secondary post-hoc analysis looking at the ability to predict any RD. Four clinical and 18 radiologic criteria were assessed, and a multivariate model predictive of RD was developed. RESULTS: From 7/2001-12/2012, 350 patients met eligibility criteria. The complete gross resection rate was 33%. On multivariate analysis, 3 clinical and 8 radiologic criteria were significantly associated with the presence of any RD: age≥60years (OR=1.5); CA-125≥600U/mL (OR=1.3); ASA 3-4 (OR=1.6); lesions in the root of the superior mesenteric artery (OR=4.1), splenic hilum/ligaments (OR=1.4), lesser sac >1cm (OR=2.2), gastrohepatic ligament/porta hepatis (OR=1.4), gallbladder fossa/intersegmental fissure (OR=2); suprarenal retroperitoneal lymph nodes (OR=1.3); small bowel adhesions/thickening (OR=1.1); and moderate-severe ascites (OR=2.2). All ORs were significant with p<0.01. A 'predictive score' was assigned to each criterion based on its multivariate OR, and the rate of having any RD for patients who had a total score of 0-2, 3-5, 6-8, and ≥9 was 45%, 68%, 87%, and 96%, respectively. CONCLUSIONS: We identified 11 criteria associated with RD, and developed a predictive model in which the rate of having any RD was directly proportional to a predictive score. This model may be helpful in treatment planning.

Serum tumor markers not useful in screening patients with pancreatic mucinous cystic lesions associated with malignant changes.

BACKGROUND: Serum cancer antigen 19-9 (CA19-9) provides additional information about mucinous cystic pancreatic neoplasm (MPN). This study was undertaken to assess both CA19-9 and carcinoembryonic antigen (CEA) serum concentrations in consecutive patients affected by MPNs and other chronic benign and malignant pancreatic diseases. We also evaluated whether serum CA19-9 and CEA determinations provide additional information such as the presence of invasive carcinoma in MPN patients. METHODS: Serum CA19-9 and CEA from 91 patients with pancreatic diseases were tested by commercially available kits at the time of diagnosis. The upper reference limit of serum CA19-9 was 37 U/mL and that of serum CEA was 3 ng/mL. RESULTS: Thirty-five patients was diagnosed with chronic pancreatitis (CP), 32 with MPN, and 24 with pancreatic ductal adenocarcinoma (PDAC) confirmed histologically. Surgery was carried out in 5 CP patients, in 10 MPN patients (7 of them had severe dysplasia), and in 9 PDAC patients. Serum CA19-9 activity was high in 12 (34.3%) CP patients, in 7 (21.9%) MPN patients, and in 12 (50.0%) PDAC patients (P=0.089). High serum CEA concentrations were noted in 6 (17.1%) CP patients, in 6 (18.8%) MPN patients, and in 12 (50.0%) PDAC patients (P=0.010). In the 7 MPN patients associated with histologically confirmed severe dysplasia, 3 (42.9%) patients had elevated serum activity of serum CA19-9, and 2 (28.6%) patients had high levels of CEA. CONCLUSION: Serum determination of oncological markers is not useful in selecting MPN patients with malignant changes.

Preoperative platelet-to-lymphocyte ratio improves the performance of the international consensus guidelines in predicting malignant pancreatic cystic neoplasms.

INTRODUCTION: To determine if neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were predictive of malignancy in pancreatic cystic neoplasms (PCN) and if these improved the performance of the international consensus guidelines (ICG) in the initial triage of these patients. METHODS: 318 patients with surgically-treated suspected PCN were retrospectively reviewed. Malignant neoplasms were defined as neoplasms harbouring invasive carcinoma. The optimal cut-off for NLR and PLR were determined by plotting the receiver operating characteristics (ROC) curves of NLR/PLR in predicting malignant PCN and utilizing the Youden index. RESULTS: The optimal NLR and PLR cut-offs were determined to be 3.33 and 205, respectively. Univariate analyses demonstrated that symptomatic PCNs, age, obstructive jaundice, presence of solid component, dilatation of main pancreatic duct ≥10 mm, high NLR and high PLR were predictive of a malignant PCN. Multivariate analyses demonstrated that obstructive jaundice, presence of solid component, MPD ≥10 mm and high PLR but not NLR were independent predictors of a malignant PCN. A high PLR significantly predicted invasive carcinoma in patients classified within the ICG(HR) group. Comparison between the ROC curves of the ICG versus ICG plus high PLR in predicting malignant PCN demonstrated a significant improvement in the accuracy of the ICG when PLR was included [AUC 0.784 (95% CI: 0.740-0.829) vs AUC 0.822 (95% CI: 0.772-0.872) (p = 0.0032)]. CONCLUSIONS: High PLR is an independent predictor of malignancy in PCN. The addition of PLR as a criterion to the ICG improved the accuracy of these guidelines in detecting invasive neoplasms.

Has serum CA 125 assay at the time of relapse a prognostic relevance for patients with recurrent ovarian carcinoma after primary cytoreduction and platinum- and paclitaxel-based chemotherapy?

PURPOSE OF INVESTIGATION: To correlate serum CA125 at relapse with survival in ovarian cancer patients who achieved a complete response after primary cytoreduction and paclitaxel- and platinum-based chemotherapy. MATERIALS AND METHODS: The study was conducted in 104 patients. RESULTS: The 25%, 50%, and 75% quantiles of CA125 levels at relapse were 46, 118, and 190 U/ml. By log-rank test, survival after recurrence was related to consolidation treatment (p = 0.046), platinum-free interval (PFI) (p < 0.000005), number of recurrence sites (p = 0.03), treatment at recurrence (p = 0.002), and serum CA125 taking 118 U/ml as cut-off (p = 0.013). On multivariate analysis, consolidation treatment (p = 0.007), PFI (p = 0.0001), treatment at recurrence (p = 0.01), and serum CA125 taking 118 U/ml as cut-off (p = 0.04) were independent prognostic variables for survival. CONCLUSIONS: Serum CA125 at relapse was an independent prognostic variable. Patients with serum CA125 > 118 U/m had 1.943 higher risk of death than those with lower antigen value.

The diagnostic role of the neutrophil-to-lymphocyte ratio in predicting pancreatic ductal adenocarcinoma in patients with pancreatic diseases.

BACKGROUND: Accurately diagnosing pancreatic ductal adenocarcinomas (PDACs) is challenging because of the loss of vascularity and poor imaging. The neutrophil-to-lymphocyte ratio (NLR) has been reported to predict poor prognosis in several types of malignancy including PDAC; however, the diagnostic role of NLR in PDAC has never been addressed. METHODS: This study retrospectively assessed 297 patients who underwent curative pancreatic resection for pancreatic tumors from 1995-2015, including 140 with PDACs, 58 with pancreatic neuroendocrine tumors (PNETs), 76 with intraductal papillary mucinous neoplasms (IPMNs), 13 with mucinous/serous cyst neoplasms, 7 with solid pseudopapillary neoplasms, and 3 with tumor-forming pancreatitis. The role of preoperative NLR in predicting PDACs was investigated. RESULTS: Preoperative NLR was significantly higher in patients with PDACs (2.52 ± 1.34) than in patients with PNETs (1.93 ± 0.68, P = 0.0004) and IPMNs (2.17 ± 0.79, P = 0.0253). Only eight patients with PDACs (5.7 %) had NLR >5; of these, three had normal carcinoembyronic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels. Multivariate analysis revealed that abnormal CA19-9 levels, abnormal CEA levels, age >67 years, and NLR >5 were independent predictors of PDACs. Both the specificity and the positive predictive value of NLR >5 for predicting PDACs were 100 %; however, the sensitivity was 4.6 % and the negative predictive value was 43.8 %. CONCLUSIONS: NLR >5 could independently predict the occurrence of PDACs in pancreatic neoplastic disease irrespective of other tumor markers, CEA and CA19-9, in pancreatic disease.

Elevated serum progesterone levels in postmenopausal women with mucinous ovarian tumors.

OBJECTIVE: The aim of the study was to evaluate the association between tumor histology and serum sex hormone levels in postmenopausal women with ovarian tumors. METHODS: We preoperatively measured serum levels of gonadotropins and sex steroids, including estradiol, progesterone, and testosterone, in 69 postmenopausal women who underwent surgical resection for ovarian tumors. Tumors were classified as surface epithelial-stromal tumors, sex cord-stromal tumors, germ cell tumors, and metastatic tumors. Surface epithelial-stromal tumors were divided into mucinous, serous, clear cell, and endometrioid tumor subgroups. Patients were divided into two groups depending on tumor type: mucinous and nonmucinous, and any association between these tumor types and serum sex hormone levels were evaluated. RESULTS: Univariate analyses revealed that serum sex steroid levels were significantly higher in women with mucinous ovarian tumors compared with women with other tumor types. Serum gonadotropin levels, age, body mass index, tumor size, and tumor malignancy status did not affect the sex steroid levels. Multivariate analysis evaluating sex steroid levels and tumor histology revealed that high serum progesterone levels were significantly and independently associated with mucinous ovarian tumors. A serum progesterone cut-off level of at least 1.3 nmol/L was the most accurate for differentiating mucinous tumors from other tumor types (area under the curve, 0.81; sensitivity, 75%; and specificity, 86%). CONCLUSIONS: Serum progesterone levels were significantly elevated in postmenopausal women with mucinous ovarian tumors. In these women, serum progesterone levels may thus represent a useful biomarker for predicting tumor histology preoperatively, which would aid treatment planning.

Biomarker Development for Intraductal Papillary Mucinous Neoplasms Using Multiple Reaction Monitoring Mass Spectrometry.

Intraductal papillary mucinous neoplasm (IPMN) is a common precursor of pancreatic cancer (PC). Much clinical attention has been directed toward IPMNs due to the increase in the prevalence of PC. The diagnosis of IPMN depends primarily on a radiological examination, but the diagnostic accuracy of this tool is not satisfactory, necessitating the development of accurate diagnostic biomarkers for IPMN to prevent PC. Recently, high-throughput targeted proteomic quantification methods have accelerated the discovery of biomarkers, rendering them powerful platforms for the evolution of IPMN diagnostic biomarkers. In this study, a robust multiple reaction monitoring (MRM) pipeline was applied to discovery and verify IPMN biomarker candidates in a large cohort of plasma samples. Through highly reproducible MRM assays and a stringent statistical analysis, 11 proteins were selected as IPMN marker candidates with high confidence in 184 plasma samples, comprising a training (n = 84) and test set (n = 100). To improve the discriminatory power, we constructed a six-protein panel by combining marker candidates. The multimarker panel had high discriminatory power in distinguishing between IPMN and controls, including other benign diseases. Consequently, the diagnostic accuracy of IPMN can be improved dramatically with this novel plasma-based panel in combination with a radiological examination.

American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data.

BACKGROUND AND AIMS: The American Gastroenterological Association (AGA) recently reported evidence-based guidelines for the management of asymptomatic neoplastic pancreatic cysts. These guidelines advocate a higher threshold for surgical resection than prior guidelines and imaging surveillance for a considerable number of patients with pancreatic cysts. The aims of this study were to assess the accuracy of the AGA guidelines in detecting advanced neoplasia and present an alternative approach to pancreatic cysts. METHODS: The study population consisted of 225 patients who underwent EUS-guided FNA for pancreatic cysts between January 2014 and May 2015. For each patient, clinical findings, EUS features, cytopathology results, carcinoembryonic antigen analysis, and molecular testing of pancreatic cyst fluid were reviewed. Molecular testing included the assessment of hotspot mutations and deletions for KRAS, GNAS, VHL, TP53, PIK3CA, and PTEN. RESULTS: Diagnostic pathology results were available for 41 patients (18%), with 13 (6%) harboring advanced neoplasia. Among these cases, the AGA guidelines identified advanced neoplasia with 62% sensitivity, 79% specificity, 57% positive predictive value, and 82% negative predictive value. Moreover, the AGA guidelines missed 45% of intraductal papillary mucinous neoplasms with adenocarcinoma or high-grade dysplasia. For cases without confirmatory pathology, 27 of 184 patients (15%) with serous cystadenomas (SCAs) based on EUS findings and/or VHL alterations would continue magnetic resonance imaging (MRI) surveillance. In comparison, a novel algorithmic pathway using molecular testing of pancreatic cyst fluid detected advanced neoplasias with 100% sensitivity, 90% specificity, 79% positive predictive value, and 100% negative predictive value. CONCLUSIONS: The AGA guidelines were inaccurate in detecting pancreatic cysts with advanced neoplasia. Furthermore, because the AGA guidelines manage all neoplastic cysts similarly, patients with SCAs will continue to undergo unnecessary MRI surveillance. The results of an alternative approach with integrative molecular testing are encouraging but require further validation.

Risk factors for readmission in patients with ovarian, fallopian tube, and primary peritoneal carcinoma who are receiving front-line chemotherapy on a clinical trial (GOG 218): an NRG oncology/gynecologic oncology group study (ADS-1236).

BACKGROUND: Readmission within 30days is a measure of care quality. Ovarian cancer patients are at high risk for readmission, but specific risk factors are not defined. This study was designed to determine risk factors in patients with ovarian cancer receiving upfront surgery and chemotherapy. METHODS: The study population was enrolled to GOG 0218. Factors predictive of admission within 30days of a previous admission or 40days of cytoreductive surgery were investigated. Categorical variables were compared by Pearson chi-square test, continuous variables by Wilcoxon-Mann-Whitney test. A logistic regression model was used to evaluate independent prognostic factors and to estimate covariate-adjusted odds. All tests were two-tailed, α=0.05. RESULTS: Of 1873 patients, 197 (10.5%) were readmitted, with 59 experiencing >1 readmission. One-hundred-forty-four (73%) readmissions were post-operative (readmission rate 7.7%). Significant risk factors include: disease stage (stage 3 vs 4, p=0.008), suboptimal cytoreduction (36% vs 64%, p=0.001), ascites, (p=0.018), BMI (25.4 vs 27.6, p<0.001), poor PS (p<0.001), and higher baseline CA 125 (p=0.017). Patients readmitted within 40days of surgery had a significantly shorter interval from surgery to chemotherapy initiation (22 versus 32days, p<0.0001). Patients treated with bevacizumab had higher readmission rates in the case of patients with >1 readmission. On multivariate analysis, the odds of re-hospitalization increased with doubling of BMI (OR=1.81, 95% CI: 1.07-3.07) and PS of 2 (OR=2.05, 95% CI 1.21-3.48). CONCLUSION: Significant risk factors for readmission in ovarian cancer patients undergoing primary surgery and chemotherapy include stage, residual disease, ascites, high BMI and poor PS. Readmissions are most likely after the initial surgical procedure, a discrete period to target with a prospective intervention.

Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma.

BACKGROUND: We compared survival outcomes and risk of venous thromboembolism (VTE) among patients with advanced and early-stage ovarian clear cell carcinoma (OCCC) and serous ovarian carcinoma (SOC), as well as potential links with interleukin-6 (IL-6) levels. METHODS: A multicenter case-control study was conducted in 370 patients with OCCC and 938 with SOC. In a subset of 200 cases, pretreatment plasma IL-6 levels were examined. FINDINGS: Patients with advanced OCCC had the highest 2-year cumulative VTE rates (advanced OCCC 43.1%, advanced SOC 16.2%, early-stage OCCC 11.9% and early-stage SOC 6.4%, P<0.0001) and the highest median levels of IL-6 (advanced OCCC 17.8 pg/mL, advanced SOC 9.0 pg/mL, early-stage OCCC 4.2 pg/mL and early-stage SOC 5.0 pg/mL, P=0.006). Advanced OCCC (hazard ratio [HR] 3.38, P<0.0001), thrombocytosis (HR 1.42, P=0.032) and elevated IL-6 (HR 8.90, P=0.046) were independent predictors of VTE. In multivariate analysis, patients with advanced OCCC had significantly poorer 5-year progression-free and overall survival rates than those with advanced SOC (P<0.01), and thrombocytosis was an independent predictor of decreased survival outcomes (P<0.01). Elevated IL-6 levels led to poorer 2-year progression-free survival rates in patients with OCCC (50% versus 87.5%, HR 4.89, P=0.016) than in those with SOC (24.9% versus 40.8%, HR 1.40, P=0.07). INTERPRETATION: Advanced OCCC is associated with an increased incidence of VTE and decreased survival outcomes, which has major implications for clinical management of OCCC.

CEA in evaluation of adnexal mass: retrospective cohort analysis and review of the literature.

BACKGROUND: The aim of this study was to estimate the diagnostic accuracy of serum carcinoembryonic antigen (CEA) levels in conjunction with Ca125 in the triage of adnexal masses. METHODS: This retrospective cohort study was carried out in 495 patients referred to the Gynecology Department at Carmel Medical Center due to adnexal mass, between 2005 and 2012. All patients underwent surgery with histopathologically confirmed diagnosis and preoperative measurements of serum Ca125 and CEA. For each marker, sensitivity, specificity, positive predictive value, negative predictive value and risk ratio were calculated. RESULTS: Combination of CEA with Ca125, compared with Ca125 levels alone, yielded a nonsignificant effect on sensitivity (87.4% vs. 88.9%, respectively, p = 0.64) and specificity (79.3% vs. 74.3%, p = 0.18) in differentiating malignant from benign adnexal masses. CEA levels were higher in mucinous histological types, but were not helpful in detection of borderline tumors. Significantly higher CEA (21.4 ± 53.6 vs. 3.2 ± 11.9 ng/mL, p = 0.0002) and lower Ca125 values (103.9 ± 84.9 vs. 796 ± 1,331.5 U/mL, p = 0.0338) were demonstrated in the 17 metastatic cases compared with 181 primary ovarian malignancies. CONCLUSIONS: The combination of the tumor markers CEA and Ca125 did not contribute significantly to the detection of malignant adnexal masses compared with Ca125 alone. As our results suggest that higher CEA levels could be useful in differentiating metastatic tumors from primary ovarian malignancy and in diagnosis of mucinous histology, this issue should be investigated in large, well-designed, prospective cohort trials.

Expression of serum miR-200a, miR-200b, and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features.

BACKGROUND: MicroRNAs (miRs) have been implicated in the etiology of various human cancers. The aim of this study was to investigate the association of the expression of three members--miR 200a, miR 200b, and miR 200c belonging to the miR-200 family with clinicopathological characteristics and their impact on the progression of epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Total RNA from serum was isolated by Trizol method, polyadenylated, and reverse transcribed into cDNA. Expression levels of miR-200a, miR-200b, and miR-200c were detected by using miRNA qRT-PCR. We measured miR expression in 70 serum samples of EOC patients with matched controls using U6 snRNA as a reference. Levels of miR expression was compared with distinct clinicopathological features. RESULTS: Expression of miR-200a was found to be greater than six-fold (p = 0.01), miR-200b and miR-200c greater than three-fold (p = 0.01) in comparison with matched normal controls. Association of miRNA expression with clinicopathological factors and progression was statistically evaluated. The expression levels of miR-200a and miR-200c were found to be significantly associated with disease progression (p = 0.04 and p < 0.001, respectively). miR-200a overexpression was found be associated with tumor histology and stage. Patients with lymph node metastasis showed significant elevation of miR-200c (p = 0.006). The AUC in ROC curve also indicated that serum levels of miR-200a and miR-200c might be worthwhile as a diagnostic tool in the near future. CONCLUSION: Our findings suggest that miR-200a, miR-200b, and miR-200c overexpressions are associated with the aggressive tumor progression and be recognized as reliable markers to predict the prognosis and survival in EOC patients.