Massive foreign body reaction and osteolysis following primary anterior cruciate ligament reconstruction with the ligament augmentation and reconstruction system (LARS): a case report with histopathological and physicochemical analysis.

BACKGROUND: Autologous hamstrings and patellar tendon have historically been considered the gold standard grafts for anterior cruciate ligament reconstruction (ACLR). In the last decades, the utilization of synthetic grafts has re-emerged due to advantageous lack of donor site morbidity and more rapid return to sport. The Ligament Augmentation and Reconstruction System (LARS) has demonstrated to be a valid and safe option for ACLR in the short term. However, recent studies have pointed out the notable frequency of associated complications, including synovitis, mechanical failure, and even chondrolysis requiring joint replacement. CASE PRESENTATION: We report the case of a 23-year-old male who developed a serious foreign body reaction with wide osteolysis of both femoral and tibial tunnels following ACLR with LARS. During first-stage arthroscopy, we performed a debridement of the pseudocystic mass incorporating the anterior cruciate ligament (ACL) and extending towards the tunnels, which were filled with autologous anterior iliac crest bone graft chips. Histological analysis revealed the presence of chronic inflammation, fibrosis, and foreign body giant cells with synthetic fiber inclusions. Furthermore, physicochemical analysis showed signs of fiber depolymerization, increased crystallinity and formation of lipid peroxidation-derived aldehydes, which indicate mechanical aging and instability of the graft. After 8 months, revision surgery was performed and ACL revision surgery with autologous hamstrings was successfully carried out. CONCLUSIONS: The use of the LARS grafts for ACLR should be cautiously contemplated considering the high risk of complications and early failure.

Increased visceral adipose tissue in male patients with non-clear cell renal cell carcinoma.

BACKGROUND: It is well known that there is a link between obesity and oncogenesis in many sites, including the kidney. Adiposopathy is characterized by an excessive accumulation of adipose tissue, principally visceral, which can lead to adipocyte and adipose tissue-related disorder, promoting metabolic syndrome. Visceral adipocytes secrete growth factors, proinflammatory cytokines and adipokines, regarded as mediating factors associated with the oncogenesis of obesity-related tumors. In this study, we evaluate the relationship between visceral adipose tissue (VAT) and non-clear cell renal cell carcinoma (nccRCC) in male patients. METHODS: In this retrospective study, two groups were included: nccRCC group and control group. Total adipose tissue (TAT) area, VAT area and subcutaneous adipose tissue (SAT) area were measured in both groups. VAT/SAT ratio was subsequently calculated. RESULTS: Statistically significant differences between the two groups were found in TAT area (p = 0.05), VAT area (p < 0.01) and VAT/SAT ratio (p < 0.05), while no significant difference was found in SAT area. CONCLUSIONS: This study demonstrates an increased visceral adipose tissue in male patients with nccRCC.

Human equilibrative nucleoside transporter 1 gene expression is associated with gemcitabine efficacy in advanced leiomyosarcoma and angiosarcoma.

BACKGROUND: The expression of human equilibrative nucleoside transporter 1 (hENT1), the major gemcitabine transporter into cells, has been thoroughly investigated as a predictive marker of response to gemcitabine in pancreatic cancer and biliary tract cancers. Since gemcitabine is widely used in the treatment of leiomyosarcoma and angiosarcoma, we investigated the correlation between hENT1 expression and gemcitabine efficacy in these sarcoma subtypes. METHODS: We retrospectively identified 71 patients affected by advanced angiosarcoma (26) or leiomyosarcoma (45) treated within five Italian referral centres for sarcoma; among them, 49 patients (15 angiosarcoma, 34 leiomyosarcoma) were treated with gemcitabine. All tumour samples were analysed for hENT1 expression by real-time PCR. Median 2-ΔCt value was used as the cutoff to dichotomise patients into 'high' expression and 'low' expression groups. Kaplan-Meier analysis was performed to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: We found a significant association between high hENT1 expression levels and favourable outcome in terms of PFS and OS compared to cases with low hENT1 expression in leiomyosarcoma treated with gemcitabine (PFS: 6.8 vs 3.2 months, P=0.004; OS: 14.9 vs 8.5 months, P=0.007). In addition, hENT1 overexpression correlated with a significant improvement in PFS (9.3 vs 4.5 months; P=0.02) and OS (20.6 vs 10.8 months; P=0.001) in angiosarcoma patients treated with gemcitabine. CONCLUSIONS: Our study suggests that higher hENT1 expression are associated to gemcitabine efficacy both in patients with advanced leiomyosarcoma and angiosarcoma.

Endoluminal Nd:YAG laser application in ex vivo biliary porcine tissue.

Adequate biliary drainage with endoscopic or percutaneous placement of self-expandable metal stents represents the goal of palliation in patients with inoperable malignant obstruction of the biliary tree. As an adjunct to stenting, various tissue ablation treatments have been proposed with conflicting results. The aim of this study was to test the effect on biliary tissue of a new ablation technique based on Nd:YAG laser light delivery. The study was conducted on ex vivo specimens of 18 healthy farm pigs, using cystic ducts that are the simplest biliary structures to isolate and cannulate ex vivo. A 22G cannula was positioned into the cystic duct and a quartz optical fibre, with a prototypal cooling system, was inserted into the cannula. Nd:YAG laser output powers of 10, 12, and 15 W were tested, with a total delivered energy of 1000 J in continuous mode in each case. After laser treatment, histological analysis was performed. At macroscopical examination, no lesions of the external wall of the cystic ducts were detected. At histopathological examination, a coagulative necrosis involving the entire mucosa up to the muscolaris propria without significant changes of periductal tissues was observed in all specimens. This study shows the possibility of using Nd:YAG laser on ex vivo porcine biliary ducts with the effect of obtaining a coagulative necrosis involving the whole mucosa.

Aberrant promoter methylation of beta-1,4 galactosyltransferase 1 as potential cancer-specific biomarker of colorectal tumors.

Epigenetic alterations, such as CpG islands methylation and histone modifications, are recognized key characteristics of cancer. Glycogenes are a group of genes which epigenetic status was found to be changed in several tumors. In this study, we determined promoter methylation status of the glycogene beta-1,4-galactosyltransferase 1 (B4GALT1) in colorectal cancer patients. Methylation status of B4GALT1 was assessed in 130 colorectal adenocarcinomas, 13 adenomas, and in paired normal tissue using quantitative methylation specific PCR (QMSP). B4GALT1 mRNA expression was evaluated in methylated/unmethylated tumor and normal specimens. We also investigated microsatellite stability and microsatellite instability status and KRAS/BRAF mutations. Discriminatory power of QMSP was assessed by receiving operating curve (ROC) analysis on a training set of 24 colorectal cancers and paired mucosa. The area under the ROC curve (AUC) was 0.737 (95% confidence interval [CI]:0.591-0.881, P = 0.005) with an optimal cutoff value of 2.07 yielding a 54% sensitivity (95% CI: 35.1%-72.1%) and a specificity of 91.7% (95% CI: 74.1%-97.7%). These results were confirmed in an independent validation set where B4GALT1 methylation was detected in 52/106 patients. An inverse correlation was observed between methylation and B4GALT1 mRNA expression levels (r = -0.482, P = 0.037). Significant differences in methylation levels and frequencies was demonstrated in invasive lesions as compared with normal mucosa (P = 0.0001) and in carcinoma samples as compared with adenoma (P = 0.009). B4GALT1 methylation is a frequent and specific event in colorectal cancer and correlates with downregulation of mRNA expression. These results suggest that the glycogene B4GALT1 represent a valuable candidate biomarker of invasive phenotype of colorectal cancer.

PML as a potential predictive factor of oxaliplatin/fluoropyrimidine-based first line chemotherapy efficacy in colorectal cancer patients.

PML regulates a wide range of pathways involved in tumorigenesis, such as apoptosis, which is also one of the main mechanisms through which oxaliplatin and fluoropyrimidine exert their antineoplastic activity. The present study aims to investigate PML expression as a predictive factor of oxaliplatin/fluoropyrimidine therapy efficacy. Seventy-four metastatic colorectal cancer patients who received oxaliplatin/floropyrimidine-based first line therapy have been included in this retrospective study. PML expression was assessed by immunohistochemistry. PML down-regulation was detected in 39 (52.7%) patients (14 complete and 25 partial PML loss). RR was significantly lower (25.6%) in patients with PML down-regulation than in patients with preserved PML expression (60%) (P = 0.006). Median TTP was 5.5 months when PML was down-regulated versus 11.9 months in case of preserved PML expression (P < 0.0001). A statistical significant difference was also detected in OS (15.6 and 24.5 months, respectively, P = 0.003). The impact of PML down-regulation on TTP and OS was statistically significant also in a multivariate model. This study represents the first evidence of a possible correlation between PML protein expression and outcome of metastatic colorectal cancer patients treated with oxaliplatin/fluoropyrimidine-based first line therapy.

High let-7a microRNA levels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractory metastatic disease.

Preclinical and experimental data in vivo indicate that Lethal-7 (Let-7) microRNA downregulates KRAS with antitumor effects in the presence of activating KRAS mutations. We quantified the Let-7a isoform in KRAS-mutated colorectal carcinomas from patients who received salvage cetuximab plus irinotecan. The study population was retrospectively identified among metastatic colorectal cancer patients who underwent third-line therapy with cetuximab plus irinotecan in a period when only epidermal growth factor receptor (EGFR) expression was required for anti-EGFR therapy. In 59 patients harboring KRAS mutations, Let-7a levels were analyzed for association with overall survival (OS) and progression-free survival (PFS) times. An exploratory subgroup analysis was performed using the rs61764370 (LCS6 T>G) polymorphism that experimentally impairs Let-7 binding to KRAS mRNA. In the whole group, higher Let-7a levels were significantly associated with better survival outcomes. For the primary OS endpoint, the multivariate hazard ratio was 0.82 (95% confidence interval, 0.73-0.91; p = .01). The same findings with an accentuated positive effect of high Let-7a levels on both OS and PFS times were observed in an exploratory analysis of the 45 wild-type LCS6 patients (excluding 14 carriers of the LCS6 G allele variant). All survival associations were confirmed after excluding patients with KRAS codon 13 mutations. Among the clinicopathologic features, high Let-7a levels were associated with grade 2-3 skin toxicity (p = .002). In patients with KRAS mutations, Let-7a analysis may serve to identify subgroups of patients who may still benefit from EGFR inhibition and this may open up new perspectives for alternative treatment strategies.

Marked pathological changes proximal and distal to the site of rupture in acute Achilles tendon ruptures.

A laboratory study was performed to evaluate the histopathological features of the macroscopically intact portion of the Achilles tendon in patients undergoing surgery for an acute rupture of the Achilles tendon. Tendon samples were harvested from 29 individuals (21 men, 8 women; mean age: 46 ± 12) who underwent repair of an Achilles tendon tear tear, and from 11 male patients who died of cardiovascular events (mean age: 61). Three pieces of tendon were harvested: at the rupture site, 4 cm proximal to the site of rupture, 1 cm proximal to the insertion of the Achilles tendon on the calcaneum. Slides were assessed using a semiquantitative grading scale assessing fiber structure and arrangement, rounding of the nuclei, regional variations in cellularity, increased vascularity, decreased collagen stainability, and hyalinization. Intra-observer reliability of the subscore readings was calculated. The pathological features were significantly more pronounced in the samples taken from the site of rupture than in the samples taken proximally and distal to it (0.008 < P < 0.01). There were no significant differences in the mean pathologic sum-scores in the samples taken proximally and distal to the site of rupture. Unruptured Achilles tendons, even at an advanced age, and ruptured Achilles tendons are clearly part of two distinct populations, with the latter demonstrating histopathological evidence of failed healing response even in areas macroscopically normal.

Scanty integration of osteochondral allografts cryopreserved at low temperatures with dimethyl sulfoxide.

PURPOSE: To compare the integration of osteochondral allografts cryopreserved at different temperatures and different concentrations of dimethyl sulfoxide in an in vivo sheep animal model. METHODS: Thirty-six adult sheep were randomly allocated to 6 groups of allograft osteochondral transplantation. Six osteochondral cylinders were stored for 6 weeks at -80°C; 6 at -80°C with 10% dimethyl sulfoxide (DMSO); 6 at -80°C with 10% DMSO for 90 min; 6 at -186°C; 6 at -186°C with 10% DMSO; 6 at -186°C for 90 min. After transplantation, all animals were euthanized at 6 months. Harvested specimens underwent gross morphologic and histologic evaluation. RESULTS: We found no statistically significant differences when comparing the gross cartilage morphology and histopathologic scores of each group. The Mankin and OARSI scores and the modified Wakitani and OARSI scores showed a good correlation grade. The Mankin and modified Wakitani scores showed a fair correlation grade. CONCLUSION: The cryopreservation protocols adopted in the present study provided scanty integration in an in vivo sheep model of osteochondral allograft transplantation. Therefore, their use in the clinical practice is discouraged.

PML down-regulation in soft tissue sarcomas.

To date, little is known concerning the promyelocytic leukemia gene (PML) status in tumors of different origin, and its expression has never been evaluated in soft tissue sarcoma. The aim of the present study is focused on the identification of differences in terms of PML protein expression between different types of soft tissue sarcoma and the corresponding normal surrounding tissue. PML protein expression has been assessed by immunohistochemistry in six different histologic types of soft tissue sarcoma (synovial sarcoma, myofibroblastic sarcoma, angiosarcoma, liposarcoma, pleomorphic sarcoma, and leiomyosarcoma) and in the corresponding normal surrounding tissue. PML resulted significantly down-regulated in synovial sarcoma and in myofibroblastic sarcoma specimens. Also in angiosarcoma samples a significative difference in PML expression in comparison with normal specimens has been detected. Interestingly PML protein detection showed a different pattern of expression in the three liposarcoma histology types compared with corresponding nontumoral tissues. In particular PML protein resulted significantly down-regulated in myxoid liposarcoma and in dedifferentiated liposarcoma. On the contrary no statistically significant difference was observed in pleomorphic liposarcoma compared to normal tissue specimens. Further investigations are needed to confirm these data and to assess the possible value of PML expression as a prognostic factor in these extremely aggressive diseases.

EUS-guided Nd:YAG laser ablation of normal pancreatic tissue: a pilot study in a pig model.

BACKGROUND: Laser ablation with a neodymium:yttrium aluminum garnet (Nd:YAG) laser can achieve a high rate of complete tissue necrosis and has been applied as a minimally invasive, palliative option in hepatocellular carcinoma, liver metastasis in colorectal cancer, and malignant thyroid nodules. OBJECTIVE: To assess the in vivo feasibility of EUS-guided laser ablation with an Nd:YAG laser of normal pancreatic tissue of a porcine model. DESIGN: Prospective investigation. SETTING: Hospital animal laboratory. SUBJECTS: Eight pigs. INTERVENTIONS: EUS-guided puncture of the pancreatic tail with a laser-beam fiber. An Nd:YAG laser (1.064 nm) was used, with an output power of 2 and 3 W and a total delivered energy of 500 and 1000 J in continuous mode. MAIN OUTCOME MEASUREMENTS: The 24-hour follow-up of the pigs was focused on clinical and laboratory aspects. Results of histological studies of the pancreas were obtained 24 hours after the procedure on necroscopy tissue. RESULTS: There were no technical limitations to the performance of the procedure. Tissue necrosis, localized in the pancreatic parenchyma, was observed in all animals on histological examination. The volume of ablation tissue ranged from a mean of 314 mm(3) to 483 mm(3). The ablation area ranged from a mean of 49 mm(2) to 80 mm(2). No major postprocedure complications were recorded, and all the pigs survived at 24 hours. LIMITATION: Animal study. CONCLUSIONS: EUS-guided laser ablation of the pancreas with an Nd:YAG laser is feasible in a porcine model.

Bilateral consecutive rupture of the quadriceps tendon in a man with BstUI polymorphism of the COL5A1 gene.

A genetic component has been implicated in tendinopathies involving tendon rupture. Type V collagen, a quantitatively minor fibrillar collagen which forms heterotypic fibrils with type I collagen, plays a role in the regulation of the size and configuration of fibrils of the much more abundant component type I collagen. To date, no data on the genetic component of bilateral rupture of the quadriceps tendon have been reported. We describe the presence of BstUI polymorphism of the COL5A1 gene in a man with bilateral rupture of the quadriceps tendon. The COL5A1 (the variant rs12722, BstUI RFLP) can be a candidate gene associated with the development of bilateral quadriceps tendon rupture.

Morphometric analysis of atypical glandular cells correctly classifies normal, reactive, and atypical cells in cervical smears.

The 2014 Bethesda System diagnostic criteria for atypical glandular cells (AGC) aid in the classification of atypical cells in cervical cytology. Anyway, AGC diagnosis remains challenging, due to low frequencies of this finding (approximately 0.5%-1% of Pap test results), abundance of AGC mimics, and significant interobserver variability. We developed an algorithm based on nuclear areas parameter that can help to differentiate AGC from Normal and Reactive glandular cells. Nuclear areas and perimeters were measured on 16 Pap smears with AGC and 18 with Reactive glandular cells of women aged between 30 and 77. Glandular cells from nonpathological Pap smears were used as controls. For each case, the means, medians, standard deviations, and the minimum and maximum values of both nuclear areas and perimeters of the cells of interest were calculated. The nuclear area analysis showed a 100% specificity in discriminating Normal from Altered cells (either Reactive or AGC), whereas the nuclear perimeter analysis showed a lower specificity (87.5%). Both nuclear area and perimeter variability analysis resulted in high specificity values in distinguishing Reactive cells from AGC. Therefore, a stepwise two-step algorithm using nuclear areas to discriminate Normal from Altered cells, and nuclear area variability to distinguish Reactive from AGC, allowed us to reliably classify the cells into these three categories. The morphometric analysis of nuclear area is a valuable and reliable aid in AGC diagnosis and standardization, easily integrable into common automatic algorithms.

Heterogeneous risk profiles among B3 breast lesions of uncertain malignant potential.

BACKGROUND: Most cases of breast lesions of uncertain malignant potential (B3) undergo surgical intervention. We aimed to analyze the outcome of B3 lesion subtypes in a large series of screen-detected cases. METHODS: We screened 2,986 core needle biopsies to classify B3 lesions. Positive predictive values (PPVs) for malignancy were calculated for a comprehensive risk characterization according to clinicopathologic and morphologic variables. RESULTS: B3 lesions comprised 35% atypical ductal hyperplasia (PPV = 20%), 16.7% flat epithelial atypia (PPV = 12%), 22.7% lobular neoplasia (PPV = 16.2%), 9% papillary lesion (PPV = 18.5%), 8.6% phyllodes tumor (PPV = 3.8%), and 8% radial scars (PPV = 4.1%) based on histopathologic diagnosis. Upgrade rates were 15.9% for calcifications, 13.7% for mass lesions, and 16.7% for architectural deformities, with 8.3% of malignant lesions classified as ductal carcinoma in situ and 6.7% as invasive cancers (PPV = 15%). CONCLUSION: B3 lesions entail a heterogeneous risk of malignancy, and careful radiologic-pathologic correlation is required for optimal treatment.

Caveolin-1 expression in human breast lobular cancer progression.

Caveolin-1 is the principal structural protein of caveolae, and caveolin-1 gene plays a role as a tumour suppressor gene in human mammary cancer-derived cells. However, limited data are available concerning caveolin-1 expression in human breast cancer tissue. We evaluated caveolin-1 expression in normal lobular epithelial cells and in the whole human lobular neoplasia spectrum disease, with the aim to examine differences of caveolin-1 expression in human lobular neoplasia progression. We selected 147 cases of pure lobular lesions, ie lobular intraepithelial neoplasia and invasive lobular carcinoma, from 112 patients. Presence of caveolin-1 was evaluated by immunohistochemistry. Among 81 lobular intraepithelial neoplasia lesions studied, 43% were associated with invasive lobular carcinoma, with positive correlation between lobular intraepithelial neoplasia grade and presence of invasive component (P=0.01). In total, 64% of lobular lesions were positive for caveolin-1 (81% lobular intraepithelial neoplasia and 42% invasive lobular carcinoma), and a significant difference in terms of caveolin-1 expression was present between lobular intraepithelial neoplasia and invasive lobular carcinoma (P=0.0001). Variations in caveolin-1 expression were evident among the different lobular intraepithelial neoplasia grades (91% grade 1, 68% grade 2, 35% grade 3); the difference was significant comparing lobular intraepithelial neoplasia grade 3 vs 1 (P=0.0001) and grade 3 vs 2 (P=0.007) but not grade 1 vs 2. Furthermore, significant differences were found between lobular intraepithelial neoplasia grades 1 and 2 vs invasive lobular carcinoma (P=0.0001), but not between lobular intraepithelial neoplasia grade 3 and invasive lobular carcinoma (P=0.196). In conclusion, variations of caveolin-1 expression may have an important role in the progression of human breast lobular cancer; in addition, they confirm the powerful clinical impact of the lobular intraepithelial neoplasia classification for lobular intraepithelial neoplasia, supporting the direct origin of invasive lobular carcinoma from clonal expansion of the lobular intraepithelial neoplasia lesions cells.

A gastrointestinal stromal tumor presenting as a pelvic mass: A case report.

Gastrointestinal stromal tumors (GISTs) represent 0.1-1% of gastrointestinal malignancies. They are commonly asymptomatic and found incidentally during laparoscopy, surgical procedures or radiological studies. Diagnosis is based on histology and immunohistochemistry, while the role of imaging studies is not diagnosis-specific. We present the case of a 38-year-old patient complaining of an increase in her abdominal circumference. Consequently, a vaginal examination, a transvaginal ultrasound and an MRI of the abdomen and pelvis were carried out. It should be noted that a preoperative diagnosis of GISTs is uncommon, due to the rarity and many presentations of the disease. Ultrasound and MRI are not able to differentiate a GIST from ovarian cancer. However, if a pelvic mass is detected, the possibility of a non-gynaecological tumor has to be considered.

Breast-like vulvar lesion with concurrent breast cancer: a case report and critical literature review.

In the current report, we describe an intriguing case of a breast-like cancer lesion located in the vulvar region in a woman lacking a remarkable past medical or family history of breast cancer but with concurrent breast cancer. Consequently, a differential diagnosis between a primary synchronous breast and vulvar cancer or a metastatic breast carcinoma to the vulva is a key point in terms of the clinical approach. In a review of the literature, 39 cases of breast-like cancer lesion have been described: 23 cases of primary infiltrating carcinoma of the vulva and 16 cases of vulvar metastases of breast carcinoma. To the best of our knowledge, this is the first report of a clinically synchronous vulvar metastasis from an invasive ductal carcinoma. The main diagnostic criteria for differential diagnosis between primary or metastatic breast-like vulvar carcinoma are also discussed.

Movin and Bonar scores assess the same characteristics of tendon histology.

The Movin scoring system and its validated modifications and the Bonar scoring system are used to classify the histopathological findings of tendinopathy. We compared the reliability of these two different histopathological evaluation scores of tendon tissue. Tendon samples were harvested from 88 individuals (49 men, 39 women; mean age, 58.2 years) who underwent arthroscopic repair of a rotator cuff tear, and from five male patients who died of cardiovascular events (mean age, 69.6 years). A piece of supraspinatus tendon that was not directly involved in the tear was harvested en bloc within the intact middle portion of the tendon. Using hematoxylin and eosin staining and Alcian blue, slides were assessed using Bonar and Movin scores. The intraclass correlation was 0.921 (confidence interval 95% 0.790-0.963). Movin's and Bonar's scores have a high correlation and assess similar characteristics and variables of tendon abnormalities.

Pancreatic intraductal papillary mucinous neoplasms: a paradigmatic case. A case report and review of the literature.

Pancreatic intraductal papillary mucinous neoplasms constitute an increasingly frequent clinical entity. The definition and clinical behaviour of these tumours are still a subject of debate. As a consequence, their clinical management is also presents controversial aspects ranging from follow-up to the advisability or otherwise of an aggressive surgical approach, even in the case of small non-malignant lesions. In 2002 we observed a patient affected by a large pancreatic mass with the endoscopic and radiological features of an intraductal papillary mucinous tumour. Over a 20-year clinical history the patient had been considered and treated as affected by chronic pancreatitis. In spite of the tumour size and possible vascular infiltration, surgical exploration was considered. Total pancreatectomy was performed and final histology revealed a non-invasive papillary mucinous carcinoma of the pancreas. Twenty-six months after surgical resection the patient is alive and free of disease. In the present paper we re-assess the clinical history of this patient and review the most recent literature on such tumours.

Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1.

Many epigenetically inactivated genes involved in ovarian cancer (OC) development and progression remain to be identified. In this study we undertook an integrated approach that consisted of identification of genome-wide expression patterns of primary OC samples and normal ovarian surface epithelium along with a pharmacologic unmasking strategy using 3 OC and 3 immortalized normal ovarian epithelial cell lines. Our filtering scheme identified 43 OC specific methylated genes and among the 5 top candidates (GULP1, CLIP4, BAMBI, NT5E, TGFß2), we performed extended studies of GULP1. In a training set, we identified GULP1 methylation in 21/61 (34%) of cases with 100% specificity. In an independent cohort, the observed methylation was 40% (146/365) in OC, 12.5% (2/16) in borderline tumors, 11% (2/18) in cystadenoma and 0% (0/13) in normal ovarian epithelium samples. GULP1 methylation was associated with clinicopathological parameters such as stage III/IV (p = 0.001), poorly differentiated grade (p = 0.033), residual disease (p < 0.0003), worse overall (p = 0.02) and disease specific survival (p = 0.01). Depletion of GULP1 in OC cells led to increased pro-survival signaling, inducing survival and colony formation, whereas reconstitution of GULP1 negated these effects, suggesting that GULP1 is required for maintaining cellular growth control.