Fetal Lung Interstitial Tumor: A Comprehensive Case Study with an Emphasis on Next-Generation Sequencing.

Fetal lung interstitial tumor (FLIT), which is characterized by immature interstitial cells resembling the fetal lung parenchyma of 20 to 24 weeks of gestation, is a rare respiratory neoplasm. This study presents the first reported FLIT in Korea. It also aims to refine the diagnostic method of FLIT and increase the accuracy of prognostic assessment by using next-generation sequencing to check for anaplastic lymphoma receptor tyrosine kinase (anaplastic lymphoma kinase) gene rearrangement. Although the initial prognosis for FLIT has been promising since its first report in 2010, certain pathological features are associated with poorer outcomes. Therefore, achieving an accurate diagnosis of FLIT is crucial for avoiding unnecessary treatments beyond surgical resection.

3D multiplexed tissue imaging reconstruction and optimized region of interest (ROI) selection through deep learning model of channels embedding.

Introduction: Tissue-based sampling and diagnosis are defined as the extraction of information from certain limited spaces and its diagnostic significance of a certain object. Pathologists deal with issues related to tumor heterogeneity since analyzing a single sample does not necessarily capture a representative depiction of cancer, and a tissue biopsy usually only presents a small fraction of the tumor. Many multiplex tissue imaging platforms (MTIs) make the assumption that tissue microarrays (TMAs) containing small core samples of 2-dimensional (2D) tissue sections are a good approximation of bulk tumors although tumors are not 2D. However, emerging whole slide imaging (WSI) or 3D tumor atlases that use MTIs like cyclic immunofluorescence (CyCIF) strongly challenge this assumption. In spite of the additional insight gathered by measuring the tumor microenvironment in WSI or 3D, it can be prohibitively expensive and time-consuming to process tens or hundreds of tissue sections with CyCIF. Even when resources are not limited, the criteria for region of interest (ROI) selection in tissues for downstream analysis remain largely qualitative and subjective as stratified sampling requires the knowledge of objects and evaluates their features. Despite the fact TMAs fail to adequately approximate whole tissue features, a theoretical subsampling of tissue exists that can best represent the tumor in the whole slide image. Methods: To address these challenges, we propose deep learning approaches to learn multi-modal image translation tasks from two aspects: 1) generative modeling approach to reconstruct 3D CyCIF representation and 2) co-embedding CyCIF image and Hematoxylin and Eosin (H&E) section to learn multi-modal mappings by a cross-domain translation for minimum representative ROI selection. Results and discussion: We demonstrate that generative modeling enables a 3D virtual CyCIF reconstruction of a colorectal cancer specimen given a small subset of the imaging data at training time. By co-embedding histology and MTI features, we propose a simple convex optimization for objective ROI selection. We demonstrate the potential application of ROI selection and the efficiency of its performance with respect to cellular heterogeneity.

Dual-modality imaging of immunofluorescence and imaging mass cytometry for whole-slide imaging and accurate segmentation.

Imaging mass cytometry (IMC) is a powerful technique capable of detecting over 30 markers on a single slide. It has been increasingly used for single-cell-based spatial phenotyping in a wide range of samples. However, it only acquires a rectangle field of view (FOV) with a relatively small size and low image resolution, which hinders downstream analysis. Here, we reported a highly practical dual-modality imaging method that combines high-resolution immunofluorescence (IF) and high-dimensional IMC on the same tissue slide. Our computational pipeline uses the whole-slide image (WSI) of IF as a spatial reference and integrates small-FOV IMC into a WSI of IMC. The high-resolution IF images enable accurate single-cell segmentation to extract robust high-dimensional IMC features for downstream analysis. We applied this method in esophageal adenocarcinoma of different stages, identified the single-cell pathology landscape via reconstruction of WSI IMC images, and demonstrated the advantage of the dual-modality imaging strategy.

MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new therapies, however, few mouse models represent the complexity of TNBC. Here, we develop a female TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. This Myc;Ptenfl model develops heterogeneous triple-negative mammary tumors that display histological and molecular features commonly found in human TNBC. Our research involves deep molecular and spatial analyses on Myc;Ptenfl tumors including bulk and single-cell RNA-sequencing, and multiplex tissue-imaging. Through comparison with human TNBC, we demonstrate that this genetic mouse model develops mammary tumors with differential survival and therapeutic responses that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC, providing a pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.

Tissue Expression and Prognostic Role of CXCL12 and CXCR4 in High-grade Serous Ovarian Carcinoma.

BACKGROUND/AIM: The complex of C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), plays an essential role in cancer cell proliferation, invasion, and metastasis. These are emerging therapeutic targets, and recent studies have reported that inhibition of CXCL12-CXCR4 signaling pathway enhances the effects of immune checkpoint inhibitors. Thus, we aimed to investigate tissue expression of CXCL12 and CXCR4 in high-grade serous ovarian carcinoma (HGSOC) and to determine their potential as prognostic markers. PATIENTS AND METHODS: We used chemotherapy-naïve, formalin-fixed paraffin-embedded primary ovarian cancer tissues obtained from patients with advanced-stage HGSOC at the time of primary cytoreductive surgery. After histological reassessment, we constructed a tissue microarray and performed immunohistochemical staining for CXCL12 and CXCR4. Thereafter, clinicopathological characteristics and survival outcomes were compared between the high- and low-expression groups. RESULTS: A total of 97 patients with FIGO stage IIIC-IV HGSOC were included: 15 (15.5%), 66 (68.0%), and 13 (13.4%) patients showed high expression of CXCL12, CXCR4, and both, respectively. The expression level of each protein was not associated with germline BRCA1/2 mutational status, FIGO stage, or residual tumor after primary cytoreductive surgery. In multivariate analysis adjusted for confounders, high CXCL12 expression was identified as an independent poor prognostic biomarker for progression-free survival (adjusted hazards ratio, 1.990; 95% confidence interval=1.090-3.633; p=0.025). However, CXCR4 expression was not associated with patient survival outcomes. CONCLUSION: The CXCL12 expression level may represent a prognostic biomarker for HGSOC. Proteins related to the CXCL12/CXCR4 complex may serve as therapeutic targets in HGSOC treatment.

Dual-modality imaging of immunofluorescence and imaging mass cytometry for whole slide imaging with accurate single-cell segmentation.

Imaging mass cytometry (IMC) is a powerful multiplexed tissue imaging technology that allows simultaneous detection of more than 30 makers on a single slide. It has been increasingly used for singlecell-based spatial phenotyping in a wide range of samples. However, it only acquires a small, rectangle field of view (FOV) with a low image resolution that hinders downstream analysis. Here, we reported a highly practical dual-modality imaging method that combines high-resolution immunofluorescence (IF) and high-dimensional IMC on the same tissue slide. Our computational pipeline uses the whole slide image (WSI) of IF as a spatial reference and integrates small FOVs IMC into a WSI of IMC. The high-resolution IF images enable accurate single-cell segmentation to extract robust high-dimensional IMC features for downstream analysis. We applied this method in esophageal adenocarcinoma of different stages, identified the single-cell pathology landscape via reconstruction of WSI IMC images, and demonstrated the advantage of the dual-modality imaging strategy. Motivation: Highly multiplexed tissue imaging allows visualization of the spatially resolved expression of multiple proteins at the single-cell level. Although imaging mass cytometry (IMC) using metal isotope-conjugated antibodies has a significant advantage of low background signal and absence of autofluorescence or batch effect, it has a low resolution that hampers accurate cell segmentation and results in inaccurate feature extraction. In addition, IMC only acquires mm 2 -sized rectangle regions, which limits its application and efficiency when studying larger clinical samples with non-rectangle shapes. To maximize the research output of IMC, we developed the dual-modality imaging method based on a highly practical and technical improvement requiring no extra specialized equipment or agents and proposed a comprehensive computational pipeline that combines IF and IMC. The proposed method greatly improves the accuracy of cell segmentation and downstream analysis and is able to obtain whole slide image IMC to capture the comprehensive cellular landscape of large tissue sections.

Deciphering the Immune Complexity in Esophageal Adenocarcinoma and Pre-Cancerous Lesions With Sequential Multiplex Immunohistochemistry and Sparse Subspace Clustering Approach.

Esophageal adenocarcinoma (EAC) develops from a chronic inflammatory environment across four stages: intestinal metaplasia, known as Barrett's esophagus, low- and high-grade dysplasia, and adenocarcinoma. Although the genomic characteristics of this progression have been well defined via large-scale DNA sequencing, the dynamics of various immune cell subsets and their spatial interactions in their tumor microenvironment remain unclear. Here, we applied a sequential multiplex immunohistochemistry (mIHC) platform with computational image analysis pipelines that allow for the detection of 10 biomarkers in one formalin-fixed paraffin-embedded (FFPE) tissue section. Using this platform and quantitative image analytics, we studied changes in the immune landscape during disease progression based on 40 normal and diseased areas from endoscopic mucosal resection specimens of chemotherapy treatment- naïve patients, including normal esophagus, metaplasia, low- and high-grade dysplasia, and adenocarcinoma. The results revealed a steady increase of FOXP3+ T regulatory cells and a CD163+ myelomonocytic cell subset. In parallel to the manual gating strategy applied for cell phenotyping, we also adopted a sparse subspace clustering (SSC) algorithm allowing the automated cell phenotyping of mIHC-based single-cell data. The algorithm successfully identified comparable cell types, along with significantly enriched FOXP3 T regulatory cells and CD163+ myelomonocytic cells as found in manual gating. In addition, SCC identified a new CSF1R+CD1C+ myeloid lineage, which not only was previously unknown in this disease but also increases with advancing disease stages. This study revealed immune dynamics in EAC progression and highlighted the potential application of a new multiplex imaging platform, combined with computational image analysis on routine clinical FFPE sections, to investigate complex immune populations in tumor ecosystems.

Role of Ischemic Preconditioning in the Cardioprotective Mechanisms of Monomeric C-Reactive Protein-Deposited Myocardium in a Rat Model.

BACKGROUND: The deposition of monomeric C-reactive protein (mCRP) in the myocardium aggravates ischemia-reperfusion injury (IRI) and myocardial infarction. Ischemic preconditioning (IPC) is known to protect the myocardium against IRI. METHODS: We evaluated the effects of IPC on myocardium upon which mCRP had been deposited due to IRI in a rat model. Myocardial IRI was induced via ligation of the coronary artery. Direct IPC was applied prior to IRI using multiple short direct occlusions of the coronary artery. CRP was infused intravenously after IRI. The study included sham (n=3), IRI-only (n=5), IRI+CRP (n=9), and IPC+IRI+CRP (n=6) groups. The infarcted area and the area at risk were assessed using Evans blue and 2,3,5-triphenyltetrazolium staining. Additionally, mCRP immunostaining and interleukin-6 (IL-6) mRNA reverse transcription-polymerase chain reaction were performed. RESULTS: In the IRI+CRP group, the infarcted area and the area of mCRP deposition were greater, and the level of IL-6 mRNA expression was higher, than in the IRI-only group. However, in the IPC+IRI+CRP group relative to the IRI+CRP group, the relative areas of infarction (20% vs. 34%, respectively; p=0.079) and mCRP myocardial deposition (21% vs. 44%, respectively; p=0.026) were lower and IL-6 mRNA expression was higher (fold change: 407 vs. 326, respectively; p=0.376), although the difference in IL-6 mRNA expression was not statistically significant. CONCLUSION: IPC was associated with significantly decreased deposition of mCRP and with increased expression of IL-6 in myocardium damaged by IRI. The net cardioprotective effect of decreased mCRP deposition and increased IL-6 levels should be clarified in a further study.

Loss of PKM2 in Lgr5+ intestinal stem cells promotes colitis-associated colorectal cancer.

The regulatory properties of pyruvate kinase M2 isoform (PKM2), the key glycolytic enzyme, influence altered energy metabolism including glycolysis in cancer. In this study, we found that PKM2 was highly expressed in patients with ulcerative colitis or colorectal cancer (CRC). We then investigated the effectiveness of conditionally ablating PKM2 in Lgr5+ intestinal stem cells (ISC) using a mouse model of colitis-associated CRC (AOM plus DSS). Tamoxifen-inducible Lgr5-driven deletion of PKM2 in ISC (PKM2ΔLgr5-Tx) significantly promoted tumor incidence and size in the colon and lower body weight compared with findings in vehicle-treated mice (PKM2ΔLgr5-Veh). Histopathologic analysis revealed considerable high-grade dysplasia and adenocarcinoma in the colon of PKM2ΔLgr5-Tx mice while PKM2ΔLgr5-Veh mice had low- and high-grade dysplasia. Loss of PKM2 was associated with dominant expression of PKM1 in Lgr5+ ISC and their progeny cells. Further, the organoid-forming efficiency of whole cancer cells or Lgr5+ cells obtained from colon polyps of PKM2ΔLgr5-Tx mice was significantly increased when compared with PKM2ΔLgr5-Veh mice. Cancer organoids from PKM2ΔLgr5-Tx mice exhibited increased mitochondrial oxygen consumption and a shift of metabolites involved in energy metabolism. These findings suggest that loss of PKM2 function in ISC promotes colitis-associated CRC.

Adrenal Cortical Neoplasm with Uncertain Malignant Potential Arising in the Heterotopic Adrenal Cortex in the Liver of a Patient with Beckwith-Wiedemann Syndrome.

Patients with Beckwith-Wiedemann syndrome (BWS) are predisposed to developing embryonal tumors, with hepatoblastoma being the most common type. Our patient showed hemihypertrophy, macroglossia, and paternal uniparental disomy in chromosome 11 and was diagnosed with BWS. When the patient was 9 months old, a 2.5×1.5 cm oval hypoechoic exophytic mass was detected in the inferior tip of his right liver. Preoperative imaging identified it as hepatoblastoma; however, histologic, immunohistochemistry, and electron microscopic findings were compatible with adrenal cortical neoplasm with uncertain malignant potential. The origin of the adrenal tissue seemed to be heterotopic. Here, we describe for the first time an adrenal cortical neoplasm with uncertain malignant potential arising in the heterotopic adrenal cortex located in the liver of a patient with BWS.

C-reactive Protein Overexpression in the Background Liver of Hepatitis B Virus-Associated Hepatocellular Carcinoma Is a Prognostic Biomarker.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). Peripheral blood C-reactive protein (CRP) concentration and CRP overexpression in HCC cells are proven to be prognostic markers for HCC, but the significance of CRP expression in non-neoplastic hepatocytes, which are the primary origin of CRP, has not been studied. This study was conducted to determine the clinicopathologic significance of CRP immunoreactivity in the background liver of HBV-associated HCC. METHODS: CRP immunostaining was done on tissue microarrays of non-neoplastic liver tissues obtained from surgically resected, treatment-naïve HBV-associated HCCs (n = 156). The relationship between CRP immunoreactivity and other clinicopathologic parameters including cancer-specific survival was analyzed. CRP immunoreactivity was determined using a 4-tier grading system: grades 0, 1, 2, and 3. RESULTS: CRP was positive in 139 of 156 cases (89.1%) of non-neoplastic liver in patients with HCCs: grade 1 in 83 cases (53.2%); grade 2 in 50 cases (32.1%); and grade 3 in six cases (3.8%). The patients with diffuse CRP immunoreactivity (grade 3) had decreased cancer-specific survival (p = .031) and a tendency for shorter interval before early recurrence (p = .050). The degree of CRP immunoreactivity correlated with serum CRP concentration (p < .001). CONCLUSIONS: CRP immunoreactivity in non-neoplastic liver is a novel biomarker for poor cancer-specific survival of HBV-associated HCC and correlates with serum CRP concentration.

Biochemical and molecular analyses of infantile sialic acid storage disease in a patient with nonimmune hydrops fetalis.

Nonimmune hydrops fetalis is the most severe clinical manifestation of lysosomal storage diseases (LSDs). Around 14 different LSDs have been accounted for as 1-15% of the cause of nonimmune hydrops fetalis. We report a Korean infant affected by an extremely rare but severe form of sialic acid storage disease. The patient presented with nonimmune hydrops fetalis, dysmorphic facial features, hepatosplenomegaly, and dysostosis multiplex and died at 39 days of age due to persistent pulmonary hypertension. LSD was suspected based on the presence of diffuse vacuolation of syncytiotrophoblast, villous stromal cells, and intermediate trophoblast in placental biopsy. Increased excretion of urinary free sialic acid was detected by liquid chromatography-tandem mass spectrometry. The patient was compound heterozygous of the c.908G>A (p.Trp303Ter) and the splicing mutation c.1259+5G>T (IVS9+5 G>T) in the SLC17A5 gene.

A Pyloric Gland-Phenotype Ovarian Mucinous Tumor Resembling Lobular Endocervical Glandular Hyperplasia in a Patient with Peutz-Jeghers Syndrome.

We describe an ovarian mucinous neoplasm that histologically resembles lobular endocervical glandular hyperplasia (LEGH) containing pyloric gland type mucin in a patient with Peutz-Jeghers syndrome (PJS). Although ovarian mucinous tumors rarely occur in PJS patients, their pyloric gland phenotype has not been clearly determined. The histopathologic features of the ovarian mucinous tumor were reminiscent of LEGH. The cytoplasmic mucin was stained with periodic acid-Schiff reaction after diastase treatment but was negative for Alcian blue pH 2.5, suggesting the presence of neutral mucin. Immunohistochemically, the epithelium expressed various gastric markers, including MUC6, HIK1083, and carbonic anhydrase-IX. Multiple ligation-dependent probe amplification detected a germline heterozygous deletion mutation at exons 1-7 of the STK11 gene (c.1-?_920+?del) in peripheral blood leukocytes and mosaic loss of heterozygosity in ovarian tumor tissue. Considering that LEGH and/or gastric-type cervical adenocarcinoma can be found in patients with PJS carrying germline and/or somatic STK11 mutations, our case indicates that STK11 mutations have an important role in the proliferation of pyloric-phenotype mucinous epithelium at various anatomical locations.

Diagnostic Significance of Cellular Neuroglial Tissue in Ovarian Immature Teratoma.

BACKGROUND: Immature teratoma (IT) is a tumor containing immature neuroectodermal tissue, primarily in the form of neuroepithelial tubules. However, the diagnosis of tumors containing only cellular neuroglial tissue (CNT) without distinct neuroepithelial tubules is often difficult, since the histological characteristics of immature neuroectodermal tissues remain unclear. Here, we examined the significance of CNT and tried to define immature neuroectodermal tissues by comparing the histological features of neuroglial tissues between mature teratoma (MT) and IT. METHODS: The histological features of neuroglial tissue, including the cellularity, border between the neuroglial and adjacent tissues, cellular composition, mitotic index, Ki-67 proliferation rate, presence or absence of tissue necrosis, vascularity, and endothelial hyperplasia, were compared between 91 MT and 35 IT cases. RESULTS: CNTs with a cellularity grade of ≥ 2 were observed in 96% of IT cases and 4% of MT cases (p < .001); however, CNT with a cellularity grade of 3 in MT cases was confined to the histologically distinct granular layer of mature cerebellar tissue. Moreover, CNT in IT exhibited significantly higher rates of Ki-67 proliferation, mitoses, and necrosis than those in MT (p < .001). Furthermore, an infiltrative border of neuroglial tissue and glomeruloid endothelial hyperplasia were significantly more frequent in IT cases than in MT cases (p < .001). CONCLUSIONS: Our results suggest that if CNT with a cellularity grade of ≥ 2 is not a component of cerebellar tissue, such cases should be diagnosed as IT containing immature neuroectodermal tissue, particularly if they exhibit an infiltrative border, mitoses, necrosis, and increased Ki-67 proliferation.

Diffuse decidual leucocytoclastic necrosis and NK cell aggregates: two distinct features of miscarriage.

AIMS: Primary histopathology of miscarriage remains undetermined in the majority of cases. This study was conducted to determine histological characteristics pertinent to miscarriage. METHODS: The study groups were composed of elective abortions (n=29) and miscarriages (n=45) comprised of chromosomally normal (n=15) and abnormal cases (n=30). Immunohistochemistry was done against CD3, CD8, TIA-1 and CD56. RESULTS: Two histological features--diffuse decidual leucocytoclastic necrosis (DDLN) and decidual natural killer cell aggregates (NKCA)--were relatively common in miscarriages. The frequencies of DDLN and NKCA were different between the groups (p<0.05 and p<0.05, respectively). DDLN was found in 13.8% (4/29) of elective abortions, while it was observed in 60.0% (9/15) and 23.3% (7/30) of chromosomally normal and abnormal miscarriages, respectively. DDLN was more frequent in chromosomally normal miscarriages than in elective abortions (p=0.004). NKCA was present in 13.8% (4/29) of elective abortions, while being found in 33.3% (5/15) and 43.3% (13/30) of chromosomally normal and abnormal miscarriages, respectively. NKCA was more frequent in chromosomally abnormal miscarriages than in elective abortions (p=0.020). CONCLUSIONS: The findings strongly suggest that defective placentation and abnormal maternal immune response are associated with miscarriage. DDLN and NKCA seem to have diagnostic values in the pathological evaluation of miscarriage.

Evaluation of the poly(lactic-co-glycolic acid)/pluronic F127 for injection laryngoplasty in rabbits.

OBJECTIVE: Poly(lactic-co-glycolic acid) (PLGA) is an aliphatic polyester and one of the most commonly used synthetic biodegradable polymers for tissue engineering. The objectives of this study were to evaluate the biocompatibility of PLGA/Pluronic F127 in the vocal fold. STUDY DESIGN: A randomized, prospective, controlled animal study. SETTING: University laboratory. SUBJECTS AND METHODS: We used 18 New Zealand white rabbits, which were divided into 5% PLGA solution (n = 9) and 10% PLGA solution (n = 9) groups. The PLGA/Pluronic F127 solutions were injected into the rabbit vocal fold. Laryngoscopic exams were performed at 1, 4, and 8 weeks after implantation; then larynx specimens were sampled. High-speed video camera examination was performed for functional analysis of vocal mucosa vibration at 8 weeks after implantation. Also, we evaluated the amplitude of the mucosal wave from the laryngeal midline on high-speed recording. Histologic study of larynx specimen was performed at 4 and 8 weeks. RESULTS: All animals survived until the scheduled period. Laryngoscopic analysis showed that both 5% and 10% PLGA/Pluronic F127 maintained after 8 weeks after injection without significant inflammatory response. On functional analysis, high-speed camera examination revealed regular and symmetric contact of vocal fold mucosa without a distorted movement by injected PLGA/Pluronic F127. Histologically, no significant inflammation was observed in the injected vocal fold. CONCLUSION: As a vocal fold injection material, PLGA/Pluronic F127 showed a good bio-compatibility without significant inflammatory response. Further experiment will follow to elucidate its role for drug or gene delivery into the vocal fold.

Comparison of the efficacy of low anterior resection with primary anastomosis and Hartmann's procedure in advanced primary or recurrent epithelial ovarian cancer.

OBJECTIVE: We compared the efficacy between low anterior resection with primary anastomosis (LARA) and Hartmann's procedure (HP) in advanced primary or recurrent epithelial ovarian cancer (EOC). STUDY DESIGN: We reviewed medical records of 61 patients with advanced primary or recurrent EOC who underwent LARA or HP between January 1998 and August 2008. In 37 patients with primary FIGO stage III-IV EOC, 22 and 15 received LARA and HP, whereas 10 and 14 underwent LARA and HP in 24 patients with recurrent EOC. RESULTS: Postoperative complications (recto-vaginal fistula, leakage at the anastomotic site, postoperative ileus for ≥ 7 days, wound dehiscence, angina pectoris, acute renal failure, febrile illness, reoperation within 30 days and postoperative death), surgical outcomes (time of operation, estimated blood loss, transfusion, postoperative hospitalization and time to normal diet) were not different between LARA and HP. Progression-free survival (median, 20 vs. 17 months) and overall survivals (median, 70 vs. 36 months) in advanced primary EOC, and surgery-specific survival (median, 32 vs. 17 months) and overall survivals (median, 52 vs. 61 months) in recurrent EOC were also not different between LARA and HP (p>0.05). Moreover, the recto-sigmoid obstruction after LARA was developed in 9.1% in advanced primary EOC and 10% in recurrent EOC, and the stoma-free rates were high in LARA (90.9% in advanced primary EOC; 90% in recurrent EOC). CONCLUSIONS: LARA may be an optimal procedure for bowel surgery without differences in postoperative complication, surgical outcomes and survival when compared with Hartmann's procedure in advanced primary or recurrent EOC. Furthermore, the high stoma-free rate after LARA can improve postoperative quality of life by avoiding the permanent stoma formation.