Adoption of minimally invasive surgery after neoadjuvant chemotherapy in women with metastatic uterine cancer.

OBJECTIVE: Utilization of neoadjuvant chemotherapy (NACT) for advanced stage uterine cancer is increasing. We analyzed the use and outcomes of open versus minimally invasive surgery (MIS) for women with stage IV uterine cancer who received NACT and underwent IDS. METHODS: The National Cancer Database was used to identify women with stage IV uterine cancer diagnosed from 2010 to 2017 and treated with NACT. Among women who underwent IDS, overall survival (OS) was compared between those who underwent laparotomy vs a minimally invasive approach. To account for imbalances in confounders, a propensity score analysis using inverse probability of treatment weighting (IPTW) was performed. RESULTS: A total of 1618 women were identified. Minimally invasive IDS was performed in 31.1% and increased from 16.2% in 2010 to 40.4% in 2017 (P < 0.001). More recent year of diagnosis and performance of surgery at a comprehensive cancer center were associated with increased use of MIS (P < 0.05). Women with serous and clear cell tumors, and carcinosarcomas (compared to endometrioid tumors), as well as Medicaid coverage (compared to commercial insurance) were less likely to undergo an MIS approach (P < 0.05). The median OS was 28 months (95% CI 23.7-30.7) and 24.3 months (95% CI 22.3-26.1) for MIS and laparotomy, respectively. After propensity score balancing, there was no association between the use of MIS and survival (HR = 0.90, 95% CI 0.71-1.14). CONCLUSIONS: Among women with stage IV uterine cancer treated with NACT performance of minimally invasive debulking surgery is increasing. Compared to laparotomy, MIS does not appear to negatively impact survival.

Total parietal peritonectomy performed during interval cytoreductive surgery for advanced epithelial serous ovarian cancer results in a low incidence of platinum resistant recurrence- results of a prospective multi-centre study.

BACKGROUND: The reported incidence of platinum resistant recurrence (PRR) (recurrence within 6 months of the last dose of platinum therapy) after interval debulking/cytoreductive surgery (CRS) is high compared to that after primary CRS. The goal was to study PRR following a total parietal peritonectomy (TPP), that addresses occult disease more completely. METHODS: This is a prospective multi-center study (CTRI/2018/08/015350). A TPP was performed during interval CRS following a fixed surgical protocol. Patients with a follow-up of 6 months(M) or more were included in this analysis. The incidence and patterns of PRR and factors affecting recurrence were analyzed. RESULTS: From July 2018 to October 2019, 70 patients with serous carcinoma were included. The median surgical PCI was 15 [range 5-37]. A CC-0 resection was obtained in 55 (78.5%); CC-1 in 10 (14.2%). Occult residual disease was seen in 40%. At a median follow-up of 13 months, 17 (24.2%) had developed recurrence/progression. PRR was seen in 5 (7.1%) patients. The sites of progression (>1 in 2 patients) were pleura (n = 1), visceral peritoneum (n = 2), retroperitoneal nodes (n = 2), mediastinal nodes (n = 1) and small bowel mesentery (n = 2). Overall, though the most common site of recurrence was the visceral peritoneum (N = 9), seven (>40%) patients did not develop recurrence in the visceral peritoneum. Patients with high PCI and grade 3-4 complications had a higher probability of developing recurrence. CONCLUSIONS: TPP performed during interval CRS resulted in a very low incidence of PRR. These findings need confirmation in a larger series. The benefit of TPP over conventional surgery should be evaluated in a randomized trial.

Brain Metastases from Endometrial Cancer: Clinical Characteristics, Outcomes, and Review of the Literature.

BACKGROUND: Brain metastases from endometrial cancer are rare and poorly described. We aimed to estimate the proportion of brain metastases at our institution that arose from endometrial cancer, and to detail clinicopathologic features and survival outcomes. METHODS: We retrospectively identified and reviewed the charts of 30 patients with brain metastases from endometrial cancer seen at Stanford Hospital from 2008 to 2018. RESULTS: Among all patients with brain metastases, the proportion arising from endometrial cancer was 0.84%. The median age at diagnosis was 62 years (range, 39-79 years), and the median overall survival from brain metastasis diagnosis was 6.8 months (range, 1.0-58.2 months). Most patients harbored endometrioid histology (53.3%), and some had concurrent metastases to lung (50.0%), bone (36.7%), and liver (20.0%). The median time from endometrial cancer diagnosis to brain metastasis development was 20.8 months (range, 1.4 months to 11.2 years), and the median number of brain metastases was 2 (range, 1-20). Patients with non-endometrioid histologies had more brain metastases than those with endometrioid histology (6.21 vs. 2.44, P = 0.029). There was no difference in overall survival by histology. CONCLUSIONS: We describe the largest cohort to date of patients with brain metastases originating from endometrial cancer. These patients represent a small fraction of all patients with brain metastases and have poor prognoses. These data enable providers caring for patients with brain metastases from endometrial cancer to appropriately counsel their patients.

Intraperitoneal hyperthermic chemotherapy after cytoreduction in patients with peritoneal metastases from endometrial cancer. The next frontier?

BACKGROUND: Endometrial cancer is the most common malignancy of the female genital tract. For cancers detected at an advanced stage or intraperitoneal relapse, the prognosis is poor. Optimal cytoreductive surgery (CRS) is the most accepted treatment; however, patients with advanced intraperitoneal disease might benefit from hyperthermic intraoperative peritoneal chemotherapy (HIPEC). The aim of this study was to analyze recurrence-free survival (RFS) after CRS and HIPEC in a large series of patients with peritoneal metastases from endometrial cancer. METHODS: Patients with a diagnosis of endometrial cancer with primary or recurrent peritoneal dissemination were included. All patients underwent CRS plus HIPEC. Data were prospectively collected in the Spanish Group of Peritoneal Oncological Surgery (GECOP) database. RESULTS: Forty-three patients with endometrial cancer and peritoneal metastasis were included. Fifteen patients (35%) were diagnosed with G3 endometrioid carcinomas and 28 (65%) with other non-endometroid histologies. A completeness of cytoreduction score of CC-0 was achieved in 41 patients (95%). RFS at 5 years was 23%, being factors related to worse RFS: treatment with preoperative chemotherapy (p = 0.027), resection of more than three peritoneal areas (p = 0.010), cytoreduction of the upper abdominal space (p = 0.023), HIPEC treatment with paclitaxel (p = 0.013), and the presence of metastatic lymph nodes (p = 0.029). CONCLUSIONS: Better RFS rates after CRS and HIPEC were observed for patients with the following characteristics: cytoreductive surgery without preoperative chemotherapy, complete surgery performed with limited surgical maneuvers, treated with cisplatin, and no lymph node metastases. SYNOPSIS: Endometrial cancer has a poor prognosis when diagnosed at advance stage. Patients with intraperitoneal metastases from endometrial cancer may benefit from CRS plus HIPEC with improvement in the recurrence-free survival results.

Identification of metastasis and prognosis-associated genes for serous ovarian cancer.

Serous ovarian cancer is one of the most fatal gynecological tumors with an extremely low 5-year survival rate. Most patients are diagnosed at an advanced stage with wide metastasis. The dysregulation of genes serves an important role in the metastasis progression of ovarian cancer. Differentially expressed genes (DEGs) between primary tumors and metastases of serous ovarian cancer were screened out in the gene expression profile of GSE73168 from Gene Expression Omnibus (GEO). Cytoscape plugin cytoHubba and weighted gene co-expression network analysis (WGCNA) were utilized to select hub genes. Univariate and multivariate Cox regression analyses were used to screen out prognosis-associated genes. Furthermore, the Oncomine validation, prognostic analysis, methylation mechanism, gene set enrichment analysis (GSEA), TIMER database analysis and administration of candidate molecular drugs were conducted for hub genes. Nine hundred and fifty-seven DEGs were identified in the gene expression profile of GSE73168. After using Cytoscape plugin cytoHubba, 83 genes were verified. In co-expression network, the blue module was most closely related to tumor metastasis. Furthermore, the genes in Cytoscape were analyzed, showing that the blue module and screened 17 genes were closely associated with tumor metastasis. Univariate and multivariate Cox regression revealed that the age, stage and STMN2 were independent prognostic factors. The Cancer Genome Atlas (TCGA) suggested that the up-regulated expression of STMN2 was related to poor prognosis of ovarian cancer. Thus, STMN2 was considered as a new key gene after expression validation, survival analysis and TIMER database validation. GSEA confirmed that STMN2 was probably involved in ECM receptor interaction, focal adhesion, TGF beta signaling pathway and MAPK signaling pathway. Furthermore, three candidate small molecule drugs for tumor metastasis (diprophylline, valinomycin and anisomycin) were screened out. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot showed that STMN2 was highly expressed in ovarian cancer tissue and ovarian cancer cell lines. Further studies are needed to investigate these prognosis-associated genes for new therapy target.

Expression of the cancer stem cell marker SSEA1 is associated with poor survival in metastatic high-grade serous carcinoma.

The objective of the present study was to perform a quantitative analysis of cancer stem cell (CSC) marker expression in ovarian carcinoma effusions. The clinical role of SSEA1 in metastatic high-grade serous carcinoma (HGSC) was additionally analyzed. CD133, Nanog, SOX2, Oct3/4, SSEA1, and SSEA4 protein expressions were quantitatively analyzed using flow cytometry (FCM) in 24 effusions. SSEA1 expression by immunohistochemistry was analyzed in 384 HGSC effusions. Highly variable expression of CSC markers by FCM was observed, ranging from 0 to 78% of Ber-EP4-positive cells in the case of CD133, with the largest number of negative specimens seen for SSEA4. SSEA1 expression by immunohistochemistry was found in HGSC cells in 336/384 (89%) effusions, most commonly focally (< 5% of cells). SSEA1 was overexpressed in post-chemotherapy disease recurrence specimens compared with chemo-naïve HGSC effusions tapped at diagnosis (p = 0.029). In univariate survival analysis, higher SSEA1 expression was significantly associated with poor overall survival (p = 0.047) and progression-free survival (p = 0.018), though it failed to retain its prognostic role in Cox multivariate survival analysis in which it was analyzed with clinical parameters (p = 0.059 and p = 0.111 for overall and progression-free survival, respectively). In conclusion, CSC markers are variably expressed in ovarian carcinoma effusions. SSEA1 expression is associated with disease progression and poor survival in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

Integration of proteomics with CT-based qualitative and radiomic features in high-grade serous ovarian cancer patients: an exploratory analysis.

OBJECTIVES: To investigate the association between CT imaging traits and texture metrics with proteomic data in patients with high-grade serous ovarian cancer (HGSOC). METHODS: This retrospective, hypothesis-generating study included 20 patients with HGSOC prior to primary cytoreductive surgery. Two readers independently assessed the contrast-enhanced computed tomography (CT) images and extracted 33 imaging traits, with a third reader adjudicating in the event of a disagreement. In addition, all sites of suspected HGSOC were manually segmented texture features which were computed from each tumor site. Three texture features that represented intra- and inter-site tumor heterogeneity were used for analysis. An integrated analysis of transcriptomic and proteomic data identified proteins with conserved expression between primary tumor sites and metastasis. Correlations between protein abundance and various CT imaging traits and texture features were assessed using the Kendall tau rank correlation coefficient and the Mann-Whitney U test, whereas the area under the receiver operating characteristic curve (AUC) was reported as a metric of the strength and the direction of the association. P values < 0.05 were considered significant. RESULTS: Four proteins were associated with CT-based imaging traits, with the strongest correlation observed between the CRIP2 protein and disease in the mesentery (p < 0.001, AUC = 0.05). The abundance of three proteins was associated with texture features that represented intra-and inter-site tumor heterogeneity, with the strongest negative correlation between the CKB protein and cluster dissimilarity (p = 0.047, τ = 0.326). CONCLUSION: This study provides the first insights into the potential associations between standard-of-care CT imaging traits and texture measures of intra- and inter-site heterogeneity, and the abundance of several proteins. KEY POINTS: • CT-based texture features of intra- and inter-site tumor heterogeneity correlate with the abundance of several proteins in patients with HGSOC. • CT imaging traits correlate with protein abundance in patients with HGSOC.

The effect of the peritoneal tumor microenvironment on invasion of peritoneal metastases of high-grade serous ovarian cancer and the impact of NEOADJUVANT chemotherapy.

Peritoneal metastases of high-grade serous ovarian cancer (HGSOC) are small-sized deposits with superficial growth toward the peritoneal cavity. It is unknown whether integrity of the peritoneal elastic lamina (PEL) correlates with the peritoneal tumor microenvironment (pTME) and whether neoadjuvant chemotherapy (NACT) affects the pTME. We explored integrity of PEL, composition of pTME, effects of NACT, and the prognostic implications in patients with extensive peritoneal metastases of HGSOC. Peritoneal samples (n = 69) were collected during cytoreductive surgery between 2003 and 2016. Clinical data were collected from medical charts. Integrity of PEL was evaluated with elastic stains. T cell (CD3, CD8) and M2-macrophage markers (CD163) were scored using algorithms created in definiens tissue studio. Patients with a disrupted PEL (n = 39; 57%), more often had residual disease after surgery (p = 0.050), compared to intact PEL. An intact PEL was associated with increased intraepithelial (ie) CD8+ cells (p = 0.032), but was not correlated with improved survival. After NACT, increased ieCD3+ cells were shown, compared to no-NACT (p = 0.044). Abundance of total CD3+ and CD8+ cells were associated with PFS (multivariate HR 0.40; 95%CI 0.23-0.69 and HR 0.49; 95%CI 0.29-0.83) and OS (HR 0.33; 95%CI 0.18-0.62 and HR 0.36; 95%CI 0.20-0.64). M2-macrophage infiltration was not correlated with survival. NACT increases abundance of ieCD3+ cells in peritoneal metastases of HGSOC. Increase of CD3+ and CD8+ cells is associated with improved PFS and OS. This suggests that CD3+ and CD8+ cells may function as prognostic biomarkers. Their role as predictive biomarker for chemotherapy or immunotherapy response in HGSOC warrants further research.

Solitary cystic metastatic lymph node of occult human papillomavirus-related oropharyngeal cancer mimicking second branchial cleft cyst: A case report.

RATIONALE: Human papillomavirus (HPV)-related oropharyngeal cancer is becoming more common, the primary cancer AQ4 usually occult and appearing only as cystic cervical lymph node (LN) metastasis. Distinguishing between a benign cystic lesion and cystic LN metastasis is challenging given their similar radiologic and histologic appearances. PATIENT CONCERNS: A 54-year-old man presented with a bulging cystic mass measuring 6.4cm on the right side of neck. DIAGNOSES: Postexcision diagnosis was second branchial cleft cyst. After 2 years, the cystic mass recurred, and HPV-related tonsillar squamous cell carcinoma with cystic metastatic LNs was confirmed after wide tonsillectomy and neck dissection. The previous cystic lesion proved to be a cystic metastatic LN from the same malignancy with additional p16 immunostain. INTERVENTIONS: The patient was treated with adjuvant concurrent chemoradiation therapy. OUTCOMES: The patient was followed up in the outpatient department with no evidence of recurrence after 1 year. LESSONS: When an adult has a cystic mass in the upper neck, we must rigorously exclude it as a cystic metastatic LN of occult HPV-related oropharyngeal cancer. Additional p16 staining might be helpful.

Appendiceal mucinous neoplasm mimics ovarian tumors: Challenges for preoperative and intraoperative diagnosis and clinical implication.

OBJECTIVE: The aim of this study was to investigate the clinicopathological characteristics of appendiceal mucinous neoplasm that had been preoperatively misdiagnosed as a mucinous ovarian tumor and to discuss the clinical impacts of misdiagnosis. METHODS: Seventy-eight patients with a final pathologic diagnosis of appendiceal mucinous neoplasm during a 10-year period were retrospectively reviewed. All patients were diagnosed with ovarian tumor before treatment. A univariate analysis was performed to evaluate predictors of the diagnostic accuracy of a frozen section. RESULTS: The patients' median age was 61 years (range, 21-82 years), and most were diagnosed as low-grade appendiceal mucinous neoplasm (LAMN) (84.62%). The diagnostic concordance between the frozen section and the final pathology was 56.92%. The most consistent diagnosis was LAMN (64.14%). Univariate analysis indicated that maximal diameter of the ovarian tumor (unilateral), laterality of the ovarian tumors (unilateral or bilateral), and frozen section site (appendix or extra-appendix) significantly correlated with the accuracy of frozen section diagnosis (all p < 0.05). Although the diagnostic discordance between the frozen section and the final pathology was 43.08%, only one patient was clinically impacted because of suboptimal surgery. CONCLUSION: Appendiceal mucinous neoplasm should be considered as a differential diagnosis of pelvic mass in women. For patients who do not require fertility-sparing surgery, excision and frozen section of the bilateral ovaries and appendix regardless of the appearance of the appendix might improve the diagnosis. For older patients with peritoneal dissemination, appropriate cytoreductive surgery is recommended to reduce the clinical impact of misdiagnosis.

Prognostic factors value of germline and somatic brca in patients undergoing surgery for recurrent ovarian cancer with liver metastases.

OBJECTIVE: To describe accurately the oncological outcomes after hepatic resection (HR) in recurrent ovarian carcinoma (ROC) evaluating clinic-pathological variables and mutational status of BRCA1/2. Although HR is considered a challenging situation in ROC patients, assessment of BRCA1/2 mutational status seems to have a relevant clinical value to guide surgical therapy. METHODS: Patients who underwent HR for ROC at the Catholic University of Rome, between June 2012 and October 2017 were included. Exclusion criteria were represented by extra-abdominal disease and presence of diffuse peritoneal carcinomatosis requiring more than 2 bowel resections. Details relative to HR were collected and BRCA analysis was performed. Predictive factors of post-HR progression free survival (PHR-PFS) were assessed by univariate analyses using Cox-proportional hazard regression models. RESULTS: Thirty-four patients undewent HR within secondary cytoreductive surgery (SCS). Six patients (17.6%) presented with hepatic relapse only, while the remaining 28 patients (82.4%) had concomitant extra-hepatic disease. In the whole series, the 3-yr PHR-PFS was 49.1% and the 3-yr post-HR overall survival was 72.9%. Univariate analysis of variables conditioning PHR-PFS showed that only BRCA mutational status played a statistically significant favourable role: the 3-yr PHR-PFS rate was 81.0% in BRCA mutated patient compared to 15.2% in wild type ones (p value: 0.001). CONCLUSIONS: Our clinical analyses suggest that in ROC patients with liver disease the assessment of germline and somatic BRCA mutational status can help to select patients elegible for SCS.

An international, phase III randomized trial in patients with mucinous epithelial ovarian cancer (mEOC/GOG 0241) with long-term follow-up: and experience of conducting a clinical trial in a rare gynecological tumor.

OBJECTIVES: We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer. METHODS: We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS: The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms. CONCLUSION: mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782.

SOX2 and SOX9 are markers of clinically aggressive disease in metastatic high-grade serous carcinoma.

OBJECTIVE: The aim of this study was to analyze the expression, biological role and clinical relevance of cancer stem cell markers in high-grade serous carcinoma (HGSC). METHODS: mRNA expression by qRT-PCR of NANOG, OCT4, SOX2, SOX4, SOX9, LIN28A and LIN28B was analyzed in 134 HGSC specimens (84 effusions, 50 surgical specimens). Nanog, OCT3/4, SOX2 and SOX9 protein expression by immunohistochemistry was analyzed in 52 HGSC effusions. Nanog protein expression in exosomes from 80 HGSC effusions was studied by Western Blotting. OVCAR3 cells underwent CRISPR/Cas9 Nanog knockout (KO), and the effect of Nanog KO on migration, invasion, proliferation and proteolytic activity was analyzed in OVCAR3 and OVCAR8 cells. RESULTS: OCT4 mRNA was overexpressed in effusions compared to solid specimens (p = 0.046), whereas SOX9 was overexpressed in the ovarian tumors compared to effusions and solid metastases (p = 0.003). Higher SOX2 and SOX9 expression was associated with primary (intrinsic) chemoresistance (p = 0.009 and p = 0.02, respectively). Higher SOX9 levels were associated with shorter overall survival in univariate (p = 0.04) and multivariate (p = 0.049) analysis. OCT3/4, SOX2 and SOX9 proteins were found in HGSC cells, whereas Nanog was detected only in exosomes. Higher SOX2 protein expression was associated with shorter overall survival in univariate analysis (p = 0.049). OVCAR cells exposed to OVCAR3 NANOG KO exosomes had reduced migration, invasion and MMP9 activity. CONCLUSIONS: SOX2 and SOX9 mRNA levels in HGSC effusions may be markers of clinically aggressive disease. Nanog is secreted in HGSC exosomes in effusions and modulates tumor-promoting cellular processes in vitro.

Long term survival and perioperative propensity score matched outcomes in diaphragmatic interventions in cytoreductive surgery + intra-peritoneal chemotherapy.

OBJECTIVES: To assess the impact of short and long term outcomes of diaphragmatic interventions in cyto-reductive surgery (CRS) and intra-peritoneal chemotherapy (IPC). METHODS: 1230 consecutive CRS/IPC procedures were preformed between 1996 and 2018 in Sydney, Australia. Redo procedures and incomplete cyto-reductions were excluded. Among these, 599 underwent diaphragmatic intervention. Preoperative heterogeneity was assessed for in 6 parameters and addressed with propensity score matching. CRS/IPC requiring diaphragmatic interventions were compared to CRS/IPC without diaphragmatic involvement. Ten perioperative outcomes were measured. Overall survival was assessed based on diagnosis type. RESULTS: Intraoperative results revealed a significant increase in operative hours (7.85 vs. 7.28, p = 0.033). Transfusion requirements were insignificantly different. Postoperatively, increased grade III and IV complications (36% vs. 26%, p = 0.052) were noted. There was no difference with regards to intensive care stay, hospital length of stay, hospital death and return to theatre. In terms of respiratory specific complications, an increased incidence of pneumothorax (13% vs. 3%, p = 0.001) and pleural effusions (24% vs. 16%, p = 0.043) were noted, whilst the differences in pneumonia were insignificant. Overall survival revealed diaphragm interventions; did not affect survival outcomes in colorectal cancers (p = 0.750, RR = 1.077, CI 0.683-1.697) and increased relative risk in low-grade appendiceal mucinous neoplasms (p = 0.025, RR = 2.437, CI 1.121-5.298). CONCLUSION: After our three-tiered research strategy, we conclude that despite the marginal increase in short term morbidity; diaphragmatic interventions do not decrease survival in colorectal cancers and diaphragmatic disease in LAMNs maybe an independent prognosticator of disease aggression.

Management and prognosis of low-grade appendiceal mucinous neoplasms: A clinicopathologic analysis of 50 cases.

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are poorly understood lesions characterized by their potential to spread to the peritoneal cavity as pseudomyxoma peritonei (PMP). The purpose of this study was to investigate the clinical and pathologic features and management of these tumors. METHODS: This was a retrospective study of consecutive patients with LAMN who underwent surgery by a surgical team at the First Affiliated Hospital of China Medical University between 2005 and 2016. Subgroup analyses were performed for patients with PMP. RESULT: The study included 50 LAMN patients, 13 of them with PMP. There were no significant differences in age (p = 0.293) or gender (p = 0.196) at diagnosis between the two groups. There was no significant difference in their presentation (p = 0.700). Although 5 patients with PMP had perforation of the appendiceal mucinous, acute peritonitis was uncommon. Microscopic examination detected that PMP without any obvious perforation in tumors shown mucin and/or mucinous epithelium herniating into the appendiceal wall, or as islands within these tissues. The patients underwent appendectomy, caecectomy and right hemicolectomy according to the intraoperative situation. The median follow-up period was 53 months (range 11-146 months). None of the patients developed clinical progression in either group during the follow-up period. CONCLUSION: The age of LAMN at presentation was almost 60 years (56.7) and there was no clear gender predilection. When LAMN was treated surgically with resection of the primary site in early stage disease or with pushing invasion, there was an excellent prognosis and expanded surgical procedures were unnecessary.

Activity and clinical relevance of autotaxin and lysophosphatidic acid pathways in high-grade serous carcinoma.

The aim of this study was to analyze the expression, biological role and clinical relevance of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA), and LPA receptors (LPAR) in high-grade serous carcinoma (HGSC). mRNA expression by qRT-PCR of LPAR1-6 was analyzed in 155 HGSC specimens (88 effusions, 67 solid lesions). ATX mRNA expression was analyzed in 97 specimens. ATX, ERK, and AKT protein expression was studied by Western blotting. LPAR2 mRNA was overexpressed in HGSC cells in effusions compared to solid lesions, with opposite findings for LPAR3 and LPAR6 mRNA and ATX protein. Higher LPAR1 levels were significantly related to longer overall survival (OS) in pre-chemotherapy effusions (p = 0.027). Conversely, higher expression of LPAR1, LPAR2, and LPAR5 in post-chemotherapy effusions was significantly associated with shorter OS (p = 0.037, p = 0.025 and p = 0.021, respectively) and progression-free survival (PFS) (p < 0.001, p = 0.007 and p < 0.001, respectively) in univariate survival analysis. LPAR1 mRNA expression was an independent prognosticator of OS in patients with pre-chemotherapy effusions and PFS in patients with post-chemotherapy effusions (p = 0.013 both). In conclusion, LPAR mRNA and ATX protein levels are anatomic site-dependent in HGSC and the former are informative of disease outcome.

Evidence for lineage continuity between early serous proliferations (ESPs) in the Fallopian tube and disseminated high-grade serous carcinomas.

The distal Fallopian tube is a site of origin for many 'ovarian' high-grade serous carcinomas (HGSCs) with intraepithelial carcinomas (STICs) that share identical TP53 mutations with metastatic tumors. TP53 mutation-positive early serous proliferations (ESPs) comprise a spectrum including p53 signatures and serous tubal intraepithelial lesions (STILs) and are not considered malignant; however, ESPs are often the only abnormality found in Fallopian tubes of women with metastatic HGSC. The purpose of this study was to determine if a relationship exists between isolated ESPs and concurrent metastatic HGSCs in the absence of STIC. Fallopian tubes from 32 HGSCs without a co-existing STIC/HGSC in the endosalpinx were exhaustively sectioned. The presence of either STIC/HGSC or ESP in the endosalpinx was documented and DNA from tissues containing ESPs, concurrent HGSC, and control epithelia were interrogated for TP53 mutations by targeted amplicon-based sequencing with average coverage reads >4000 across DNA replicate samples. Serial sectioning revealed a previously unrecognized STIC/HGSC in 3 of 32 (9.3%) and ESPs in 13 (40.6%). Twelve contained TP53 mutations. Nine (75%) shared identical TP53 mutations with concurrent HGSCs, four at high (≥ 5%) and five at low (< 5%) allele frequency. All control epithelia were TP53 mutation-negative. This study, for the first time, indicates lineage identity between ESPs in the distal tube and some metastatic HGSCs via a shared site-specific TP53 mutation. It supports a novel serous carcinogenic sequence in which an ESP could eventually culminate in a metastatic serous cancer via 'precursor escape' and would explain the apparent sudden onset of cancers without co-existing STICs. This paradigm for serous cancer development underscores the likelihood that multiple precursor types in the Fallopian tube contribute to serous cancer development with implications for the evolution, pathologic classification, and prevention of this lethal malignancy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Predominantly cystic clear cell renal cell carcinoma and multilocular cystic renal neoplasm of low malignant potential form a low-grade spectrum.

Multilocular cystic renal cell carcinoma has been recently excluded from clear cell renal cell carcinoma (CCRCC) category and re-designated as multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) due to its uniformly good outcomes. While strict distinction between MCRNLMP from predominantly cystic CCRCC (pc-CCRCC) is being emphasized, the significance of extensive true cystic component in CCRCC has not been investigated. Herein, we analyzed 57 MCRNLMP, 69 pc-CCRCC, and 46 non-cystic CCRCC. There were no statistically significant differences between the three subtypes in age, gender, and laterality. ISUP grades were 1 (73%) or 2 (27%) for MCRNLMP; for pc-CCRCC were 1 (31%), 2 (60%), and 3 (9%); and for non-cystic CCRCC were 1 (9%), 2 (52%), 3 (26%), and 4 (13%). MCRNLMP were either pT stage 1 (91%) or 2 (9%), pT stages for pc-CCRCC were 1 (92.5%), 2 (1.5%), and 3 (6%) and for non-cystic CCRCC were 1 (58.7%), 2 (6.5%), and 3 (34.8%). None of MCRNLMP patients developed recurrences or metastases, and only 1 contralateral kidney tumor and 1 metastasis developed in pc-CCRCC. In contrast, 19 patients with non-cystic CCRCC developed metastases (5-year PFS 58%, CI 38.3-73.5%), and 1 patient died of disease. Monosomy 3 was common in both MCRNLMP (3/3) and pc-CCRCC (6/7). This large series of MCRNLMP confirms its indolent behavior, shows that pc-CCRCC has significantly better prognosis than non-cystic CCRCC and may define the lower grade spectrum of CCRCC. We recommend that the presence and extent of CCRCC cystic component should be documented in the pathology report.

Peritoneal Carcinomatosis of Rare Ovarian Origin Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multi-Institutional Cohort from PSOGI and BIG-RENAPE.

PURPOSE: Ovarian cancer is the most common deadly cancer of gynecologic origin. Patients often are diagnosed at advanced stage with peritoneal metastasis. There are many rare histologies of ovarian cancer; some have outcomes worse than serous ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be considered for patients with recurrence. This study was designed to assess the impact of CRS and HIPEC on survival of patient with peritoneal metastasis from rare ovarian malignancy. METHODS: A prospective, multicentric, international database was retrospectively searched to identify all patients with rare ovarian tumor (mucinous, clear cells, endometrioid, small cell hypercalcemic, and other) and peritoneal metastasis who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI) and BIG-RENAPE working group. The postoperative complications, long-term results, and principal prognostic factors were analyzed. RESULTS: The analysis included 210 patients with a median follow-up of 43.5 months. Median overall survival (OS) was 69.3 months, and the 5-year OS was 57.7%. For mucinous tumors, median OS and DFS were not reached at 5 years. For granulosa tumors, median overall survival was not reached at 5 years, and median DFS was 34.6 months. Teratoma or germinal tumor showed median overall survival and DFS that were not reached at 5 years. Differences in OS were not statistically significant between histologies (p = 0.383), whereas differences in DFS were (p < 0.001). CONCLUSIONS: CRS and HIPEC may increases long-term survival in selected patients with peritoneal metastasis from rare ovarian tumors especially in mucinous, granulosa, or teratoma histological subtypes.

Expression and clinical role of long non-coding RNA in high-grade serous carcinoma.

OBJECTIVE: To profile long non-coding RNA (lncRNA) expression at the various anatomic sites of high-grades serous carcinoma (HGSC) and in effusion-derived exosomes. METHODS: LncRNA profiling was performed on 60 HGSC specimens, including 10 ovarian tumors, 10 solid metastases and 10 malignant effusions, as well as exosomes from 30 effusion supernatants. Anatomic site-related expression of ESRG, Link-A, GAS5, MEG3, GATS, PVT1 H19, Linc-RoR, HOTAIR and MALAT1 was validated by quantitative PCR and assessed for clinical relevance in a series of 77 HGSC effusions, 40 ovarian carcinomas, 21 solid metastases and 42 supernatant exosomes. RESULTS: Significantly different (p<0.05) expression of 241, 406 and 3634 lncRNAs was found in comparative analysis of the ovarian tumors to solid metastases, effusions and exosomes, respectively. Cut-off at two-fold change in lncRNA expression identified 54 lncRNAs present at the 3 anatomic sites and in exosomes. Validation analysis showed significantly different expression of 5 of 10 lncRNAs in the 4 specimen groups (ESRG, Link-A, MEG3, GATS and PVT1, all p<0.001). Higher ESRG levels in HGSC effusions were associated with longer overall survival in the entire effusion cohort (p=0.023) and in patients with pre-chemotherapy effusions tapped at diagnosis (p=0.048). Higher Link-A levels were associated with better overall (p=0.015) and progression-free (p=0.023) survival for patients with post-chemotherapy effusions. Link-A was an independent prognostic marker in Cox multivariate analysis in the latter group (p=0.045). CONCLUSIONS: We present the first evidence of differential LncRNA expression as function of anatomic site in HGSC. LncRNA levels in HGSC effusions are candidate prognostic markers.