A randomized phase II trial of bevacizumab vs. bevacizumab and erlotinib as first-line consolidation after carboplatin, paclitaxel, and bevacizumab in newly diagnosed patients with mullerian tumors.

BACKGROUND: The combination of paclitaxel to platinum remains the backbone of therapy in patients with advanced Mullerian tumors. In patients with newly diagnosed Mullerian tumors, we investigated the progression-free survival benefit of bevacizumab and bevacizumab and erlotinib as consolidation therapy post-induction therapy. METHODS: Sixty patients were enrolled in a phase II trial of carboplatin, paclitaxel, and bevacizumab (induction therapy). After the completion induction therapy, patients were stratified by response (≥ SD) and then randomized (1:1) to either bevacizumab (A) or bevacizumab and erlotinib (AE.) The primary endpoint was PFS. Secondary endpoints included the response rate of induction and consolidation therapy and toxicity profile of each consolidative arm. Each consolidative arm was compared to the historical control GOG 111. RESULTS: Forty-eight patients advanced to the consolidative phase of the trial. Twelve patients were removed in the induction phase, the majority for toxicity. The most common toxicity (grade ≥ 3) was diarrhea (20%: arm AE; 0%: arm A). One patient in the AE arm had a fatal cardiac arrest deemed unrelated to the study treatment. No gastrointestinal perforations were reported. The median PFS in the AE and A arm was 18.9 months (p < 0.0001) and 13.3 months (p: ns), respectively. The overall rate of grade 3/4 toxicities in the AE arm was 72% and in the A arm 30%. Six patients remain free of disease 10 years after enrollment. CONCLUSION: Combinatorial consolidation therapy with AE was associated with an improved progression-free survival in patients with Mullerian tumors.

Open access phone triage for veterans with suspected malignant pleural mesothelioma.

BACKGROUND: Phone triaging patients with suspected malignant pleural mesothelioma (MPM) within the Veterans Healthcare Administration (VHA) system offers a model for rapid, expert guided evaluation for patients with rare and treatable diseases within a national integrated healthcare system. To assess feasibility of national open access telephone triage using evidence-based treatment recommendations for patients with MPM, measure timelines of the triage and referral process and record the impact on "intent to treat" for patients using our service. METHODS: A retrospective study. The main outcome measures were: (1) ability to perform long distance phone triage, (2) to assess the speed of access to a mesothelioma surgical specialist for patients throughout the entire VHA, and (3) to determine if access to a specialist would alter the plan of care. RESULTS: Sixty veterans were screened by our phone triage program, 38 traveled an average of 997 miles to VA Boston Healthcare system. On average, 14 d elapsed from initial phone contact until the patient was physically evaluated in our general thoracic clinic in Boston. The treatment plan was altered for 71% of patients evaluated at VA Boston Healthcare system based on 2012 International Mesothelioma Interest Group guidelines. CONCLUSIONS: Our initial experience demonstrates that in-network centralized care for Veterans with MPM is feasible within the VHA. National open access phone triage improves access to expert surgical advice and can be delivered in a timely manner for Veterans using our service. Guideline-based treatment recommendations ("intent to treat") changed the therapeutic course for the majority of patients who used our service.

Combined Single-Shot Infiltration Between the Popliteal Artery and Capsule of the Knee and Adductor Canal Block With Bupivacaine, Dexmedetomidine, and Dexamethasone for Total Knee Arthroplasty: A Propensity-Matched Analysis.

Background: To investigate if combined single-shot adductor canal blockade (ACB) and infiltration between the popliteal artery and capsule of the knee (IPACK) provide better postoperative pain management compared to ACB alone for patients undergoing unilateral total knee arthroplasty (TKA). Methods: This retrospective cohort study included adult patients who underwent primary, unilateral TKA. Patients were separated into 2 cohorts: single-shot ACB alone (performed with bupivacaine 0.25%) and combined single-shot ACB + IPACK (performed with bupivacaine 0.25%, dexmedetomidine 1 mg/kg, and dexamethasone 4 mg). Patients were propensity-matched 1:1. The primary study outcome was total opioid consumption converted to morphine milligram equivalents (MME) per eight-hour interval and postoperative day. Secondary outcomes included pain scores, length of stay, ambulation distance, return to emergency department, hospital readmission, and 30-day adverse events. Results: One hundred eighty patients were identified, of which propensity matching used 71% to yield 64 patients receiving ACB alone and 64 receiving combined ACB + IPACK. Combined ACB + IPACK had significantly lower total summative MME throughout the entire postoperative stay (P = .002) and cumulatively after the first 24 hours (P < .001). Combined ACB + IPACK also had lower mean pain scores for 0-8 hours (P = .005) and 8-16 hours (P = .009) postoperatively. There were no significant differences in secondary outcomes. Conclusions: Combined single-shot ACB + IPACK block was associated with lower total narcotic intake and mean pain scores during most of the immediate postoperative period following primary, unilateral TKA compared to ACB alone. Implementing longer-acting, single-shot ACB + IPACK for TKA can balance effective and more selective pain management with early rehabilitation.

Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix.

BACKGROUND: Cervical cancer is the second leading cause of cancer deaths among women worldwide. The objective of this study was to describe the most common oncogenic mutations in cervical cancers and to explore genomic differences between the 2 most common histologic subtypes: adenocarcinoma and squamous cell carcinoma. METHODS: A high-throughput genotyping platform, termed Oncomap, was used to interrogate 80 cervical tumors for 1250 known mutations in 139 cancer genes. Samples were analyzed using a mass spectrometry-based genotyping platform and were validated using orthogonal chemistry. Epidermal growth factor receptor (EGFR) mutations were further validated by massive parallel sequencing. Human papilloma virus (HPV) genotyping also was performed. RESULTS: Validated mutations were detected in 48 of 80 tumors (60%) examined. The highest mutation rates were in the genes phosphatidylinositol 3-kinase, catalytic subunit α (PIK3CA) (31.3%); Kirsten rat sarcoma viral oncogene homolog (KRAS) (8.8%); and EGFR (3.8%). PIK3CA mutation rates did not differ significantly between adenocarcinomas and squamous cell carcinomas (25% vs 37.5%, respectively; P = .33). In contrast, KRAS mutations were identified only in adenocarcinomas (17.5% vs 0%; P = .01), and a novel EGFR mutation was detected only in squamous cell carcinomas (0% vs 7.5%; P = .24). There were no associations between HPV-16 or HPV-18 and somatic mutations or overall survival. In adjusted analyses, PIK3CA mutations were associated with shorter survival (67.1 months vs 90.3 months; hazard ratio, 9.1; 95% confidence interval, 2.8-29.5 months; P < .001). CONCLUSIONS: Cervical cancers harbor high rates of potentially targetable oncogenic mutations. In addition, cervical squamous cell carcinoma and adenocarcinoma have distinct molecular profiles, suggesting that clinical outcomes may be improved with the use of more tailored treatment strategies, including PI3K and MEK inhibitors.

p-21-Activated kinase-1, -4 and -6 and estrogen receptor expression pattern in normal placenta and gestational trophoblastic diseases.

OBJECTIVES: To delineate the potential role of p21-activated kinases (PAKs) in the pathogenesis of gestational trophoblastic diseases (GTD) by defining the expression pattern of PAK-1, -4 and -6 and their potential implication in estrogen receptor (ER) regulation of normal placental tissue and GTD. METHODS: We evaluated immunohistochemically 10 normal first-trimester placentas (NP), 10 partial moles (PM), 15 complete moles (CM) and 3 choriocarcinomas (CCA) for PAK-1, PAK-4, PAK-6 and ER expression intensity and localization. Staining outcomes were assessed utilizing non-parametric Kruskal-Wallis one-way analysis of variance test followed by pairwise Wilcoxon Rank Sum tests. Statistical significance was determined by two-sided p-value of <0.05. RESULTS: In NP, PAK-6 immunoreactivity was predominantly cytoplasmic. Compared to NP, PM and CM demonstrated significant increase of cytoplasmic PAK-6 in cytotrophoblast (p=0.012, p=0.033 respectively), accompanied by significantly increased nuclear immunoreactivity in cytotrophoblast (p=0.008, p=0.045 respectively) and intermediate trophoblast (p=0.003, p=0.015 respectively). PAK-4 was found significantly upregulated in both cytoplasmic and nuclear compartments of cytotrophoblast and syncytiotrophoblast in PM (p=0.004 and p=0.002 for cytotrophoblast; p=0.018 and p=0.002 for syncytiotrophoblast, respectively) and CM (p=0.001 and p=0.001 for cytotrophoblast; p=0.002 and p=0.001 for syncytiotrophoblast, respectively) when compared to NP, whereas PAK-1 expression was significantly reduced in the syncytiotrophoblast of PM (p=0.025 for cytoplasm and p=0.008 for nucleus). Nuclear expression of ER was undetectable in all stained samples. CONCLUSION: Our results reveal PAK-6 upregulation in GTD compared to NP. The absence of nuclear expression of ER might stem in part from the repressive effect of PAK-6 in trophoblastic tissue.

Low-grade and high-grade serous Mullerian carcinoma: review and analysis of publicly available gene expression profiles.

OBJECTIVE: Mullerian low grade serous carcinoma (LGSC) and high grade serous carcinoma (HGSC) have distinct molecular profiles, clinical behavior and treatment response. Our objective was to study the biological profiles of these carcinomas. METHODS: This study examines publicly available gene expression profiles of LGSC and HGSC to identify differentially expressed genes and key pathways involved in carcinogenesis and chemotherapy response. RESULTS: Our analysis supports the hypothesis that serous mullerian carcinoma develop through two different pathways yielding two distinct malignancies, namely LGSC and HGSC. Furthermore, genes potentially involved in chemotherapeutic resistance of LGSC were identified. Suppressing the levels of these genes/proteins may increase clinical response to standard chemotherapy in patients with LGSC. CONCLUSION: In summary, this review shows the molecular profile of LGSC and HGSC through multi-center analysis of gene expression profiles of these tumors. The gene signatures of these neoplasms may potentially be used to develop disease-specific, targeted therapy for LGSC and HGSC.

Preoperative leukocytosis imposes an increased risk of recurrence and death among patients with nonendometrioid endometrial carcinoma.

OBJECTIVE: To evaluate the impact of preoperative leukocytosis among patients with nonendometrioid endometrial carcinoma. METHODS: The medical records of all patients with nonendometrioid endometrial carcinoma who underwent surgical treatment between January 2005 and December 2010 were retrospectively reviewed. The patients were separated into 2 groups based on the presence or absence of preoperative leukocytosis (white blood cell count ≥ 10,000/µL). The groups were then compared with respect to pathologic findings, progression-free survival, and overall survival. RESULTS: A total of 222 patients were identified, and preoperative leukocytosis was observed in 33 patients (14.9%). The leukocytosis group was associated with a larger mean size of the primary tumor (6.8 vs 4.6 cm, P = 0.016) and a greater percentage of patients with cervical stromal involvement (36.4% vs 20.1%, P = 0.039), adnexal involvement (42.4% vs. 22.8%, P = 0.017), and pelvic/para-aortic lymph node involvement (50% vs 27.4%, P = 0.025). On multivariate analysis, preoperative leukocytosis was independently associated with an increased risk of recurrence (hazard ratio, 2.07; 95% confidence interval, 1.12-3.84) and an increased risk of death (hazard ratio, 3.33; 95% confidence interval, 2.01-5.53). CONCLUSIONS: Among patients with nonendometrioid endometrial carcinoma, preoperative leukocytosis is independently associated with an increased risk of recurrence and death.

Prognostic determinants in patients with uterine and ovarian carcinosarcoma.

OBJECTIVE: To analyze and compare the demographics, treatment, recurrence, and survival rates in patients with carcinosarcoma of the uterus and ovary. STUDY DESIGN: All patients with uterine and ovarian carcinosarcoma who underwent surgical staging at the 2 participating institutions between 1995 and 2007 were identified. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS: Analysis of 87 women with uterine carcinosarcoma and 71 with ovarian carcinosarcoma was performed. Of those, 47% of the patients with uterine carcinosarcoma, compared to 14% of the patients with ovarian carcinosarcoma, were diagnosed with localized disease (p < 0.001). Age > 65 years old (p < 0.001), tumor extension (local versus regional versus distant, p < 0.001), and platinum-based chemotherapy (p = 0.05) were all independent predictors of survival. In a multivariate Cox regression model, age > 65 years old (hazard ratio [HR] = 2.5, p < 0.001), tumor extension (locoregional versus distant, HR = 3.9, p = 0.006), and uterine versus ovarian carcinosarcoma (HR = 2.2, p = 0.009) were identified as independent predictors of OS. CONCLUSION: Uterine carcinosarcoma presents at an earlier stage than does ovarian carcinosarcoma. In the multivariate analysis uterine carcinosarcoma demonstrated shorter survival than did ovarian carcinosarcoma after adjustment for extent of disease spread, age, and platinum-based chemotherapy.

The significance of preoperative leukocytosis in endometrial carcinoma.

OBJECTIVE: To evaluate the impact of preoperative leukocytosis among patients with endometrial carcinoma. METHODS: The medical records of all patients that underwent surgical treatment for endometrial carcinoma between January 2005 and December 2010 were retrospectively reviewed. Patients were separated into two groups based on the presence or absence of preoperative leukocytosis (WBC ≥ 10,000 cells per µl). The groups were then compared with respect to pathologic findings, progression-free survival and overall survival. RESULTS: 1144 patients were identified, 156 (13.6%) with preoperative leukocytosis and 988 (86.4%) without leukocytosis. The leukocytosis group had a greater percentage of patients with stage 3 (15.4% vs. 9.8%, crude p=0.02) and 4 (7.1% vs. 3.0%, crude p=0.007) disease. Leukocytosis was associated with a greater mean tumor size (4.4 vs. 3.4 cm, p=0.0002) and a greater percentage of patients with cervical stromal involvement (14.8% vs. 8.7%, crude p=0.02), adnexal involvement (14.1% vs. 7.5%, crude p=0.007) and lymphvascular space invasion (24% vs. 16.3%, crude p=0.02). On multivariate analysis, mean tumor size (OR, 95% CI; 1.10, 1.02-1.18) remained significantly associated with preoperative leukocytosis. There was no difference between groups, with respect to time to recurrence. However, leukocytosis was independently associated with an increased risk of death (HR, 95% CI; 1.69, 1.07-2.68). CONCLUSIONS: Preoperative leukocytosis, among endometrial cancer patients, was independently associated with increasing tumor size and independently imposed an increased risk of death.

Changes in serum CA-125 can predict optimal cytoreduction to no gross residual disease in patients with advanced stage ovarian cancer treated with neoadjuvant chemotherapy.

OBJECTIVE: To evaluate the predictive power of serum CA-125 changes in the management of patients undergoing neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) for a new diagnosis of epithelial ovarian carcinoma (EOC). METHODS: Using the Cancer Registry databases from our institutions, a retrospective review of patients with FIGO stage IIIC and IV EOC who were treated with platinum-based NACT-IDS between January 2006 and December 2009 was conducted. Demographic data, CA-125 levels, radiographic data, chemotherapy, and surgical-pathologic information were obtained. Continuous variables were evaluated by Student's t test or Wilcoxon-Mann-Whitney test. RESULTS: One hundred-three patients with stage IIIC or IV EOC met study criteria. Median number of neoadjuvant cycles was 3. Ninety-nine patients (96.1%) were optimally cytoreduced. Forty-seven patients (47.5%) had resection to no residual disease (NRD). The median CA-125 at diagnosis and before interval debulking was 1749U/mL and 161U/mL, respectively. Comparing patients with NRD v. optimal macroscopic disease (OMD), there was no statistical difference in the mean CA-125 at diagnosis (1566U/mL v. 2077U/mL, p=0.1). There was a significant difference in the mean CA-125 prior to interval debulking, 92 v. 233U/mL (p=0.001). In the NRD group, 38 patients (80%) had preoperative CA-125≤100U/mL compared to 33 patients (63.4%) in the OMD group (p=0.04). CONCLUSIONS: Patients who undergo NACT-IDS achieve a high rate of optimal cytoreduction. In our series, after treatment with taxane and platinum-based chemotherapy, patients with a preoperative CA-125 of ≤100U/mL were highly likely to be cytoreduced to no residual disease.

Complete hydatidiform mole in women aged 40 to 49 years.

OBJECTIVE: To describe the clinical course of women aged 40 to 49 presenting with complete hydatidiform mole. STUDY DESIGN: All cases of complete mole diagnosed at the New England Trophoblastic Disease Center were reviewed. A total of 82 patients met the study criteria. RESULTS: Study patients had a mean age of 44.2 years, gravidity of 4.6 and parity of 2.6. The mean hCG on presentation was 230,484 mIU/mL. Most patients presented with abnormal vaginal bleeding (77%). Of the 82 patients, 83% underwent dilation and curettage without prophylactic chemotherapy; 53% of those patients developed gestational trophoblastic neoplasia (GTN). Patients who developed GTN were significantly more likely both before and after evacuation to have higher hCG levels than those who did not. There were no GTN cases among patients receiving either prophylactic chemotherapy or upfront hysterectomy. Aggressive upfront therapy was associated with shortened time to hCG normalization and fewer lines of surgical or chemotherapeutic therapy. CONCLUSION: All women in their 40s with complete mole are at high risk for GTN and might benefit from aggressive upfront therapy. Those patients with hCG levels >175,000 mIU/mL constitute an "ultra-high-risk" group for whom prophylactic chemotherapy or hysterectomy should be especially considered.

Oncologic Outcomes of Surgery Versus SBRT for Non-Small-Cell Lung Carcinoma: A Systematic Review and Meta-analysis.

BACKGROUND: The optimal treatment of stage I non-small-cell lung carcinoma is subject to debate. The aim of this study was to compare overall survival and oncologic outcomes of lobar resection (LR), sublobar resection (SR), and stereotactic body radiotherapy (SBRT). METHODS: A systematic review and meta-analysis of oncologic outcomes of propensity matched comparative and noncomparative cohort studies was performed. Outcomes of interest were overall survival and disease-free survival. The inverse variance method and the random-effects method for meta-analysis were utilized to assess the pooled estimates. RESULTS: A total of 100 studies with patients treated for clinical stage I non-small-cell lung carcinoma were included. Long-term overall and disease-free survival after LR was superior over SBRT in all comparisons, and for most comparisons, SR was superior to SBRT. Noncomparative studies showed superior long-term overall and disease-free survival for both LR and SR over SBRT. Although the papers were heterogeneous and of low quality, results remained essentially the same throughout a large number of stratifications and sensitivity analyses. CONCLUSION: Results of this systematic review and meta-analysis showed that LR has superior outcomes compared to SBRT for cI non-small-cell lung carcinoma. New trials are underway evaluating long-term results of SBRT in potentially operable patients.

Intraoperative Anesthetic Management of the Thoracic Patient.

The intraoperative anesthetic management for thoracic surgery can impact a patient's postoperative course, especially in patients with significant lung disease. One-lung ventilation poses an inherent risk to patients, including hypoxemia, acute lung injury, and right ventricular dysfunction. Patient-specific ventilator management strategies during one-lung ventilation can reduce postoperative morbidity.

Oncological Outcomes of Lobar Resection, Segmentectomy, and Wedge Resection for T1a Non-Small-Cell Lung Carcinoma: A Systematic Review and Meta-Analysis.

The optimal treatment of early-stage non-small-cell lung cancer (NSCLC) remains subject to debate. Lobar resection is considered the standard of care, but sublobar resections are a lung parenchymal-sparing treatment offering promising results. We conducted a systematic review and meta-analysis to compare oncological outcomes of lobar resections and parenchymal-sparing resections for T1a NSCLC. PubMed, EMBASE, Web of Knowledge Search, and the Cochrane Central Register of Controlled Trials were searched for studies reporting oncological outcomes following lobar or parenchymal-sparing resections. Two researchers independently identified studies and extracted data. Oncological outcomes were compared for each surgical modality using the Mantel-Haenszel method, and outcomes were pooled for each modality using the inverse variance method. A total of 11,195 studies were identified and 28 articles were included. For pT1a tumors, there was no difference in 5-year overall survival when lobar resection (n = 15,003) was compared to parenchymal-sparing resection (n = 1224), with a relative risk of 0.92 (95% confidence interval: 0.84-1.01). Five-year overall survival and disease-free survival after segmentectomy yielded equal survival compared to lobar resection in directly comparing studies and point estimates of noncomparative studies. In most comparisons, wedge resection showed comparable results to lobar resections and segmentectomy. Subanalysis of intentional parenchymal-sparing surgery showed favorable results. This study shows that parenchymal-sparing surgery yields equivocal survival compared to lobar surgery for stage T1a NSCLC. However, a drawback in implementing parenchymal-sparing resection for lobectomy-tolerable patients is the risk of nodal upstaging.

Survival After Stereotactic Body Radiation Therapy for Clinically Diagnosed or Biopsy-Proven Early-Stage NSCLC: A Systematic Review and Meta-Analysis.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is a promising curative treatment for early-stage NSCLC. It is unclear if survival outcomes for SBRT are influenced by a lack of pathological confirmation of malignancy and staging of disease in these patients. In this systematic review and meta-analysis, we assess survival outcomes after SBRT in studies with patients with clinically diagnosed versus biopsy-proven early-stage NSCLC. METHODS: The main databases were searched for trials and cohort studies without restrictions to publication status or language. Two independent researchers performed the screening and selection of eligible studies. Outcomes were overall survival, cancer-specific survival, and disease-free survival. The inverse variance method and the random effects method for meta-analysis were used to assess pooled survival estimates. RESULTS: A total of 11,195 nonduplicate records were identified by the original search strategy. After screening by title and abstract, 1051 potentially eligible records were identified. A total of 43 articles were included. The comparative studies showed lower 3-year overall survival and lower 2-year and 5-year cancer-specific survival for biopsy-proven disease compared to clinical disease. However, 5-year overall survival was the same for both groups. For the pooled estimates, 3-year disease-free survival and 2-year cancer-specific survival were lower for biopsied disease. CONCLUSIONS: Results of this systematic review and meta-analysis show a discrepancy in oncological outcomes for patients undergoing SBRT for suspected early-stage NSCLC in whom there is pathologic conformation of malignancy and those who there is only a clinical diagnose of NSCLC. These results emphasize the importance of obtaining pathologic proof of malignancy.

Benign Metastasizing Leiomyomas to the Lungs: An Institutional Case Series and a Review of the Recent Literature.

BACKGROUND: Benign metastasizing leiomyomas (BMLs) represent the extrauterine spread of a benign uterine process. Pulmonary BMLs are the most common example of distant spread of uterine leiomyomas and are usually found incidentally in premenopausal women. The rarity of BMLs accounts for the limited literature that currently exists regarding their underlying pathophysiology, disease course, and management. METHODS: A retrospective analysis was performed of all BML cases diagnosed and managed at Brigham and Women's Hospital during a 22-year period. The demographic and clinical characteristics of these patients were compared with a PubMed-derived cohort of BML cases reported since 2006. RESULTS: Benign metastasizing leiomyoma tumors were identified in 10 Brigham and Women's Hospital patients, whereas 57 cases were reported in the literature. The average age at diagnosis was 54.1 and 46.7 years, respectively. Mean interval time from a pertinent gynecologic procedure to BML diagnosis was 23 years at Brigham and Women's Hospital. All patients demonstrated positivity for actin, desmin, and estrogen/progesterone receptors, confirming the diagnosis of uterine leiomyomas. Management primarily consisted of diagnostic resection with subsequent observation with or without hormonal suppression for residual pulmonary nodules. Progression of residual BMLs was noticed in 30% and 8.3% of Brigham and Women's Hospital and literature patients, respectively, when follow-up was reported. One patient in our series required further surgical management. CONCLUSIONS: Benign metastasizing leiomyomas are a rare cause of pulmonary nodules. They likely represent a clonal spread of uterine leiomyomas to the lungs. Management includes pathologic diagnosis with long-term surveillance with or without hormonal manipulation.

Molecular changes in endometriosis-associated ovarian clear cell carcinoma.

BACKGROUND: Endometriosis is frequently associated with and thought of having propensity to develop into ovarian clear cell carcinoma (OCCC), although the molecular transformation mechanism is not completely understood. METHODS: We employed immunohistochemical (IHC) staining for marker expression along the potential progression continuum. Expression profiling of microdissected endometriotic and OCCC cells from patient-matched formalin-fixed, paraffin-embedded samples was performed to explore the carcinogenic pathways. Function of novel biomarkers was confirmed by knockdown experiments. RESULTS: PTEN was significantly lost in both endometriosis and invasive tumour tissues, while oestrogen receptor (ER) expression was lost in OCCC relative to endometriosis. XRCC5, PTCH2, eEF1A2 and PPP1R14B were significantly overexpressed in OCCC and associated endometriosis, but not in benign endometriosis (p ⩽ 0.004). Knockdown experiments with XRCC5 and PTCH2 in a clear cell cancer cell line resulted in significant growth inhibition. There was also significant silencing of a panel of target genes with histone H3 lysine 27 trimethylation, a signature of polycomb chromatin-remodelling complex in OCCC. IHC confirmed the loss of expression of one such polycomb target gene, the serous ovarian cancer lineage marker Wilms' tumour protein 1 (WT1) in OCCC, while endometriotic tissues showed significant co-expression of WT1 and ER. CONCLUSIONS: Loss of PTEN expression is proposed as an early and permissive event in endometriosis development, while the loss of ER and polycomb-mediated transcriptional reprogramming for pluripotency may play an important role in the ultimate transformation process. Our study provides new evidence to redefine the pathogenic programme for lineage-specific transformation of endometriosis to OCCC.

Protein kinases and associated pathways in pluripotent state and lineage differentiation.

Protein kinases (PKs) mediate the reversible conversion of substrate proteins to phosphorylated forms, a key process in controlling intracellular signaling transduction cascades. Pluripotency is, among others, characterized by specifically expressed PKs forming a highly interconnected regulatory network that culminates in a finely-balanced molecular switch. Current high-throughput phosphoproteomic approaches have shed light on the specific regulatory PKs and their function in controlling pluripotent states. Pluripotent cell-derived endothelial and hematopoietic developments represent an example of the importance of pluripotency in cancer therapeutics and organ regeneration. This review attempts to provide the hitherto known kinome profile and the individual characterization of PK-related pathways that regulate pluripotency. Elucidating the underlying intrinsic and extrinsic signals may improve our understanding of the different pluripotent states, the maintenance or induction of pluripotency, and the ability to tailor lineage differentiation, with a particular focus on endothelial cell differentiation for anti-cancer treatment, cell-based tissue engineering, and regenerative medicine strategies.

The role of para-aortic lymphadenectomy in the surgical staging of women with intermediate and high-risk endometrial adenocarcinomas.

Objectives. To characterize clinical outcomes in patients with intermediate or high-risk endometrial carcinoma who underwent surgical staging with or without para-aortic lymphadenectomy. Methods. This is a retrospective cohort study of patients with intermediate or high-risk endometrial adenocarcinoma who underwent surgical staging with (PPALN group) or without (PLN) para-aortic lymphadenectomy. Data were collected, Kaplan-Meier curves were generated, and univariate and multivariate analyses performed to compare differences in adjuvant therapy, disease recurrence, disease-free survival (DFS), and overall survival (OS). Results. 118 patients were included in the PPALN group and 139 in the PLN group. Patients in the PPALN group were more likely to receive adjuvant vaginal brachytherapy (25.4% versus 11.5%, OR = 2.5, P = 0.03) and less likely to receive adjuvant multimodal combination therapy (17.81% versus 28.8%, OR = 0.28, P = 0.002). DFS was improved in the PLN group as compared to PPALN (80% versus 62%, P = 0.02). OS was equivalent (P = 0.93). Patients in the PPALN group who had less than 10 para-aortic nodes removed were twice as likely to recur than patients who had 10 or more para-aortic nodes or patients in the PLN group (HR 2.08, CI 1.20-3.60, P = 0.009). Conclusions. Patients in the PLN group were more likely to receive multimodal adjuvant therapy and had better DFS than the PPALN group. Pelvic lymphadenectomy followed by adjuvant radiation and chemotherapy may represent an effective treatment option for patients with intermediate or high-risk disease. If systematic para-aortic lymphadenectomy is performed and less than 10 para-aortic lymph nodes are obtained, multimodality adjuvant therapy should be considered to improve DFS.