A multicenter, randomized, double-blinded, placebo-controlled, phase â ¢ study evaluating the efficacy and safety of Xeligekimab (GR1501) in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Xeligekimab is a fully human monoclonal antibody that selectively neutralizes IL-17A and had shown potential efficacy in preliminary trials. OBJECTIVE: To evaluate the efficacy and safety of Xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg Xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by extending the treatment schedule to GR1501 every 4 weeks for further 40 weeks. Efficacy was assessed by evaluating the Physician's Global Assessment (PGA) 0/1 and Psoriasis Area and Severity Index (PASI) 75/90/100 improvement. The safety profile was also evaluated. RESULTS: At week 12, The PASI 75/90/100 were achieved in 90.7%/74.4%/30.2%% patients in GR1501 group compared with 8.6%/1.4%/0% patients in placebo group, respectively. The PGA 0/1 were achieved in 74.4% patients of GR1501 group and 3.6% patients in placebo group, respectively. The PASI 75 and PGA 0/1 maintained until week 52. No unexpected adverse events were observed. CONCLUSION: Xeligekimab showed high efficacy and is well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

A Feature Selection Approach Guided an Early Prediction of Anthocyanin Accumulation Using Massive Untargeted Metabolomics Data in Mulberry.

Identifying the early predictive biomarkers or compounds represents a pivotal task for guiding a targeted agricultural practice. Despite the various available tools, it remains challenging to define the ideal compound combination and thereby elaborate an effective predictive model fitting that. Hence, we employed a stepwise feature selection approach followed by a maximum relevance and minimum redundancy (MRMR) on the untargeted metabolism in four mulberry genotypes at different fruit developmental stages (FDSs). Thus, we revealed that 7 out of 226 differentially abundant metabolites (DAMs) explained up to 80% variance of anthocyanin based on linear regression model and stepwise feature selection approach accompanied by an MRMR across the genotypes over the FDSs. Among them, the phosphoenolpyruvate, d-mannose and shikimate show the top 3 attribution indexes to the accumulation of anthocyanin in the fruits of these genotypes across the four FDSs. The obtained results were further validated by assessing the regulatory genes expression levels and the targeted metabolism approach. Taken together, our findings provide valuable evidences on the fact that the anthocyanin biosynthesis is somehow involved in the coordination between the carbon metabolism and secondary metabolic pathway. Our report highlights as well the importance of using the feature selection approach for the predictive biomarker identification issued from the untargeted metabolomics data.

The Ethylene Response Factor ERF5 Regulates Anthocyanin Biosynthesis in 'Zijin' Mulberry Fruits by Interacting with MYBA and F3H Genes.

Ethylene promotes ripening in fruits as well as the biosynthesis of anthocyanins in plants. However, the question of which ethylene response factors (ERFs) interact with the genes along the anthocyanin biosynthesis pathway is yet to be answered. Herein, we conduct an integrated analysis of transcriptomes and metabolome on fruits of two mulberry genotypes ('Zijin', ZJ, and 'Dashi', DS, with high and low anthocyanin abundance, respectively) at different post-flowering stages. In total, 1035 upregulated genes were identified in ZJ and DS, including MYBA in the MBW complex and anthocyanin related genes such as F3H. A KEGG analysis suggested that flavonoid biosynthesis and plant hormone signaling transduction pathways were significantly enriched in the upregulated gene list. In particular, among 103 ERF genes, the expression of ERF5 showed the most positive correlation with the anthocyanin change pattern across both genotypes and in the post-flowering stages, with a Pearson correlation coefficient (PCC) of 0.93. Electrophoresis mobility shift assay (EMSA) and luciferase assay suggested that ERF5 binds to the promoter regions of MYBA and F3H and transcriptionally activates their gene expression. We elucidated a potential mechanism by which ethylene enhances anthocyanin accumulation in mulberry fruits and highlighted the importance of the ERF5 gene in controlling the anthocyanin content in mulberry species. This knowledge could be used for engineering purposes in future mulberry breeding programs.

Does Radical Hysterectomy for Clinically Apparent Stage II Endometrial Cancer Affect Risk of Local Recurrence?

OBJECTIVE: Compare recurrence-free survival (RFS) and morbidity between radical hysterectomy (RH) and simple hysterectomy (SH) for clinically diagnosed stage II endometrial cancer. METHODS: A multicentre, retrospective study, from 2000 to 2015, involving patients with endometrial cancer with cervical involvement preoperatively and stromal invasion on final pathology. Wilcoxon rank-sum test, Fisher exact test, Kaplan-Meier survival functions, and Cox proportional hazards models were used for analysis. RESULTS: Ninety of 1613 patients had clinical stage II endometrial cancer; 57 underwent RH and 33 underwent SH, with no difference in adjuvant treatment or morbidity. About half of patients (51%) had pathologic stage III-IV disease. Mean follow-up was 3.3 and 3.8 years for SH and RH, respectively. Thirty-three percent of patients with RH and SH experienced a recurrence. Most recurrences were distant: 90% with SH and 79% with RH. There was no difference in RFS between groups (2-year: SH 65% vs. RH 75%; 5-year: SH 54% vs. RH 63%; P = 0.72). Controlling for stage, adjuvant treatment, and margin status, RH was not associated with RFS (HR 0.62; 95% CI 0.28-1.35). Among 44 patients with pathologic stage II disease, 7 had a recurrence (4 SH and 3 RH); 6 of 7 had distant recurrences. CONCLUSIONS: Fifty-one percent of patients with clinical stage II endometrial cancer had advanced disease on final pathology, highlighting the importance of surgical staging. RH was not associated with RFS or reduced morbidity. Most recurrences were distant. Although RH could be performed to achieve negative surgical margins, SH may be sufficient for central, small tumours given the high risk of advanced disease and distant recurrence. Research efforts should further elucidate the ideal management of these patients.

Endometriosis-associated Ovarian Cancer is a Subset With a More Favorable Outcome and Distinct Clinical-pathologic Characteristics.

There is a controversy about whether endometriosis-associated ovarian cancer (EAOC) might represent a different entity from the corresponding ovarian cancer occurring de novo, in the absence of endometriosis. This study investigated the clinical-pathologic characteristics and outcome of EAOC compared with other ovarian carcinomas that are not associated with endometriosis (non-EAOC) in a large cohort. Seven hundred two patients meeting the inclusion criteria were further subclassified as group I when patients had ovarian carcinoma associated with or arising within endometriosis (EAOC) and group II when patients had non-EAOC. Age, gross features, histologic type, International Federation of Gynecology and Obstetrics stage, and disease-free survival (DFS) were compared between the groups. One hundred sixty-eight (23.9%) patients had EAOC, whereas 534 (76.1%) patients had non-EAOC. EAOCs were mostly endometrioid and clear cell type. Patients with EAOC were younger, present early, and had a lower rate of recurrence when compared with patients with non-EAOC, P<0.001. Patients with EAOC had longer DFS time, 51.9 mo (95% confidence interval, 44.9-58.8) versus 30.5 mo (95% confidence interval, 27.7-33.3) in non-EAOC patients. The 5 yr Kaplan-Meier estimate of DFS rate was 70% in 166 patients of group I and was 39.3% in 532 patients of group II, P<0.001. On multivariate analysis, International Federation of Gynecology and Obstetrics staging, histologic type, and treatment were the only significant factors affecting the hazards of recurrence. Patients with tumors associated with endometriosis are usually, younger, present early, have lower rate of recurrence, longer DFS, and their tumors are of lower grade and are more likely endometrioid or clear cell carcinoma.

Uterine Clear Cell Carcinoma: Does Adjuvant Chemotherapy Improve Outcomes?

OBJECTIVES: Women with uterine clear cell carcinoma (UCCC) are at high risk of relapse. Adjuvant chemotherapy (CT) is often recommended, although its effectiveness remains controversial. Our objective was to evaluate treatment-related outcomes of patients with UCCC, particularly those treated with adjuvant CT. METHODS: In this retrospective cohort study, patients diagnosed with UCCC at 2 academic cancer centers from 2000 to 2014 were included. Clinical, surgical, and pathological data were collected. Survival estimates were obtained using the Kaplan-Meier method and compared by log rank test. Multivariable analysis was used to determine the effect of CT and radiation therapy (RT) on overall survival (OS) and progression-free survival (PFS). RESULTS: We included 146 patients with UCCC, with a median follow-up of 27 months (range, 1-160). Ninety-five (65%) patients presented with stage I to II disease and 51 (35%) with stage III to IV disease. Forty-six percent of patients with clinical stage I were upstaged after surgery: 29% were upstaged to stages III and IV. Thirty-one percent of patients with early-stage disease and 70% with advanced-stage received CT. Among recurrences, the majority had distant relapse in both early-stage (61.5%) and advanced-stage (96.3%) diseases. In both patients with early-stage and advanced-stage diseases, adjuvant CT did not improve OS or PFS. On multivariate analysis, CT was not a significant factor associated with improved PFS (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.69-2.71; P = 0.37) or OS (HR, 0.58; 95% CI, 0.24-1.38; P = 0.22), whereas RT was associated with improved PFS (HR, 0.51; 95% CI, 0.29-0.90; P = 0.02) and OS (HR, 0.19; 95% CI, 0.09-0.42; P < 0.001). CONCLUSIONS: The high rate of upstaging after surgery highlights the importance of lymph node assessment. The high rate of distant recurrence questions the effectiveness of current CT regimens and warrants the development of novel systemic approaches. The role of adjuvant RT deserves further study.

Comorbid Conditions are Associated With Emergency Department Visits, Hospitalizations, and Medical Charges of Patients With Systemic Lupus Erythematosus.

BACKGROUND/OBJECTIVES: In addition to increase mortality, comorbidities can increase medical costs for systemic lupus erythematosus (SLE). Healthcare utilization can dramatically increase medical costs. It is essential to better understand the comorbidities that can lead to healthcare utilization, such as emergency department visit and/or hospitalization, for SLE patients. Therefore, the objective of this study was to examine the associations between comorbidities and healthcare utilization and medical charges of patients with SLE. METHODS: Nebraska statewide emergency departments (ED) discharge and hospitals discharge data from 2007 to 2012 were used to study the comorbid conditions of patients with SLE. SLE was defined using the standard International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes (710.0). RESULTS: There were more comorbid conditions in patients with SLE than patients without SLE. Comorbid conditions were majorly related to ED visits and hospitalizations of patients with SLE. Chest pain, abdominal pain, injury, acute respiratory infections, symptoms of digestive systems, headache, myalgia and myositis, noninfectious gastroenteritis and colitis, and symptoms of skin and other integumentary systems are common comorbid conditions for ED visits. Infections, cardiovascular diseases, fractures, chronic obstructive pulmonary disease (COPD) and allied conditions, cerebrovascular diseases, and episodic mood disorder are common comorbid conditions for hospitalizations of patients with SLE. In addition, the numbers of comorbid conditions were significantly associated with the length of hospital stay and hospital charges for SLE patients. CONCLUSION: The findings in this study indicated that comorbid conditions are associated with healthcare utilization and medical charges of patients with SLE.

Accelerated progression of Hodgkin's-like lymphomas in golli deficient SJL mice.

Spontaneously occurring lymphomas in SJL mice have many pathological features similar to Hodgkin's lymphoma in humans. The malignant growth of the tumor cells is dependent on the support of host FoxP3(+)CD4(+) regulatory T cells (Tregs). In this study, we report that the ablation of golli protein, a negative regulator of CRAC (calcium release activated calcium) channel, in SJL mice results in an accelerated progression of Hodgkin's-like lymphoma which is accompanied by a facilitated conversion of FoxP3(+) Treg cells. Our results suggest that golli protein might affect the progression of Hodgkin's-like lymphomas through regulating the induction of Treg cells.

Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial cancer consortium (CHREC).

OBJECTIVE: The lack of randomized clinical data pertaining to optimal surgery and adjuvant treatment in women with high-risk histotypes of endometrial cancer has resulted in selective management based on institutional policies. The objective of this study was to assess differences in treatment strategies and their outcomes among various institutions. METHOD: High-risk endometrial cancer cases (2000-2012) with corresponding clinicopathologic data were collected from 7 academic cancer centers. Histotypes included grade 3 endometrioid (EC3), serous (ESC), clear cell (CCC) and carcinosarcoma (CS). Associations with overall survival were performed using Cox proportional hazard regression. RESULTS: 1260 patients treated between 2000 and 2012 were included in the study: 398 EC3, 449 ESC, 91 CCC, 236 CS and 83 'other'. The use of adjuvant chemotherapy, adjuvant radiation, and extent of surgical staging were statistically different among the 7 centers (P<0.001). Histotype was independently associated with overall survival (OS) in patients with stage 1 and 2 disease who underwent surgical staging (P=0.0324). Adjuvant radiation was associated with improved OS for EC3 and CCC and adjuvant chemotherapy was associated with improved OS for ESC and CS. There was a high rate of recurrence (17.8% and 21.4%) in completely staged, stage 1A patients with ESC and CS respectively. CONCLUSION: There exists a wide variation in practice and outcomes for high-risk histotypes of endometrial cancer. The relative impact of adjuvant therapy appears to be histotype dependent and prospective studies examining adjuvant treatment in high-risk histotypes should use caution combining them together.

The influence of BMI on the association between serum lycopene and the metabolic syndrome.

Overweight and obese individuals have an increased risk of developing the metabolic syndrome because of subsequent chronic inflammation and oxidative stress, which the antioxidant nutrient lycopene can reduce. However, studies indicate that different BMI statuses can alter the positive effects of lycopene. Therefore, the purpose of this study was to examine how BMI influences the association between serum lycopene and the metabolic syndrome. The tertile rank method was used to divide 13 196 participants, aged 20 years and older, into three groups according to serum concentrations of lycopene. The associations between serum lycopene and the metabolic syndrome were analysed separately for normal-weight, overweight and obese participants. Overall, the prevalence of the metabolic syndrome was significantly higher in the first tertile group (OR 38·6%; 95% CI 36·9, 40·3) compared with the second tertile group (OR 29·3%; 95% CI 27·5, 31·1) and the third tertile group (OR 26·6%; 95% CI 24·9, 28·3). However, the associations between lycopene and the metabolic syndrome were only significant for normal-weight and overweight participants (P0·05), even after adjusting for possible confounding variables. In conclusion, BMI appears to strongly influence the association between serum lycopene and the metabolic syndrome.

Canadian high risk endometrial cancer (CHREC) consortium: analyzing the clinical behavior of high risk endometrial cancers.

OBJECTIVES: The objective of this study is to analyze the clinical behavior of endometrial carcinomas by high risk(HR) histotype, including stage, overall survival, recurrence free survival and patterns of failure. METHODS: This is a retrospective multi-institutional cohort study performed at 7 tertiary care centers across Canada between 2000 and 2012 and included: grade 3 endometrioid (EC3), endometrial serous cancer (ESC), clear cell carcinomas (CCC) and carcinosarcoma (CS). Clinicopathological and outcome data was collected. RESULTS: 1260 women with endometrial carcinoma with 1013 having staging procedures were identified; 398 EC3, 449 ESC, 236 CS and 91 CCC. 51.8% had lymphovascular space invasion (LVSI) and 18.5% had omental involvement with a statistically significant difference between tumor types (p=0.0005 and 0.0047 respectively); ESC had a significantly greater rate of omental involvement compared to EC3 (22% to 9%, p=0.0005). Within the entire cohort 49.3% were stage 1, 10.6% were stage 2, 27.4% were stage 3 and 12.7% were stage 4. Overall survival and recurrence free survival were significantly different between histotypes (p<0.0001) with CS having the worst outcome. Overall 31.5% of patients recurred. CS and ESC had a higher distant recurrence rate compared to EC3 (29.6%, 31.0% compared to 16.4%, p=0.0002 and p<0.001). CONCLUSION: This study is one of the largest clinical cohorts of HR endometrial cancers. We have further clarified the impact of histotype and stage on recurrence and survival, and the high likelihood of distant recurrence. However, the differences are modest and risk prediction models will require additional molecular markers.

Immunophenotypic Analysis in Early Müllerian Serous Carcinogenesis.

Studies on the immunophenotypes of early forms of serous carcinoma arising from female genital tract are limited. We aimed to examine p53, p16(Ink4a), estrogen receptor (ER), progesterone receptor (PR), ERBB2, WT1, and Ki-67 protein expression in endometrial intraepithelial carcinoma (n=29), serous tubal intraepithelial lesion (n=4) and carcinoma (STIC, n=10), and the putative precursor p53 signature (n=11). Among endometrial intraepithelial carcinoma, 80% demonstrated p53 overexpression and 10% were consistent with a null phenotype. p16(Ink4a) immunostaining were observed in all endometrial intraepithelial carcinoma cases. ER, PR, ERBB2, and WT1 were positive in 54%, 25%, 11%, and 18% of cases, respectively. STIC cases demonstrated p53 overexpression and null phenotype in 90% and 10%, respectively. All STIC cases were p16(Ink4a) and WT1 positive, whereas ER and PR were positive in 70% and 20%, respectively. All STICs were negative for ERBB2. Among serous tubal intraepithelial lesion cases, 75% demonstrated p53 overexpression and 25% a null phenotype. p53 was positive in all 11 p53 signature cases, whereas p16(Ink4a) was universally negative. Finally, ER and PR were positive in 100% and 73% of p53 signature cases, respectively. These results suggest that p16(Ink4a) has a role in early Müllerian serous carcinogenesis but is absent in the earliest noncommitted lesion. p16(Ink4a) immunohistochemistry can be used as an adjunct confirmatory tool in p53-null cases with limited surface area.

Endometrial Carcinomas With Clear Cells: A Study of a Heterogeneous Group of Tumors Including Interobserver Variability, Mutation Analysis, and Immunohistochemistry With HNF-1ß.

Endometrial clear cell carcinoma (CC) is an uncommon tumor and often carries a poor prognosis. It has histologic features that overlap with other endometrial carcinomas and is frequently misclassified. Accurate classification is crucial, however, to improve treatment options. The objectives of this study were (1) to assess diagnostic interobserver variability among 5 gynecologic pathologists for tumors originally diagnosed as CC or with a component of CC (n=44); (2) to determine the utility of immunohistochemical markers estrogen receptor and HNF-1ß; and (3) to detect mutations in select genes. Clinical data and morphologic features were also recorded. Agreement among reviewers was only moderate: only 46% of the original CC remained classified as such. After reclassification, estrogen receptor was positive in 8% of CC, 67% of endometrioid carcinomas (EC), and 47% of serous carcinomas (SC). Sensitivities of HNF-1ß in CC, SC, and EC were 62%, 27%, and 17%, respectively, whereas specificity for CC versus EC or SC was 78%. Mutations in PIK3CA, PIK3R1, PTEN, KRAS, and NRAS were detected in 41% of 37 cases that had adequate material for study. At least 1 mutation was identified in 33% of CC, 67% of EC, and 33% of SC. This group of patients had poor outcomes: 72% of the patients with follow-up information had died of disease. In summary, this study suggests that the current pool of CC is a heterogeneous group of tumors from the morphologic, immunophenotypic, and molecular point of views and that only a percentage of them represent true CC.

Histological features associated with occult lymph node metastasis in FIGO clinical stage I, grade I endometrioid carcinoma.

AIMS: Lymph node involvement affects prognosis/treatment in endometrial carcinoma patients. We assessed various histological features associated with nodal metastasis in patients with grade I, stage I endometrial endometrioid carcinoma (EEC). METHODS AND RESULTS: Eighteen stage I EECs with occult positive lymph nodes and 36 controls were assessed for depth of myoinvasion; microcystic, elongated and fragmented (MELF) pattern of myometrial invasion; lymphovascular invasion (LVI); and epithelial metaplasia. Nodal metastases were subclassified as isolated tumour cells (ITCs; ≤0.2 mm), micrometastasis (>0.2 mm and <2 mm), or macrometastasis (≥2 mm). Node-positive cases had significantly higher rates of LVI (P < 0.001) and MELF invasion (P = 0.003) on univariate analysis. Only LVI was associated significantly with nodal metastasis on multivariate analysis (P = 0.002). Tumours with MELF invasion demonstrated reduced E-cadherin expression. Macrometastases were identified in seven cases (39%) with or without micrometastasis/ITCs. Eight (44%) contained only ITCs. Eleven (61%) had histiocyte-like nodal metastases. Biopsy material from four of six (67%) and five of 17 (29%) cases with and without nodal metastasis showed detached eosinophilic tumour cell buds. Of the former, three were associated with histiocyte-like nodal metastases - a feature absent in biopsies without tumour budding. CONCLUSIONS: Lymph nodes from grade I EEC exhibiting cellular budding or LVI should be examined for occult metastases, especially in the form of histiocyte-like cells.

Immunohistochemical characterization of prototypical endometrial clear cell carcinoma--diagnostic utility of HNF-1ß and oestrogen receptor.

AIMS: The great majority of ovarian clear cell carcinomas have a hepatocyte nuclear factor 1 homeobox B (HNF-1ß)-positive and oestrogen receptor (ER)-negative immunoprofile. However, the pattern of HNF-1ß and ER immunostaining in clear cell carcinomas of the endometrium and the usefulness of this panel in distinguishing clear cell carcinoma from other histological types of endometrial carcinoma have yet to be well defined. METHODS AND RESULTS: We examined the immunostaining patterns of HNF-1ß, ER and p53 in 15 morphologically classic pure endometrial clear cell carcinomas, and compared these patterns with 15 endometrioid and 15 serous carcinomas of the endometrium. We observed the presence of diffuse (>70%) moderate to strong nuclear HNF-1ß staining and negative ER staining in 14 of 15 clear cell carcinomas, with the remaining case showing both diffuse strong nuclear HNF-1ß staining and focal ER staining. In comparison, only one of 15 serous carcinomas and none of 15 endometrioid carcinomas showed a combination of diffuse moderate to strong HNF-1ß nuclear staining and negative ER staining. Aberrant p53 immunostaining was observed in five of 15 (33%) clear cell carcinomas. CONCLUSIONS: Overall, our findings demonstrate that, similarly to the situation for the ovary, a diagnostic panel of HNF-1ß and ER may be considered for separating clear cell carcinoma from endometrioid and serous carcinoma of the endometrium.

Design and Force/Angle Independent Control of a Bionic Mechanical Ankle Based on an Artificial Muscle Matrix.

Inspired by the natural skeletal muscles, this paper presents a novel shape memory alloy-based artificial muscle matrix (AMM) with advantages of a large output force and displacement, flexibility, and compactness. According to the composition of the AMM, we propose a matrix control strategy to achieve independent control of the output force and displacement of the AMM. Based on the kinematics simulation and experiments, we obtained the output displacement and bearing capacity of the smart digital structure (SDS) and confirmed the effectiveness of the matrix control strategy to achieve force and displacement output independently and controllably. A bionic mechanical ankle actuated by AMM was proposed to demonstrate the actuating capability of the AMM. Experimental results show that the angle and force of the bionic mechanical ankle are output independently and have a significant gradient. In addition, by using a self-sensing method (resistance self-feedback) and PD control strategy, the output angle and force of the bionic mechanical ankle can be maintained for a long time without overheating of the AMM.

Tumor-associated macrophages and survival in classic Hodgkin's lymphoma.

BACKGROUND: Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score. METHODS: Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis. RESULTS: Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies. CONCLUSIONS: An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification.

Reproducibility of histological cell type in high-grade endometrial carcinoma.

Subclassification of endometrial carcinoma according to histological type shows variable interobserver agreement. The aim of this study was to assess specifically the interobserver agreement of histological type in high-grade endometrial carcinomas, recorded by gynecological pathologists from five academic centers across Canada. In a secondary aim, the agreement of consensus diagnosis with immunohistochemical marker combinations was assessed including six routine (TP53, CDKN2A (p16), ER, PGR, Ki67, and VIM) and six experimental immunohistochemical markers (PTEN, ARID1A, CTNNB1, IGF2BP3, HNF1B, and TFF3). The paired interobserver agreement ranged from κ 0.50 to 0.63 (median 0.58) and the intraobserver agreement from κ 0.49 to 0.67 (median 0.61). Consensus about histological type based on morphological assessment was reached in 72% of high-grade endometrial carcinomas. A seven-marker immunohistochemical panel differentiated FIGO grade 3 endometrioid from serous carcinoma with a 100% concordance rate compared with the consensus diagnosis. More practically, a three-marker panel including TP53, ER, and CDKN2A (p16) can aid in the differential diagnosis of FIGO grade 3 endometrioid from endometrial serous carcinoma. Our study demonstrates that the inter- and intraobserver reproducibility of histological type based on morphology alone are mostly moderate. Ancillary techniques such as immunohistochemical marker panels are likely needed to improve diagnostic reproducibility of histological types within high-grade endometrial carcinomas.

The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumors.

Low-grade serous carcinomas and serous borderline tumors, combined herein and referred to as low-grade serous tumors, show distinct molecular alterations and clinical behaviors compared with high-grade serous carcinomas. The discrimination between low-grade serous tumors and high-grade serous carcinomas can be challenging on small tissue samples, such as cell blocks of paracentesis fluid or biopsies from omental disease. The purpose of this study was to test the ability of TP53 and CDKN2A immunohistochemistry to distinguish between high-grade serous carcinomas and low-grade serous tumors on small tissue samples. Tissue microarrays containing 582 high-grade serous carcinomas, 45 low-grade serous carcinomas, and 49 serous borderline tumors, confirmed by contemporary histopathological review, were stained for TP53 and CDKN2A (DO7 and E6H4 antibody clones, respectively). TP53 was scored as completely absent, wild-type pattern or overexpressed (>60%), and CDKN2A was scored as either negative/patchy (<90%) or block expression (>90%). The combination of the two markers, ie, the TP53 wild-type pattern and CDKN2A patchy expression, had sensitivity for low-grade serous tumors of 89%, a specificity of 93%, a positive predictive value of 68%, and a negative predictive value of 98%. These markers can, therefore, be used on small biopsies/cell blocks to refute a diagnosis of low-grade serous tumors. These findings may inform emerging neoadjuvant therapeutic strategies in advanced ovarian cancers and may be crucial for future clinical trials on molecular-based therapies.