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Introduction Substantial as opposed to focal or no lymphovascular space invasion (LVSI) is proposed as an independent adverse prognostic factor in patients with early-stage endometrioid endometrial cancer (EEC). We reviewed outcomes of patients treated with adjuvant vaginal brachytherapy (VB) alone in a single institution, stratified by LVSI extent. Methods and Materials Retrospective review identified Stage I-II EEC patients receiving VB alone from 2010 to 2017. Extent of LVSI was reported as none, focal, or substantial. Kaplan–Meier estimates and Log-Rank test were used to determine significance between variables. Cox proportional hazards model was used for multivariate analyses. Results In total, 325 patients were identified with a median follow-up of 35 (23–48) months. LVSI was found in 112 patients with extent reported in 78, 45 (58%) had focal, and 33 (42%) substantial LVSI. Estimated disease-free survival for those with substantial LVSI was 73 (57–94)%, focal LVSI 89 (79–100)%, and no LVSI 94 (90–98)% at 48 months (p = 0.012). On multivariate analyses substantial LVSI was the only risk factor predictive of pelvic [HR substantial vs no: 7.2 (1.0–51.6); p = 0.048] and distant failure [HR substantial vs no: 4.4 (1.2–16.3); p = 0.027]. Both high-grade disease [HR 3 vs 1: 5.5 (1.2–25.6); p = 0.031] and extent of LVSI [HR substantial vs no: 4.4 (1.7–11.4); p = 0.002] predicted for worse disease-free survival. Discussion Substantial LVSI was the strongest adverse prognostic factor for pelvic and distant failure in this cohort of EEC patients receiving adjuvant VB alone, suggesting this subset may benefit from additional adjuvant therapy. This study underscores the importance of quantifying LVSI extent in EEC.

Background Levodopa-carbidopa intestinal gel (LCIG) is administered directly to the small intestine of patients with advanced Parkinson's disease (APD) to help maintain stable plasma levodopa levels. Objective The objective of this study was to investigate the effect of LCIG in reducing polypharmacy for the treatment of APD. Methods The COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) is a large, real-world, multinational observational study investigating comedication use with LCIG. All enrolled patients had used LCIG for ≥12 months and data were collected cross-sectionally (study visit) and retrospectively. The primary endpoint was the percentage of patients using LCIG as monotherapy (without add-on PD medications) at initiation and at 3, 6, 9, and 12 months thereafter. Results Overall, 409 patients were enrolled from 14 countries and were treated with LCIG for a mean of 35.8 ± 23.2 months. A total of 15.2% of patients initiated LCIG as monotherapy and 31.7% were receiving monotherapy at 12 months after initiation. The mean duration of LCIG monotherapy was 39.3 ± 25.6 months. Use of add-on medications decreased over time with all LCIG regimens. From LCIG initiation to the patient visit, mean off time decreased by 3.8, 4.6, and 3.9 hours/day for LCIG monotherapy, LCIG daytime monotherapy, and LCIG polytherapy groups, respectively, while duration of dyskinesia decreased by 1.7, 2.0, and 1.9 hours/day, respectively. Adverse events likely related to study treatment occurred in 112 patients (27.4%) during LCIG treatment. Conclusions LCIG is an effective long-term monotherapy option with a positive risk-benefit profile and contributes to reduced polypharmacy for patients with APD. © 2021 The AbbVie Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objectives: To compare the characteristics of patients undergoing treatment with continuous intestinal infusion of levodopa–carbidopa (CIILC) for advanced Parkinson's disease and the data on the effectiveness and safety of CIILC in the different autonomous communities (AC) of Spain. Methods: A retrospective, longitudinal, observational study was carried out into 177 patients from 11 CAs who underwent CIILC between January 2006 and December 2011. We analysed data on patients’ clinical and demographic characteristics, variables related to effectiveness (changes in off time/on time with or without disabling dyskinesia; changes in Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale scores; non-motor symptoms; and Clinical Global Impression scale scores) and safety (adverse events), and the rate of CIILC discontinuation. Results: Significant differences were observed between CAs for several baseline variables: duration of disease progression prior to CIILC onset, off time (34.9%–59.7%) and on time (2.6%–48.0%; with or without disabling dyskinesia), Hoehn and Yahr score during on time, Unified Parkinson's Disease Rating Scale-III score during both on and off time, presence of =4 motor symptoms, and CIILC dose. Significant differences were observed during follow-up (>24 months in 9 of the 11 CAs studied) for the percentage of off time and on time without disabling dyskinesia, adverse events frequency, and Clinical Global Impression scores. The rate of CIILC discontinuation was between 20% and 40% in 9 CAs (78% and 80% in remaining 2 CAs). Conclusions: This study reveals a marked variability between CAs in terms of patient selection and CIILC safety and effectiveness. These results may have been influenced by patients’ baseline characteristics, the availability of multidisciplinary teams, and clinical experience. Resumen: Objetivos: Comparar las características de los pacientes con enfermedad de Parkinson avanzada en tratamiento con infusión intestinal continua de levodopa-carbidopa (IICLC) y los datos de efectividad y seguridad de IICLC entre diferentes comunidades autónomas (CC. AA.). Métodos: Estudio longitudinal observacional y retrospectivo. Se incluyeron 177 pacientes de 11 CC. AA. que iniciaron tratamiento con IICLC entre enero de 2006 y diciembre de 2011. Se compararon las características clínicas y demográficas, las variables de efectividad (cambios en el tiempo OFF, ON con y sin discinesias discapacitantes, cambios en la escala de Hoehn y Yahr y puntuación de la Unified Parkinson's Disease Rating Scale, síntomas no motores e Impresión Clínica Global) y seguridad (acontecimientos adversos), y la tasa de suspensión de IICLC. Resultados: Se hallaron diferencias significativas entre las CC. AA. en diversas variables basales: duración de la enfermedad hasta el inicio de IICLC, tiempo OFF (34,9-59,7%) y ON (con o sin discinesias; 2,6-48,0%), Hoehn y Yahr en ON, Unified Parkinson's Disease Rating Scale-III en ON y OFF, presencia de = 4 síntomas motores y dosis de IICLC. En el seguimiento (> 24 meses en 9 de 11 CC. AA.) hubo diferencias significativas en el porcentaje de tiempo OFF, tiempo ON sin discinesias discapacitantes, frecuencia de acontecimientos adversos e Impresión Clínica Global. La tasa de suspensión fue de entre 20-40% en todas las CC. AA., excepto en 2 (78 y 80%). Conclusiones: Este estudio muestra una amplia variabilidad en la selección de los pacientes y en la efectividad y seguridad de IICLC entre las diferentes CC. AA. Podrían influir las características basales de los pacientes, la disponibilidad de un equipo multidisciplinar y la experiencia clínica.

The International Society of Gynecological Pathologists (ISGyP) Endocervical Adenocarcinoma Project aims to provide evidence-based guidance for the pathologic evaluation, classification, and reporting of endocervical adenocarcinoma. This review presents the recommendations pertaining to gross evaluation and intraoperative consultation of specimens obtained from patients in the setting of cervical cancer. The recommendations are the product of review of published peer-reviewed evidence, international guidelines and institutional grossing manuals, as well as deliberation within this working group. The discussion presented herein details the approach to the different specimen types encountered in practice: loop electrosurgical excision procedure, cone, trachelectomy, radical hysterectomy, pelvic exenteration, and lymphadenectomy specimens. Guidelines for intraoperative evaluation of trachelectomy and sentinel lymph node specimens are also addressed. Correlation with ISGyP recommendations on cancer staging, which appear as a separate review in this issue, is also included when appropriate. While conceived in the framework of endocervical adenocarcinoma, most of the discussion and recommendations can also be applied to other cervical malignancies.

Histopathologic classification of endocervical adenocarcinomas (EAC) has recently changed, with the new system based on human papillomavirus (HPV)-related morphologic features being incorporated into the 5th edition of the WHO Blue Book (Classification of Tumours of the Female Genital Tract). There has also been the introduction of a pattern-based classification system to assess invasion in HPV-associated (HPVA) endocervical adenocarcinomas that stratifies tumors into 3 groups with different prognoses. To facilitate the introduction of these changes into routine clinical practice, websites with training sets and test sets of scanned whole slide images were designed to improve diagnostic performance in histotype classification of endocervical adenocarcinoma based on the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and assessment of Silva pattern of invasion in HPVA endocervical adenocarcinomas. We report on the diagnostic results of those who have participated thus far in these educational websites. Our goal was to identify areas where diagnostic performance was suboptimal and future educational efforts could be directed. There was very good ability to distinguish HPVA from HPV-independent adenocarcinomas within the WHO/IECC classification, with some challenges in the diagnosis of HPV-independent subtypes, especially mesonephric carcinoma. Diagnosis of HPVA subtypes was not consistent. For the Silva classification, the main challenge was related to distinction between pattern A and pattern B, with a tendency for participants to overdiagnose pattern B invasion. These observations can serve as the basis for more targeted efforts to improve diagnostic performance.

Mullerian adenosarcoma is a biphasic neoplasm composed of benign or atypical Müllerian epithelium and a malignant mesenchymal component that is usually, but not always, of low grade. Focal architectural or cytologic atypia of the epithelial component resembling atypical hyperplasia may uncommonly be present and foci of adenocarcinoma have been rarely reported. Whether the coexistence of these 2 tumor components is a result of independent primaries (collision tumor), adenocarcinoma arising from the epithelial component of the adenosarcoma, an unusual form of carcinosarcoma or some other mechanism is uncertain. To establish the diagnostic criteria and clinical significance of the coexistence of adenocarcinoma in close association with Müllerian adenosarcoma, we conducted a multi-institutional study of these rare tumors. Twenty-six patients were identified with "mixed" adenosarcoma and adenocarcinoma; they ranged in age from 43 to 87 years (median: 66 y). Tumors occurred in the uterine corpus (n=22), ovary (n=2), and the pelvis (n=2). All but 6 had International Federation of Gynecology and Obstetrics (FIGO) stage I disease. All extrauterine tumors were associated with endometriosis. The tumor size ranged from 2 to 25 cm (median: 7.9 cm). The sarcomatous component was of low grade in 18 and high grade in 8 (the majority demonstrating rhabdomyoblastic differentiation); 9 had stromal overgrowth. Twenty-five carcinomas were endometrioid in type (23 FIGO grade 1; 3 FIGO grade 2) and 1 carcinoma was dedifferentiated with FIGO grade 1 endometrioid adenocarcinoma component; 33% of the uterine neoplasms were associated with adjacent endometrial hyperplasia. Next-generation sequencing in 2 tumors identified similar molecular abnormalities in the sarcomatous and carcinomatous components supporting a clonal relationship. Of 10 patients with available follow-up (median: 18 mo), 8 had no evidence of disease and 2 died of recurrent sarcoma at 7 and 8 months. Endometrioid adenocarcinomas that arise in close spatial association with Müllerian adenosarcoma appear to be clonally related to the sarcoma. Unlike carcinosarcomas, these tumors are usually early stage at presentation. The prognosis appears to be driven by the sarcomatous component. These tumors should be distinguished from carcinosarcomas, dedifferentiated endometrial carcinomas, and corded and hyalinized endometrioid carcinomas.

Inflammatory myofibroblastic tumor of the uterus (uIMT) is rare. However, it has been increasingly recognized in recent years, largely due to more awareness of its occurrence in the gynecologic tract and the characterization of features that help distinguish it from more common lesions in the differential diagnosis, particularly smooth muscle neoplasms. One of these features is expression of anaplastic lymphoma kinase (ALK, also known as CD246), which has been documented in most uIMTs described in the literature. This review concentrates on the role of ALK testing in the diagnosis and management of uIMT. In terms of immunohistochemistry, an emphasis on antibody selection, sensitivity/specificity, interpretation and quality control is given. Regarding molecular analysis for ALK alterations, this review appraises fluorescence in situ hybridization and RNA sequencing technologies. Lastly, the role of tyrosine kinase inhibitor therapy in patients with uIMT is discussed, highlighting the importance of a correct diagnosis of this entity.

In order to understand the structure and effectiveness of national cancer control systems, the International Cancer Control Partnership, the World Health Organization, the National Cancer Institute and the Union for International Cancer Control underwent a review of available national cancer health plans (NCCPs) and noncommunicable diseases plans (NCDPs) worldwide. Pathology and Laboratory Medicine (PALM) plays a major role in cancer management, from prevention and screening to patient care (diagnosis and treatment) and population-level cancer surveillance. This review concentrates on the analysis of elements in national cancer care plans pertaining to PALM. Of 157 countries surveyed, 90 (57%) had a NCCP and 123 (78%) had a NCDP. While 54% of plans included guidelines on cancer diagnosis or plans to develop standards protocols for diagnosis, only 14% included PALM as a component of the plan. PALM-related variables such as synoptic pathology reporting, cancer staging guidelines and cancer genetics programs were similarly underrepresented (being mentioned in only 6%, 17% and 16% of plans, respectively). Absence of PALM-related variables tended to be more frequent in lower-income countries. Our analysis highlights an important gap in national cancer control initiatives worldwide represented by the overall lack of inclusion of PALM resources. Cancer control will only be effective if laboratory sciences are placed as a priority. Based on the data presented herein, there is a need to increase awareness about the importance of PALM in cancer care, and to incorporate this discipline in the design and implementation of multilevel cancer control strategies.

ObjectivePrognostic factors for endocervical adernocarcinomas are well known, but little is known about prognostic biomarkers influencing outcome for the newly defined International Federation of Gynecology and Obstetrics (FIGO) 2018 IB sub-stages. The aim of this study was to identify prognostic biomarkers influencing recurrence-free and overall survival for FIGO 2018 stage IB cervical adenocarcinoma sub-types. We sought to identify these factors using a large international multi-institutional series of cases.MethodsStage IB endocervical adenocarcinomas were retrospectively collected from nine international institutions; full slide sets (n=464) were used to assign prognostic biomarkers. Inclusion criteria were the following: FIGO stage IB endocervical adenocarcinomas with follow-up in which all paraffin blocks/glass slides were available for review and/or additional studies and the patient was surgically treated from 1985 to 2019. The types of specimens included in the study were conizations, trachelectomies, and simple/radical hysterectomies with or without lymph node samples. We excluded in situ carcinomas, squamous cell carcinomas, adenosquamous carcinomas, tumors with a neuroendocrine component, carcinosarcomas, and any tumor showing clinical, macroscopic, or microscopic features suggesting a lower uterine segment, uterine corpus, or an adnexal primary origin. Tumors treated with neoadjuvant chemotherapy and/or radiation therapy were also excluded, as well as biopsies and loop electrosurgical excision procedures.ResultsOf 464 cases, 225 (48%) were stage IB1, 177 (38%) were stage IB2, and 62 (13%) were stage IB3. Five-year and 10-year recurrence-free survivals were statistically different among stage IB sub-types (p=0.005). Silva pattern of invasion was significant for recurrence-free survival at 5 and 10 years (p=0.04); overall survival and recurrence-free survival were higher in human papillomavirus (HPV)-associated cases (p=0.007 and p=0.001, respectively) and in cases without lymphovascular invasion (p=0.004 and p=0.00001, respectively). Factors that significantly influenced recurrence-free survival were HPV-independent status (p=0.05; HR 2.31; 95% CI 1.02 to 5.46), presence of lymphovascular invasion (p=0.011; HR 3.50; 95% CI 1.33 to 9.19), and presence of lymph node metastasis (p=0.016; HR 2.66; 95% CI 1.20 to 5.90).ConclusionHPV status and the presence of lymphovascular invasion are prognosticators in stage IB endocervical adenocarcinoma sub-types. These parameters should be included in future sub-staging modifications of FIGO stage IB endocervical adenocarcinomas and in treatment strategies.

Verruciform proliferations of the vulva unrelated to HPV infection are rare. The term differentiated exophytic vulvar intraepithelial lesion (DEVIL) was recently proposed for these lesions, which harbor recurrent PIK3CA mutations. It is still unclear whether DEVIL is related to verrucous carcinoma, a neoplasm characterized by persistence and local recurrence but nil risk of distant spread. Specimens identified using the words “verruciform” and “verrucous” were reviewed. Diagnosis of DEVIL required verruciform acanthosis, hyper and/or parakeratosis, hypogranulosis, cytoplasmic pallor, and bland nuclei. Verrucous carcinoma required, in addition, discontinuous, bulbous, puzzle-like nests in the stroma. A targeted next-generation sequencing using a custom 11-gene panel was performed. Eighteen specimens corresponding to ten patients with DEVIL and/or verrucous carcinoma were included. Median age at presentation was 66 years for DEVIL and 70 years for verrucous carcinoma. A similar spectrum of prevalent mutations was found in both lesions involving HRAS, PIK3CA, and BRAF. DEVIL preceded verrucous carcinoma and/or was diagnosed concurrently or in subsequent follow-up in five patients. In four of these, the same mutation was identified in DEVIL and synchronous or metachronous carcinoma. All cases showed wild-type 53 staining and lacked pathogenic TP53 mutations. DEVIL is a rare form of squamous proliferation characterized by prevalent PIK3CA and HRAS mutations. Its temporal relationship with verrucous carcinoma and their shared mutational profile in some patients suggest that DEVIL is a precursor of verrucous carcinoma. Moreover, given their morphologic and molecular overlap and the nil risk of verrucous carcinoma for distant spread, it is conceivable that DEVIL and verrucous carcinoma represent a spectrum of the same entity.

Dedifferentiated endometrial adenocarcinoma (DEC) is defined by the coexistence of undifferentiated carcinoma with low-grade (FIGO grade 1 or 2) endometrioid carcinoma. Few cases of DEC arising in the background of high-grade carcinoma (DEC-HG) have been reported, however, this phenomenon is poorly characterized. In this study we describe the morphologic, immunohistochemical and clinico-pathologic characteristics of DEC-HG. 18 DECs were diagnosed at our institution between 2008-2019, and in 11 (61%), the undifferentiated component was associated with high-grade carcinoma (8 endometrioid FIGO grade 3, 2 with ambiguous features, 1 serous). The remaining 7 (39%) represented DEC-LG (3 FIGO grade 1 and 4 FIGO grade 2). 7/11 (64%) patients with DEC-HG presented with advanced stage (FIGO stage III/IV), whereas most with DEC-LG (6/7, 86%) were stage I. On follow up, 2 patients in the DEC-HG group died of disease and 2 had progressive disease within 2 months of surgery. There was only one recurrence in the DEC-LG, 6 months post-surgery. The DEC component in both groups showed similar morphology and immunophenotype, with predominantly focal or complete loss of expression of pan-keratin, EMA, E-cadherin, CK8/18, PAX8 and ER. The DEC component in the DEC-HG group had wild-type p53 expression in 8/11 (73%) cases, loss of MLH1 and PMS2 in 6/11 (55%) and loss of SMARCA4 in 3/9 (33%). Although numbers are small, we show that DEC-HG is a previously under-recognized phenomenon, with morphologic and immunophenotypic similarities to DEC-LG, which supports expanding the definition of DEC to include DEC-HG. DEC-HG may be more aggressive than DEC-LG.

Deep learning-based computer vision methods have recently made remarkable breakthroughs in the analysis and classification of cancer pathology images. However, there has been relatively little investigation of the utility of deep neural networks to synthesize medical images. In this study, we evaluated the efficacy of generative adversarial networks to synthesize high-resolution pathology images of 10 histological types of cancer, including five cancer types from The Cancer Genome Atlas and the five major histological subtypes of ovarian carcinoma. The quality of these images was assessed using a comprehensive survey of board-certified pathologists (n = 9) and pathology trainees (n = 6). Our results show that the real and synthetic images are classified by histotype with comparable accuracies and the synthetic images are visually indistinguishable from real images. Furthermore, we trained deep convolutional neural networks to diagnose the different cancer types and determined that the synthetic images perform as well as additional real images when used to supplement a small training set. These findings have important applications in proficiency testing of medical practitioners and quality assurance in clinical laboratories. Furthermore, training of computer-aided diagnostic systems can benefit from synthetic images where labeled datasets are limited (e.g. rare cancers). We have created a publicly available website where clinicians and researchers can attempt questions from the image survey (http://gan.aimlab.ca/). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

CTNNB1 mutations and aberrant β-catenin expression have adverse prognosis in endometrial endometrioid carcinoma, and recent evidence suggests a prognostic role of β-catenin in ovarian endometrioid carcinoma. Thus, we aimed to determine the prognostic value of the CTNNB1 mutational status, and its correlation with β-catenin expression, in a well-annotated cohort of 51 ovarian endometrioid carcinomas. We performed immunohistochemistry for β-catenin and developed an 11-gene next-generation sequencing panel that included whole exome sequencing of CTNNB1 and TP53. Results were correlated with clinicopathologic variables including disease-free and disease-specific survival. Tumor recurrence was documented in 14 patients (27%), and cancer-related death in 8 patients (16%). CTNNB1 mutations were found in 22 cases (43%), and nuclear β-catenin in 26 cases (51%). CTNNB1 mutation highly correlated with nuclear β-catenin (P

AIMS Grading of primary ovarian mucinous carcinoma (OMC) is inconsistent among practices. The International Collaboration on Cancer Reporting recommends grading OMC using the International Federation of Gynecology and Obstetrics (FIGO) system for endometrial endometrioid carcinoma, when needed. The growth pattern (expansile versus infiltrative), a known prognostic variable in OMC, is not considered in any grading system. We herein analysed the prognostic value of various grading methods in a well-annotated cohort of OMC. METHODS AND RESULTS Institutional OMCs underwent review and grading by the Silverberg and FIGO schemes and a novel system, growth-based grading (GBG), defined as G1 (expansile growth or infiltrative invasion in ≤10%) and G2 (infiltrative growth >10% of tumour). Of 46 OMCs included, 80% were FIGO stage I, 11% stage II and 9% stage III. On follow-up (mean = 52 months, range = 1-190), five patients (11%) had adverse events (three recurrences and four deaths). On univariate analysis, stage (P = 0.01, Cox proportional analysis), Silverberg grade (P = 0.01), GBG grade (P = 0.001) and percentage of infiltrative growth (P

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described tumor with similar morphology to the stratified mucin-producing intraepithelial lesion. Stratified mucin-producing intraepithelial lesion and ISMC likely arise from human papillomavirus (HPV)-infected reserve cells in the cervical transformation zone that retain their pluripotential ability to differentiate into various architectural and cytologic patterns. This is important, as small studies have suggested that ISMC may be a morphologic pattern associated with more aggressive behavior than usual HPV-associated adenocarcinoma. We sought to study the morphologic spectrum of this entity and its associations with other, more conventional patterns of HPV-associated carcinomas. Full slide sets from 52 cases of ISMC were reviewed by an international panel of gynecologic pathologists and classified according to the new International Endocervical Criteria and Classification system. Tumors were categorized as ISMC if they demonstrated stromal invasion by solid nests of neoplastic cells with at least focal areas of mucin stratified throughout the entire thickness, as opposed to conventional tall columnar cells with luminal gland formation. Tumors comprising pure ISMC, and those mixed with other morphologic patterns, were included in the analysis. Twenty-nine pure ISMCs (56%) and 23 ISMCs mixed with other components (44%) were identified. Other components included 13 cases of usual-type adenocarcinoma, 6 adenosquamous carcinoma, 3 mucinous-type adenocarcinoma, 1 high-grade neuroendocrine carcinoma. ISMC displayed architectural diversity (insular, lumen-forming, solid, papillary, trabecular, micropapillary, single cells) and variable cytologic appearance (eosinophilic cytoplasm, cytoplasmic clearing, histiocytoid features, glassy cell-like features, signet ring-like features, bizarre nuclei, squamoid differentiation). Awareness of the spectrum of morphologies in ISMC is important for accurate and reproducible diagnosis so that future studies to determine the clinical significance of ISMC can be conducted.

Rhytidanthera is the only genus of Ochnaceae with compound leaves, and it forms sparse, small populations restricted to the primary forest of the Colombian and Venezuelan Andes and the sandstone hills of La Macarena and Chiribiquete. It has been suggested to be related to Godoya, Cespedesia and Krukoviella in taxonomic and phylogenetic studies. However, the relationships in this group remain poorly resolved, due to the lack of a wider molecular and taxonomic sampling. We present a phylogenetic study of tribe Sauvagesieae including three Rhytidanthera spp. and one species each of Godoya and Cespedesia, using sequences from one nuclear (ITS) and four plastid DNA regions (matK, ndhF, rbcL and trnL-F), in order to clarify the relationships among these four genera. We recover a new and well-supported phylogenetic hypothesis, with Rhytidanthera as sister to a clade comprising Godoya and the clade formed by Cespedesia and Krukoviella. This Neotropical clade was recovered as sister to the monotypic and African genus Fleurydora. The clade comprising Rhytidanthera, Godoya, Cespedesia and Krukoviella is supported by the presence of glandular structures (colleters) at the base of stipules and bracts. The colleters also evolved at the base of the sepals in this clade, with a secondary loss in Cespedesia and Krukoviella. We suggest that the combination of unequal-sized sepals enclosing the floral bud and the presence of colleters in members of this clade could have a role in the protection of leaves and flowers in the early stages of development, instead of acting in pollinator attraction.

En el año 2002 el grupo de Rosenberg en el Instituto Nacional de Cáncer en Estados Unidos demostró por primera vez que los linfocitos T pueden mediar regresiones tumorales notables, incluida la curación completa de pacientes con cáncer metastásico (1). Estos resultados logrados con la transferencia adoptiva de linfocitos T infiltrantes de tumor amplificados in vitro y luego restituidos al paciente, fue seguido de la implementación exitosa de terapias celulares con células CAR-T y el uso de anticuerpos anti-punto de control para el tratamiento de los tumores, con lo cual la Inmunoterapia junto a la Cirugía, la Quimioterapia y la Radioterapia se ha posicionado como el cuarto pilar de tratamiento del cáncer.

Glaucoma is the world’s leading cause of irreversible blindness, and falls are a major public health concern in glaucoma patients. Although recent evidence suggests the involvements of the brain toward advanced glaucoma stages, the early brain changes and their clinical and behavioral consequences remain poorly described. This study aims to determine how glaucoma may impair the brain structurally and functionally within and beyond the visual pathway in the early stages, and whether these changes can explain visuomotor impairments in glaucoma. Using multi-parametric magnetic resonance imaging, glaucoma patients presented compromised white matter integrity along the central visual pathway and around the supramarginal gyrus, as well as reduced functional connectivity between the supramarginal gyrus and the visual occipital and superior sensorimotor areas when compared to healthy controls. Furthermore, decreased functional connectivity between the supramarginal gyrus and the visual brain network may negatively impact postural control measured with dynamic posturography in glaucoma patients. Taken together, this study demonstrates that widespread structural and functional brain reorganization is taking place in areas associated with visuomotor coordination in early glaucoma. These results implicate an important central mechanism by which glaucoma patients may be susceptible to visual impairments and increased risk of falls.

BACKGROUND: There are few studies that directly investigate disparities in outcome within the African diaspora in the US. We investigated the association between nativity of Black women diagnosed with breast cancer (Caribbean or USA place of birth) and ethnicity, age at diagnosis, treatment, tumor characteristics and outcome. METHODS: The data were obtained from the University of Miami Health System, and Jackson Health System. Individual-level data from 1132 cases was used to estimate hazard rations (HRs) of women born in the Caribbean (Caribbean Blacks, CB) or in the USA (US Black, USB) using Cox proportional hazards regression analysis for overall survival. RESULTS: The cohort contains data from 624 (54.9%) USB women and 507 (45%) CB women diagnosed with breast cancer between 2006 and 2017. Compared to CB patients, USB patients had more Estrogen Receptor negative (31.4% vs. 39.1%, P = 0.018) and triple negative breast cancers (19.6% vs. 27.9%, P = 0.003). CB women presented at more advanced stages III/IV (44.2% vs. 35.2%; P = 0.016). CB patients showed a better overall survival (hazard ratio, HR = 0.75; 95% CI 0.59–0.96; P = 0.024). Overall Black Hispanic patients had a better overall survival (HR = 0.51; 95% CI 0.28–0.93; P = 0.028) compared to non-Hispanic Black patients. CONCLUSION: In conclusion the study found that CB immigrants diagnosed with breast cancer have an improved overall survival when compared with USB patients. This finding suggests that within the African diaspora in the USA, additional factors beyond race contribute to worse outcomes in African Americans.

Ductal carcinoma in situ (DCIS) is a neoplastic proliferation of mammary ductal epithelial cells confined to the ductal-lobular system, and a non-obligate precursor of invasive disease. While there has been a significant increase in the diagnosis of DCIS in recent years due to uptake of mammography screening, there has been little change in the rate of invasive recurrence, indicating that a large proportion of patients diagnosed with DCIS will never develop invasive disease. The main issue for clinicians is how to reliably predict the prognosis of DCIS in order to individualize patient treatment, especially as treatment ranges from surveillance only, breast-conserving surgery only, to breast-conserving surgery plus radiotherapy and/or hormonal therapy, and mastectomy with or without radiotherapy. We conducted a semi-structured literature review to address the above issues relating to "pure" DCIS. Here we discuss the pathology of DCIS, risk factors for recurrence, biomarkers and molecular signatures, and disease management. Potential mechanisms of progression from DCIS to invasive cancer and problems faced by clinicians and pathologists in diagnosing and treating this disease are also discussed. Despite the tremendous research efforts to identify accurate risk stratification predictors of invasive recurrence and response to radiotherapy and endocrine therapy, to date there is no simple, well-validated marker or group of variables for risk estimation, particularly in the setting of adjuvant treatment after breast-conserving surgery. Thus, the standard of care to date remains breast-conserving surgery plus radiotherapy, with or without hormonal therapy. Emerging tools, such as pathologic or biologic markers, may soon change such practice. Our review also includes recent advances towards innovative treatment strategies, including targeted therapies, immune modulators, and vaccines.

The spectrum of mesenchymal neoplasia in the uterus has expanded in recent years. First, the identification of prevalent, recurrent molecular alterations has led to a more biologically and clinically congruent classification of endometrial stromal tumors. Likewise, the diagnostic criteria of several rare and miscellaneous tumor types have been refined in recent case series (Perivascular Epithelioid Cell tumor, inflammatory myofibroblastic tumor). Pure mesenchymal tumors are still broadly classified based on morphology according to the tumor cell phenotype. Smooth muscle tumors predominate in frequency, followed by tumors of endometrial stromal derivation; the latter are covered in depth in this article with an emphasis on defining molecular alterations and their morphologic and clinical correlates. The remaining entities comprise a miscellaneous group in which cell derivation does not have a normal counterpart in the uterus (eg, rhabdomyosarcoma) or is obscure (eg, undifferentiated uterine sarcoma). This article discusses their clinical relevance, recent insights into their molecular biology, and the most important differential diagnoses. Regarding the latter, immunohistochemistry and (increasingly) molecular diagnostics play a role in the diagnostic workup. We conclude with a few considerations on intraoperative consultation and macroscopic examination, as well as pathologic staging and grading of uterine sarcomas as per the most recent American Joint Cancer Commission and the Federation Internationale de Gynecologie et d'Obstetrique staging systems.

Background There are currently no standard diagnostic criteria for characterizing advanced Parkinson’s disease (APD) in clinical practice, a critical component in determining ongoing clinical care and therapeutic strategies, including transitioning to device-aided treatment. The goal of this analysis was to determine the proportion of APD vs. non-advanced PD (non-APD) patients attending specialist PD clinics and to demonstrate the clinical burden of APD. Methods OBSERVE-PD, a cross-sectional, international, observational study, was conducted with 2615 PD patients at 128 movement disorder centers in 18 countries. Motor and non-motor symptoms, activities of daily living, and quality-of-life end points were assessed. The correlation between physician’s global assessment of advanced PD and the advanced PD criteria from a consensus of an international group of experts (Delphi criteria for APD) were evaluated. Results According to physician’s judgment, 51% of patients were considered to have APD. There was a moderate correlation between physician’s judgment and Delphi criteria for APD (K = 0.430; 95% CI 0.406–0.473). Activities of daily living, motor symptom severity, dyskinesia duration/disability, “Off” time duration, non-motor symptoms, and quality-of-life scores were worse among APD vs. non-APD patients (p

The current World Health Organization (WHO) classification for endocervical adenocarcinoma (EA) is based on descriptive morphologic characteristics; however, it does not fully reflect our current knowledge of the diverse pathogenesis of cervical glandular neoplasia. A novel classification system, the International Endocervical Adenocarcinoma Criteria and Classification (IECC), which incorporates etiology and biological behavior into the morphologic scheme, has been recently proposed. We aimed to validate the IECC by assessing its interobserver reproducibility in comparison to the WHO system. A cohort of 75 EAs was reviewed independently by 7 gynecologic pathologists and categorized following IECC and WHO criteria based on hematoxylin and eosin material alone and after immunohistochemistry results for p16, PR, p53, Napsin-A, vimentin, CDX2, and GATA3 were provided. Human papillomavirus (HPV) in situ hybridization and polymerase chain reaction results were compared with consensus diagnoses. IECC was superior to WHO in terms of interobserver agreement with κ=0.46 versus 0.3, respectively, on hematoxylin and eosin review and κ=0.51 versus 0.33, respectively, with immunohistochemistry. Under the IECC, 73 (97%) of EAs had majority agreement (≥4 reviewers in agreement) whereas 42 (56%) had perfect agreement (7/7 reviewers in agreement). Conversely, WHO showed majority agreement in 56 (75%) and perfect agreement in only 7 (10%) EAs. Reproducibility was poor in HPV-related WHO types (usual κ=0.36, mucinous not otherwise specified κ=0.13, intestinal κ=0.31, villoglandular κ=0.21) and good in major HPV-unrelated categories (gastric type κ=0.63, clear cell κ=0.81, mesonephric κ=0.5). Classification as per the IECC had excellent correlation with HPV status (by RNA in situ hybridization or polymerase chain reaction). We have shown that the IECC has superior interobserver agreement compared with the WHO classification system, and that distinction between HPV-related and HPV-unrelated EA can be made with good reproducibility and excellent prediction of HPV status. WHO morphologic variants of HPV-related EA are poorly reproducible. Conversely, agreement is high among important high-risk HPV-unrelated subtypes. Thus, our results further support replacing the current WHO classification with the IECC.

The Silva pattern-based classification for human papilloma virus-associated invasive adenocarcinoma has emerged as a reliable system to predict risk of lymph node metastasis and recurrences. Although not a part of any staging system yet, it has been incorporated in synoptic reports as established by the College of American Pathologists (CAP) and the International Collaboration on Cancer Reporting (ICCR). Moreover, the current National Comprehensive Cancer Network (NCCN) guidelines include this classification as an "emergent concept." In order to facilitate the understating and application of this new classification by all pathologists, the ISGyP Endocervical Adenocarcinoma Project Working Group presents herein all the current evidence on the Silva classification and aims to provide recommendations for its implementation in practice, including interpretation, reporting, and application to biopsy and resection specimens. In addition, this article addresses the distinction of human papilloma virus-associated adenocarcinoma in situ and gastric type adenocarcinoma in situ from their invasive counterparts.

Background and Objective Operating Rooms (ORs) are among the most expensive services in hospitals. A challenge to optimize the OR efficiency is to improve the surgery scheduling task, which requires the estimation of surgical time duration. Surgeons or programming units (based on people's experience) typically do the duration estimation using an experience-based strategy, which may include some bias, such as overestimating the surgery time, increasing ORs' operational cost. Methods This paper analyzes a machine learning-based solution for surgical time predictions. We apply and compare four machine-learning algorithms (Linear Regression, Support Vector Machines, Regression Trees, and Bagged Trees) to predict the surgical time duration at a tertiary referral university hospital in Bogota, Colombia. Historical data from 2004 until 2019 was used to train the algorithms. Comparison among algorithms was given in terms of the Root Mean Square Error (RMSE) of the predicted surgery duration and the algorithms' computing time. The algorithm with the best performance was compared to the currently used experience-based method. Results All the ML algorithms predict the surgery duration with an error between 26 and 37 min. The best overall performance was obtained using Bagged Trees (26 min RMSE, 3.16 min training time, 0.49 min testing time) when using a subset of the DB with the nine specialties containing 80% of the surgeries. Bagged Trees also outperformed the experience-based method with a lower RMSE; however, it also shifted from a predominant overestimation to underestimating surgeries' duration. Conclusions Different ML algorithms for predicting the surgical time duration, showing and comparing their performance. Bagged Trees showed the best performance in terms of RMSE and computing time. Depending on the initial data, Bagged Trees outperformed the experience-based method, but future work is necessary to suit it, like any other ML algorithm, to the hospitals' needs.

Targeted anti-human epidermal growth factor receptor 2 (HER2) therapy has recently been proven to improve progression-free and overall survival of patients with advanced stage or recurrent endometrial serous carcinoma. To date, no specific pathology HER2 testing or scoring guidelines exist for endometrial cancer. However, based on evidence from the recent successful clinical trial and comprehensive pre-trial pathologic studies, a new set of HER2 scoring criteria have been proposed for endometrial serous carcinoma—distinct from the existing breast and gastric cancer-specific criteria. We present the first study assessing interobserver agreement of HER2 scores using the proposed serous endometrial cancer-specific scoring system. A digitally scanned set of 40 HER2-immunostained slides of endometrial serous carcinoma were sent to seven gynecologic pathologists, who independently assigned HER2 scores for each slide following a brief tutorial. Follow-up fluorescent in situ hybridization (FISH) for HER2 gene amplification was performed on cases with interobserver disagreement when a 2+ HER2 score was assigned by at least one observer. Complete agreement of HER2 scores among all 7 observers was achieved on 15 cases, and all but one case had an agreement by at least 4 observers. The overall agreement was 72.3% (kappa 0.60), 77.5% (kappa 0.65), and 83.3% (kappa 0.65), using four (0 to 3+ ), three (0/1+ , 2+ , 3+ ), or two (0/1+ , 2/3+ ) HER2 scoring categories, respectively. Based on the combination of HER2 immunostaining scores and FISH, the interobserver disagreement may have potentially resulted in a clinically significant difference in HER2 status only in three tumors. We conclude, that the proposed serous endometrial cancer-specific HER2 scoring criteria are reproducible among gynecologic pathologists with moderate to substantial interobserver agreement rates comparable to those of previously reported in breast and gastric carcinomas. Our findings significantly strengthen the foundation for establishing endometrial cancer-specific HER2 scoring guidelines in the future.

Glaucoma is a neurodegenerative disease of the visual system and is the leading cause of irreversible blindness worldwide. To date, its pathophysiological mechanisms remain unclear. This study evaluated the feasibility of advanced diffusion magnetic resonance imaging techniques for examining the microstructural environment of the visual pathway in glaucoma. While conventional diffusion tensor imaging (DTI) showed lower fractional anisotropy and higher directional diffusivities in the optic tracts of glaucoma patients than healthy controls, diffusion kurtosis imaging (DKI) and the extended white matter tract integrity (WMTI) model indicated lower radial kurtosis, higher axial and radial diffusivities in the extra-axonal space, lower axonal water fraction, and lower tortuosity in the same regions in glaucoma patients. These findings suggest glial involvements apart from compromised axonal integrity in glaucoma. In addition, DKI and WMTI but not DTI parameters significantly correlated with clinical ophthalmic measures via optical coherence tomography and visual field perimetry testing. Taken together, DKI and WMTI provided sensitive and comprehensive imaging biomarkers for quantifying glaucomatous damage in the white matter tract across clinical severity complementary to DTI.

Clonal anergy and depletion of antigen-specific CD8+ T cells are characteristics of immunosuppressed patients such as cancer and post-transplant patients. This has promoted translational research on the adoptive transfer of T cells to restore the antigen-specific cellular immunity in these patients. In the present work, we compared the capability of PBMCs and two types of mature monocyte-derived DCs (moDCs) to prime and to expand ex-vivo antigen-specific CD8+ T cells using culture conditioned media supplemented with IL-7, IL-15, and IL-21. The data obtained suggest that protocols involving moDCs are as efficient as PBMCs-based cultures in expanding antigen-specific CD8+ T cell to ELA and CMV model epitopes. These three gamma common chain cytokines promote the expansion of naive-like and central memory CD8+ T cells in PBMCs-based cultures and the expansion of effector memory T cells when moDCs were used. Our results provide new insights into the use of media supplemented with IL-7, IL-15, and IL-21 for the in-vitro expansion of early-differentiated antigen-specific CD8+ T cells for immunotherapy purposes.

Objectives The primary objective of this study is to determine if early administration of intraperitoneal (IP) chemotherapy and intra-operative insertion of an IP port are associated with increased complications in patients who undergo a bowel resection procedure as part of primary cytoreductive surgery for ovarian cancer. Methods This was a multi-centre retrospective cohort study, at 2 high volume cancer centers. For our primary outcomes, univariate logistic regression was completed to assess the impact of timing of IP chemotherapy administration and IP port insertion on perioperative complications. Kaplan Meier survival curves were compared using the Log-Rank test. Results We identified 131 patients treated with IP chemotherapy after bowel resection during primary cytoreduction for advanced ovarian cancer; 75 patients started IP treatment at the first adjuvant chemotherapy, while 56 patients received intravenous (IV) chemotherapy and later transitioned to IP chemotherapy. The majority of patients had stage III/IV disease (87%) and high-grade serous histology (91.6%). Compared to patients who received their first cycle of chemotherapy IV, patients who started with IP chemotherapy were not at increased risk of intra-abdominal infections (8% vs 16% (p = 0.15)), IP port related complications (20% vs 19.6% (p = 0.96)), or anastomotic leak (2.7% vs 3.6% (p = 0.8)). There was a non-statistically significant trend for increased rates of anastomotic leak (5.6% vs 3.3% (p = 0.62)), intra-abdominal infection (16.7% vs 6.7% (p = 0.17)) and IP port related complications (24.1% vs 13.3% (p = 0.21)) in patients who had intra-operative IP port insertion compared to delayed post-operative port insertion. Conclusions Administration of IP chemotherapy in the first post-operative cycle after bowel resection is not associated with increased post-operative complications in women with advanced ovarian carcinoma undergoing primary cytoreductive surgery. Intra-operative IP port insertion may be associated with a small increase in major complications in this population.

The FIGO 2019 update on cervical cancer staging removed horizontal tumor extent (HZTE) as a staging variable. Evidence is needed to substantiate this change. The prognostic significance of HZTE and a related variable, circumferential tumor extent (%CTE), is similarly unknown. We aimed to investigate the association of HZTE and %CTE with survival outcomes in cervical cancer patients.We identified patients treated with primary surgery for stage I cervical cancer in a single institution during a 9-year period. HZTE and, when available, %CTE were obtained from pathology records. Cases were staged using 2019 FIGO staging. Correlations between HZTE, %CTE and FIGO stage with recurrence-free (RFS) and disease-specific survival (DSS) were determined using univariable and multivariable analyses.285 patients were included with a median follow-up of 48 (range 7-123) months. HZTE was statistically associated with RFS and DSS on univariate and multivariate analysis. None of the 168 stage IA patients in our series had tumor recurrence or death during follow-up, including 42 with HZTE ≥7 mm. None of the patients with a tumor horizontal extent7 mm experienced recurrence or death. %CTE correlated only with RFS on univariate analysis. 2019 FIGO stage did not independently correlate with RFS or DSS in our sample.HZTE is an independent predictor of survival in cervical carcinoma. In stage IA tumors, however, HZTE does not offer superior prognostic value, supporting the 2019 FIGO recommendations to remove this variable from staging in these cases. HZTE may be useful in larger tumors in which staging depends on maximum tumor size. %CTE is not an independent prognostic variable in cervical cancer, and we advise against its use.

Invasive stratified mucinous carcinoma (iSMC) has been suggested to represent an aggressive subtype of endocervical adenocarcinoma. We sought to investigate the outcomes of iSMC and determine which clinical and pathologic parameters may influence the prognosis. Slides from 52 cases of iSMC were collected and classified as follows: pure iSMC (>90% of the entire tumor) and iSMC mixed with other human papillomavirus-associated adenocarcinoma components (miSMC) (>10%, but

High grade cancers account for a disproportionate number of recurrences in patients with endometrial cancer. Accurately identifying these cases on endometrial biopsies allows for better surgical planning. This study evaluates the diagnostic accuracy of general pathologists (GP) compared to gynecological pathologists (GYNP) in interpreting preoperative biopsies.A retrospective cohort study was conducted of patients diagnosed with high grade endometrial cancer (HGEC) between 2012 and 2016 at eight Canadian cancer centres. Data was collected from medical records. Pre-operative biopsies were categorized into groups; biopsies read by GP, GYNP and GP reviewed by GYNP. Rates of HGEC on pre-operative biopsy were calculated. Fisher exact test was used to compare differences between the groups. Univariate logistic regression analysis was conducted for HGEC prediction.Of 1237 patients diagnosed with HGEC, 245 (19.8%) did not have a preoperative diagnosis of high-grade disease. Discordancy was identified in 91/287 (31.71%) of biopsies reported by GP, and in 114/910 (12.53%) of biopsies reported by a GYNP (p 0.0001). Compared to GP, GYNP were 3.24 (CI 2.36-4.45) times more likely to identify high grade disease on preoperative biopsy. Patients whose biopsy was reported by a GYNP were more likely to have a comprehensive staging procedure (OR 1.77 CI 1.33-2.38) and less likely to receive adjuvant therapy (OR 0.71 CI 0.52-0.96).GYNP are more likely to identify HGEC on pre-operative biopsies. Due to high rates of overall discordancy, it is possible that surgical staging procedures should not be based solely on preoperative biopsy. Further strategies to improve pre-operative biopsies' accuracy are needed.

Ovarian carcinoma with a somatically derived yolk sac tumor component is a phenomenon known to mostly occur in postmenopausal women. Herein, we report an ovarian endometriosis-associated somatic yolk sac tumor arising in the background of a low-grade endometrioid adenocarcinoma in a young woman. A 27-yr-old woman presented with abdominal pain, subsequently recognized to be caused by a right ovarian mass undergoing torsion. Following operative management, microscopic examination of the salpingo-oophorectomy specimen showed endometriosis and a predominantly cystic ovarian neoplasm with 2 distinct phenotypic areas: (1) a yolk sac tumor component containing Schiller-Duval bodies and (2) a low-grade endometrioid carcinoma component with squamous metaplasia. Immunohistochemical evaluation showed distinct profiles in the yolk sac tumor (estrogen receptor/progesterone receptor/PAX8 negative, SALL4/Glypican 3 positive) and endometrioid (estrogen receptor/progesterone receptor/PAX8 positive, SALL4/Glypican 3 negative) components. Given these findings, the diagnosis of an endometriosis-associated endometrioid adenocarcinoma with a somatically derived yolk sac tumor was rendered. The tumor was staged as pT1c1 due to intraoperative spillage. The patient underwent chemotherapeutic treatment and after 15 mo of follow-up, she was alive with no evidence of recurrence. This example demonstrates that somatic yolk sac tumor differentiation in ovarian epithelial neoplasia can occur in young patients; awareness of this phenomenon is important as somatic and germ cell yolk sac neoplasia have different behavior and therapy.

Debilitating neurodegenerative conditions, such as multiple sclerosis, Alzheimer’s and Parkinson’s disease, are often presented with the accumulation of metabolic byproducts in brain tissues. Recent studies also suggest linkages between ocular and cerebral diseases, yet the underlying mechanisms remain unclear (1-5). Unlike the rest of the body, the central nervous system (CNS) does not comprise lymphatic vasculature for metabolic waste removal. Instead, several hypotheses have been proposed that rely on the complex but highly regulated clearance mechanisms responsible for an adequate neuronal environment and fluid homeostasis. Understanding the mechanisms of clearance systems in the eye and the brain can help exploit fluid transport and potentially offer new targets for therapy to the visual system and beyond. In this editorial, we describe and criticize how quantitative imaging can play a role in evaluating different models of clearance systems.

[ES] Objetivos: Comparar las características de los pacientes con enfermedad de Parkinson avanzada en tratamiento con infusión intestinal continua de levodopa-carbidopa (IICLC) y los datos de efectividad y seguridad de IICLC entre diferentes comunidades autónomas (CC. AA.). Métodos: Estudio longitudinal observacional y retrospectivo. Se incluyeron 177 pacientes de 11 CC. AA. que iniciaron tratamiento con IICLC entre enero de 2006 y diciembre de 2011. Se compararon las características clínicas y demográficas, las variables de efectividad (cambios en el tiempo OFF, ON con y sin discinesias discapacitantes, cambios en la escala de Hoehn y Yahr y puntuación de la Unified Parkinson's Disease Rating Scale, síntomas no motores e Impresión Clínica Global) y seguridad (acontecimientos adversos), y la tasa de suspensión de IICLC. Resultados: Se hallaron diferencias significativas entre las CC. AA. en diversas variables basales: duración de la enfermedad hasta el inicio de IICLC, tiempo OFF (34,9-59,7%) y ON (con o sin discinesias; 2,6-48,0%), Hoehn y Yahr en ON, Unified Parkinson's Disease Rating Scale-III en ON y OFF, presencia de ≥ 4 síntomas motores y dosis de IICLC. En el seguimiento (> 24 meses en 9 de 11 CC. AA.) hubo diferencias significativas en el porcentaje de tiempo OFF, tiempo ON sin discinesias discapacitantes, frecuencia de acontecimientos adversos e Impresión Clínica Global. La tasa de suspensión fue de entre 20-40% en todas las CC. AA., excepto en 2 (78 y 80%). Conclusiones: Este estudio muestra una amplia variabilidad en la selección de los pacientes y en la efectividad y seguridad de IICLC entre las diferentes CC. AA. Podrían influir las características basales de los pacientes, la disponibilidad de un equipo multidisciplinar y la experiencia clínica., [EN] Objectives: To compare the characteristics of patients undergoing treatment with continuous intestinal infusion of levodopa-carbidopa (CIILC) for advanced Parkinson's disease and the data on the effectiveness and safety of CIILC in the different autonomous communities (AC) of Spain. Methods: A retrospective, longitudinal, observational study was carried out into 177 patients from 11 CAs who underwent CIILC between January 2006 and December 2011. We analysed data on patients’ clinical and demographic characteristics, variables related to effectiveness (changes in off time/on time with or without disabling dyskinesia; changes in Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale scores; non-motor symptoms; and Clinical Global Impression scale scores) and safety (adverse events), and the rate of CIILC discontinuation. Results: Significant differences were observed between CAs for several baseline variables: duration of disease progression prior to CIILC onset, off time (34.9-59.7%) and on time (2.6-48.0%; with or without disabling dyskinesia), Hoehn and Yahr score during on time, Unified Parkinson's Disease Rating Scale-III score during both on and off time, presence of ≥ 4 motor symptoms, and CIILC dose. Significant differences were observed during follow-up (> 24 months in 9 of the 11 CAs studied) for the percentage of off time and on time without disabling dyskinesia, adverse events frequency, and Clinical Global Impression scores. The rate of CIILC discontinuation was between 20-40% in 9 CAs (78 and 80% in remaining 2 CAs). Conclusions: This study reveals a marked variability between CAs in terms of patient selection and CIILC safety and effectiveness. These results may have been influenced by patients’ baseline characteristics, the availability of multidisciplinary teams, and clinical experience., AbbVie Spain, S. L. U. financió este estudio, fue responsable del diseño y coordinó la recogida de datos.

The majority of endocervical adenocarcinomas (EAs) are caused by human papillomavirus (HPV). Gastric-type EA, the second most common EA and unrelated to HPV, is biologically different with a more aggressive clinical course. Our knowledge of the molecular fingerprint of these important EA types and its role in diagnosis, prognosis and management is still evolving. Thus, we sought to evaluate the genomic profile of HPV-related and gastric EA. Clinical information including patient outcome was gathered for fifty-six tumors (45 HPV-associated and 11 gastric-type) which were evaluated by a targeted massively parallel sequencing assay (OncoPanel platform) which surveys exonic DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement detection. KRAS, TP53, and PIK3CA were the most commonly mutated genes (10, 10, and 9 cases, respectively). Alterations in TP53, STK11, CDKN2A, ATM, and NTRK3 were significantly more common in gastric-type EA (p < 0.05, Fisher’s exact test). Disease recurrence and/or death occurred in 14/49 (29%) cases with clinical information available (7 HPV-related (18% of HPV-related cases with clinical information available) and 7 gastric-type (64% of gastric-type cases with clinical information available). Tumors associated with adverse outcome, regardless of histotype, more commonly had alterations in KRAS (2 HPV-related, 4 gastric-type), GNAS (3 HPV-related, 1 gastric-type), and CDKN2A (0 HPV-related, 3 gastric type) compared to indolent-behaving cases (p < 0.05, Fisher’s exact test). A total of 8/56 (14%) tumors harbored at least one actionable mutation; of these, 6 (75%) were associated with recurrence and/or cancer-related death. Copy number variations were detected in 45/56 cases (80%). The most frequent were chromosome 20 gain and 16q loss, identified in 7 cases each (all HPV-associated EA). The mutational profile of EA is diverse and correlates with clinical behavior and EA subtype. Thus, targeted sequencing assays can potentially serve as a diagnostic and prognostic tool. It can also identify targetable alterations, which may benefit patients with recurrent/metastatic disease.

Mammary fibroepithelial lesions encompass a wide spectrum of tumors ranging from an indolent fibroadenoma to potentially fatal malignant phyllodes tumor. The criteria used for their classification based on morphological assessment are often challenging to apply and there is no consensus as to what constitutes an adequate resection margin. We studied a retrospective cohort of 213 fibroepithelial lesions in 178 patients (80 fibroadenomas with unusual features and 133 phyllodes tumors: 63 benign, 41 borderline, and 29 malignant) in order to describe the spectrum of changes within each group, with special emphasis on margin evaluation. Outcome data were available for 153 fibroepithelial lesions in 139 patients (median 56 months, range 3-249 months). Positive final margin (tumor transected), age 50 years and a predominantly myxoid stroma were statistically significant predictors of local recurrence, while age 50, stromal overgrowth, diffuse marked atypia, necrosis and mitotic index of ≥ 10 per 10 HPF were predictive of distant metastases. Tumors with satellite/bulging nodules were at a significantly higher risk to have a final positive resection margin. Our findings highlight important aspects of the interpretation and reporting of fibroepithelial lesions: the amount of myxoid stroma and the presence of satellite nodules are clinically relevant and should be routinely assessed and reported; infiltrative border might not be a prerequisite for the diagnosis of malignant phyllodes tumor, while the presence of tumor necrosis, massive stromal overgrowth or mitotic index of ≥ 25 per 10 HPF is diagnostic of malignant phyllodes tumor. On the other hand, increased mitotic index outside of the range of the World Health Organization guidelines in the absence of other worrisome features should be treated with caution, as it can be found in benign tumors.

Background: The knowledge of predictive factors in depression should help to deal with the disease. Aim: To assess potential predictors of remission of major depressive disorders (MDD) in secondary care and to propose a predictive model. Material and methods: A 12 month follow-up study was conducted in a sample of 112 outpatients at three psychiatric care centers of Chile, with baseline and quarterly assessments. Demographic, psychosocial, clinical and treatment factors as potential predictors, were assessed. A clinical interview with the checklist of DSM-IV diagnostic criteria, the Hamilton Depression Scale and the List of Threatening Experiences and Multidimensional Scale of Perceived Social Support were applied. Results: The number of stressful events, perceived social support, baseline depression scores, melancholic features, time prior to beginning treatment at the secondary level and psychotherapeutic sessions were included in the model as predictors of remission. Sex, age, number of previous depressive episodes, psychiatric comorbidity and medical comorbidity were not significantly related with remission. Conclusions: This model allows to predict depression score at six months with 70% of accuracy and the score at 12 months with 72% of accuracy.

Studies on the pattern-based classification for invasive endocervical adenocarcinoma showed that tumors with nondestructive invasion (pattern-A) have a 0% rate of nodal metastases. Our understanding of pattern-A tumors and their distinction from in-situ adenocarcinoma requires further study. Thirteen sections diagnosed independently as pattern-A adenocarcinoma by three gynecologic pathologists, and 14 sections of benign endocervix were selected. Three additional pathologists (reviewers) evaluated a digital image from each section and classified it as pattern-A or benign based on architecture only. To blind the interpretation to cytologic features, nuclei and cytoplasm were obscured using morphometric software (Zen 2011, Carl Zeiss Microscopy, Germany). 13/27 cases (48%; 8 pattern-A, 5 benign) were correctly classified by all reviewers; 19/27 (70%; 10 pattern-A, 9 benign) were correctly classified by ≥2 reviewers. 3/13 pattern-A cases (23%) were interpreted as benign by ≥2 reviewers. Conversely, 5/14 benign cervices (36%) were misinterpreted as pattern-A by ≥2 reviewers. The number of glands per 20× field was higher in pattern-A cases with high reviewer agreement (p=0.004). An abnormal architecture is seen in many pattern-A adenocarcinomas in support of their invasive nature; some, however, have architecture that overlaps with that of benign endocervix thus may actually represent in-situ lesions. Likewise, normal cervix can be architecturally complex and mirror patterns that pathologists would classify as pattern-A if malignant cytologic features were present. Based on this overlap and the nil risk of nodal spread, an emphasis on the non-destructive, rather than the invasive, nature of pattern-A adenocarcinoma is recommended.

Background: Depression is considered the second leading cause of disability worldwide. Aim: To describe the clinical characteristics and the evolution of major depressive disorder (MDD) in secondary care. To evaluate the association between socio-demographic and clinic variables with the first or recurrent major depressive events (MDE). Material and Methods: Clinical features, treatment, remission and duration of MDE were evaluated during a follow up lasting 12 months in 112 participants aged 44 ± 15 years (79% women). Patients were assessed as outpatients every three months at three psychiatric care centers of Chile. Clinical interviews were carried out using DSM-IV diagnostic criteria checklists and the Hamilton Depression Scale was applied. Results: Most patients were referred from primary care. The mean time lapse for referral to the secondary level was 10.8 months. Most patients had episodes that were recurrent, severe, with a high rate of psychosis, with suicide attempts and melancholic features and with psychiatric and medical comorbidities. Remission rate was 27.5%. In only 16 % of patients, the episode lasted six months or less. The group with recurrent episodes had different age, sex and clinical features. Conclusions: MDD treated at the secondary care level is severe and its symptoms are intense. The time lapse prior to referral was prolonged. Primary care management and referral of these patients should be studied more closely.

Purpose The purpose of this paper is to translate consumer requirements regarding olive-oil quality attributes into specific olive-growing practices that most contribute to satisfy these attributes. Design/methodology/approach After identifying consumer requirements or needs regarding different attributes of olive-oil quality, through a survey of 439 olive-oil consumers, the authors determine the olive-growing practices that optimally satisfy consumer needs through expert opinions. Finally, the use of expert knowledge to construct the House of Quality or the first matrix of quality function deployment allow the authors to define the relative contribution of the various olive-farming practices to the satisfaction of consumer requirements. Findings The findings have shown that the olive-oil quality attributes most requested by consumers incorporate organoleptic (e.g. acidity, flavour, colour), sociocultural (e.g. creating employment in rural areas, maintenance of the rural population) and environmental ones (environmental externalities). The “separation of olives collected from ground and trees” (separation), “timing of harvesting” (according to a fruit-ripeness index), the “method of the ground harvest” (no picking from the ground), and the “method of tree harvest” (handpicking) were some of the most commonly identified olive-farming practices that contribute the most to meeting consumers’ needs with regard to olive-oil quality. Research limitations/implications The study suggests detailed analyses of the relationships between customer requirements and other agents practices involved in the olive sector (processing industries: mills, distribution, and marketing management, etc.) to more fully investigate the impact of all these practices on consumers’ perceived olive-oil quality attributes. This is the most reliable way to guarantee that the most sought-after quality characteristics are taken into account, not only in the farming stage but also in the various different stages of the olive agri-food chain. Practical implications Findings represent an opportunity in the market value chain to develop a quality olive oil which is more oriented towards the consumer and able to face future segmentations in the market. This is one of the main innovative features of this study, as it offers “good practice” guidelines to agents of the olive-oil sector from the consumer perspective. Social implications This study provides positive implications to consumers, providing them important tools to make an informed choice, and producers and marketers helping the design of production strategies to optimally satisfy the consumer preference with regard to olive-oil quality, and attain a competitive advantage by adding value to the product. Originality/value This paper is regarded as the pioneer in the literature translating the “consumer voice” regarding olive-oil quality into specific olive-growing practices “good-practices guidelines”. Thus, the relevant required quality olive-oil attributes should be clearly described on the label, to enable consumers to identify the quality features and make an informed choice. Furthermore, to meet consumers’ needs, the olive-oil sector should focus on the olive-growing practices that optimally satisfy consumer requirements concerning olive-oil quality attributes. This would help to improve legitimacy and boost public support for the Common Agricultural Policy subsidies for the agricultural sector in general, and the olive sector in particular. The findings are particularly valuable in helping policy makers to design marketing strategies to improve the sustainability and competitiveness of Spanish olive oil.

Recession on the lingual aspect of mandibular incisors may occur in patients with history of tongue piercing and other factitious traumatic habits. Treatment of these areas is challenging due to the site-specific anatomical features of the region. This case report presents a novel approach for a specific type of mandibular lingual defect caused by tongue piercing. A nonresorbable titanium-reinforced barrier membrane combined with an allograft and enamel matrix derivatives was used to promote regeneration of periodontal attachment. Reentry surgery for membrane removal was performed at 8 weeks. The time from initial surgery to final follow-up was 18 months.

The PROMISE diagnostic algorithm, which uses p53, mismatch repair (MMR) protein immunohistochemistry, and DNA polymerase e (POLE) exonuclease domain mutation testing, is a reliable surrogate of the molecular group in endometrial carcinoma. Its prognostic value has been validated in endometrial carcinoma and ovarian endometrioid carcinoma. Moreover, a similar prognostic grouping has been recently documented in endometrial clear cell carcinoma. Thus, we aimed to explore the role of these markers in ovarian clear cell carcinoma, another endometriosis-associated malignancy. A total of 90 cases were identified and confirmed after secondary review. Immunohistochemistry for p53, MLH1, MSH2, MSH6, and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. POLE mutational analysis was performed in 47 cases. Results were correlated with clinicopathologic variables including disease-free survival (DFS), overall survival, and disease-specific survival (DSS). Endometriosis was found in 67 (74%) cases. Six (7%) tumors were p53 abnormal, 82 (91%) were p53 normal, and 2 (2%) tumors had MMR deficiency (1 MSH6 loss and 1 MSH2/6 loss; both were p53 normal). Several POLE variants of unknown significance were detected, but no pathogenic mutations. The mean follow-up period was 43 months (median: 34, range: 1 to 189). Abnormal p53 status was associated with advanced Federation of Gynecology and Obstetrics stage, lymph node metastases, DFS and DSS (P

Uterine myxoid smooth muscle tumors, including myxoid leiomyosarcoma, are rare and their genomic profile has not been fully characterized. With the discovery of uterine sarcomas with ZC3H7B-BCOR fusion and BCOR internal tandem duplications, the differential diagnosis of myxoid smooth muscle lesions is expanding to include molecularly-defined tumors. Thus, we aimed to explore the genomic landscape of myxoid smooth muscle tumor using comprehensive tools. We performed whole exome next-generation sequencing and a pan-sarcoma RNA fusion assay in tumoral paraffin-embedded tissue from nine well-characterized uterine myxoid smooth muscle tumors (seven myxoid leiomyosarcomas and two myxoid smooth muscle tumors of unknown malignant potential). By immunohistochemistry, all tumors were strongly positive for smooth muscle markers and negative for BCOR staining; 4/6 expressed PLAG1. None of the tumors harbored known fusions including ZC3H7B-BCOR, TRPS1-PLAG1, and RAD51B-PLAG1. None harbored exon 15 BCOR internal tandem duplications; however, four tumors contained BCOR internal tandem duplications of unknown significance (mostly intronic). Mutational burden was low (median 3.8 mutations/megabase). DNA damage repair pathway gene mutations, including TP53 and BRCA2, were found. Copy number variation load, inferred from sequencing data, was variable with genomic indexes ranging from 2.2 to 74.7 (median 25.7), with higher indexes in myxoid leiomyosarcomas than myxoid smooth muscle tumors of unknown malignant potential. The absence of clear driver mutations suggests myxoid smooth muscle tumors to be genetically heterogeneous group of tumours and that other genetic (eg., undiscovered translocation) or epigenetic events drive the pathogenesis of uterine myxoid smooth muscle neoplasia.

AIMS Gastric-type endocervical adenocarcinoma (EA) is characterised by aggressive behaviour and pathogenesis independent of human papillomavirus infection. Because of its morphology and frequent mutation-pattern expression of p53, gastric-type EA may be confused with several types of endometrial carcinoma, particularly in biopsy and curettage specimens. HIK1083 and MUC6 are immunohistochemical markers used to support a diagnosis of gastric-type EA; however, the rates of expression of these markers in endometrial tumours are largely unknown. We therefore aimed to assess the expression of HIK1083 and MUC6 in a cohort of different types of endometrial carcinoma. METHODS AND RESULTS Ninety-one endometrial carcinomas (56 endometrioid, 16 clear cell, and 19 serous) from 91 patients treated with hysterectomy were included. A representative tumour block from each case was used for immunohistochemical staining with HIK1083 and MUC6. The percentage of stained cells (0-100%) and average staining intensity (weak, moderate, and strong) were recorded for both markers. None of 91 cases expressed HIK1083. In contrast, 66% (60/91) of cases showed at least focal expression of MUC6; importantly, 54 of 60 (90%) positive cases showed moderate or strong staining. Five of 60 (8%) cases showed MUC6 staining in ≥50% of tumour cells. Endometrioid tumours (49/56, 88%) were more likely to express MUC6 than cases of clear cell (1/16, 6%) or serous (10/19, 53%) carcinoma. DISCUSSION Endometrial carcinoma often expresses MUC6. In contrast, HIK1083 is consistently negative, and thus, when positive, is a more reliable marker for distinguishing gastric-type EA from some of its endometrial mimics.

[Background] Levodopa-carbidopa intestinal gel (LCIG) is effective in the treatment of advanced Parkinson’s disease (PD). However, the patients’ profile that might benefit from treatment with LCIG has not been characterized., [Objective]This retrospective study explored the influence of disease duration (DD) on the effectiveness of LCIG and identified factors associated with treatment discontinuation in a cohort of advanced PD patients., [Methods] Patients initiating LCIG therapy between Jan-2006 and Dec-2011 in 18 Spanish centers were included. Effectiveness in treating motor symptoms (MSs), non-motor symptoms (NMSs), and adverse events (AEs) occurrence was compared in DD≥10 or, [Results] Overall, 177 PD patients were included (52.5% male; mean age 70.6±8.4 years; mean LCIG duration 35.6±18.6 months). Patients with DD≥10 years (n = 125) experienced less reduction in “off” time (–29%) than those with DD, [Conclusions] Advanced PD patients with DD

AimsThe International Endocervical Adenocarcinoma Criteria and Classification (IECC) was recently proposed as an improved method for categorising endocervical adenocarcinoma (EA) into human papillomavirus (HPV)–associated adenocarcinomas (HPVAs) and non-HPV-associated adenocarcinomas (NHPVAs). Such categorisation correlates with patient age and tumour size; however, its association with patient outcome remains to be established.MethodsInstitutional cases of EA with histological material available were selected. Three gynaecological pathologists independently classified all tumours according to the IECC with consensus review used when necessary. Clinicopathologic variables were recorded for each case.ResultsOf a total of 87 EAs, 71 (82%) were classified as HPVA and 16 (18%) as NHPVA. Among HPVA, most were usual type (51/71, 72%) followed by mucinous not otherwise specified (10/71, 14%) and invasive stratified mucin-producing carcinoma (ISMC, 8/71, 11%). Most NHPVAs were of gastric type (12/16, 71%) followed by clear cell and mesonephric (two each, 12%). Compared with HPVAs, NHPVAs were significantly associated with older age (pConclusionsThe simple morphological approach of the IECC appears to be prognostically valuable. NHPVA (in particular gastric type) and ISMC (a recently recognised subset of HPVA) have an adverse outcome and their recognition following the IECC is important. We provide further evidence to replace the current WHO classification with the IECC.

Endometrial ablation is commonly performed to manage heavy menstrual bleeding. However, failure in symptom control eventually requiring hysterectomy is frequent. Adenomyosis is common in such failure cases. Ablations using a resectoscope will produce an Endo-Myometrial Resection (EMR) specimen. The value of histopathologic examination of EMRs in predicting treatment failure and adenomyosis has not been addressed. We retrieved histologic material from subjects with failed ablation (persistent symptoms requiring hysterectomy) and subjects with ablation followed by clinical improvement and no hysterectomy (control group). Material was evaluated for features of an abnormal endometrial distribution suggestive of adenomyosis: myometrial fragments with endometrium on opposite edges, myometrium with endometrium in ≥3 edges and areas of endometrium completely surrounded by myometrium (endometrial islands). Hysterectomy specimens from the study group were evaluated for the presence of adenomyosis and its distribution (superficial/deep). Both study and control groups consisted of 18 patients each. The number of fragments with endometrium on opposite sides was significantly higher in the study group: 2.11 vs 0.94 in the control group (p=0.005). Conversely, maximum aggregate dimension (2.3cm vs 2.79cm), number of fragments with endometrium on three sides (4.5 vs 2.78) and number of fragments with endometrial islands (4.5 vs 4.11) did not significantly differ between groups. Adenomyosis was seen in 72.2% hysterectomies from the study group; 27.8% involved deep myometrium. None of the EMR features were statistically associated with adenomyosis. Certain endomyometrial distribution patterns in EMR specimens correlate with future ablation failure and need for definitive surgery. This may be explained by residual endometrial tissue not resected due to a markedly irregular endomyometrial interface. Adenomyosis is frequent in cases of ablation failure. However, a significant association between EMR patterns studied and adenomyosis was not observed.