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Purpose: Pure mucinous breast carcinomas (PMBC) are rare cancers that are managed per standard breast cancer treatment protocols. In this study, we review the clinicopathologic features, treatment, and outcomes of patients with PMBC treated at our academic cancer center. Methods: We searched institutional pathology databases for patients with histologically confirmed PMBC over a 20-year period (January 1998 - October 2018) who received any portion of clinical care at our institution. Archival pathology slides were re-reviewed to confirm the diagnosis and record pathologic features, including the presence or absence of a micropapillary component. We estimated recurrence free survival (RFS) probabilities using the Kaplan-Meier method and evaluated prognostic factors using Cox regression. Results: A total of 70 cases of PMBC were identified, including 13 with micropapillary features. Median patient age was 65 years (range, 39-94) and approximately 40% were African American or Asian. The majority of patients had negative lymph nodes (84%), tumors < 2 cm (79%), grade I-II (94%), and hormone receptor positive (99%) disease, with Ki-67 proliferation indices ‎≤10% (54%). All patients underwent surgery, 50% received adjuvant radiation therapy, 6% adjuvant chemotherapy, and 63% adjuvant hormone therapy. Five-year RFS was 94% with no identified clinicopathologic or treatment factors significantly affecting survival, including the presence of micropapillary features. Conclusion: We report one of the more diverse single institution series of patients with PMBC based in the United States.This rare breast cancer subtype is associated with a favorable prognosis and may benefit from omission of aggressive standard treatment approaches.

Combined p57 immunohistochemistry and DNA genotyping refines classification of products of conception specimens into specific types of hydatidiform moles and various nonmolar entities that can simulate them. p57 expression is highly correlated with genotyping and in practice can reliably be used to identify virtually all complete hydatidiform moles (CHM), but aberrant retained or lost p57 expression in rare CHMs and partial hydatidiform moles (PHM), as well as loss in some nonmolar abortuses, has been reported. Among a series of 2329 products of conceptions, we identified 10 cases for which loss of p57 expression was inconsistent with genotyping results (none purely androgenetic). They displayed a spectrum of generally mild abnormal villous morphology but lacked better developed features of CHMs/early CHMs, although some did suggest subtle forms of the latter. For 5 cases, genotyping (4 cases) and/or ancillary testing (1 case) determined a mechanism for the aberrant p57 results. These included 3 PHMs-2 diandric triploid and 1 triandric tetraploid-and 1 nonmolar specimen with loss of p57 expression attributable to partial or complete loss of the maternal copy of chromosome 11 and 1 nonmolar specimen with Beckwith-Wiedemann syndrome. For 5 cases, including 2 diandric triploid PHMs and 3 biparental nonmolar specimens, genotyping did not identify a mechanism, likely due to other genetic alterations which are below the resolution of or not targeted by genotyping. While overdiagnosis of a PHM as a CHM may cause less harm since appropriate follow-up with serum β-human chorionic gonadotropin levels would take place for both diagnoses, this could cause longer than necessary follow-up due to the expectation of a much greater risk of persistent gestational trophoblastic disease for CHM compared with PHM, which would be unfounded for the correct diagnosis of PHM. Overdiagnosis of a nonmolar abortus with loss of p57 expression as a CHM would lead to unnecessary follow-up and restriction on pregnancy attempts for patients with infertility. Genotyping is valuable for addressing discordance between p57 expression and morphology but cannot elucidate certain mechanisms of lost p57 expression. Future studies are warranted to determine whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying the risk of persistent gestational trophoblastic disease for PHMs and nonmolar conceptions that are not purely androgenetic but have some abnormal paternal imprinting of the type seen in CHMs.

We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX-TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12-year-old boy who presented with a large left renal mass with extension into the inferior vena cava. The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break-apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX-TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come-together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break-apart might be below the FISH resolution, resulting in a false negative result.

ObjectivesIncreasingly, acute promyelocytic leukemia (APL) is treated with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). This study characterizes bone marrow findings after ATRA/ATO therapy.MethodsBone marrow biopsies from 16 patients treated with ATRA/ATO and seven patients treated with ATRA/chemotherapy (CTX) for APL were evaluated.ResultsIn ATRA/ATO cases, the marrow was likely to be hypercellular (79%) with a decreased myeloid:erythroid (M:E) ratio (88%), megaloblastoid maturation of erythroid precursors (100%), erythroid atypia (75%), and increased (88%) and atypical (75%) megakaryocytes. Significant myeloid atypia was only seen in extensive residual disease. The ATRA/CTX cases were less likely to be hypercellular (38%), have a M:E ratio of 1:1 or less (0%), exhibit significant erythroid atypia (0%), or have increased (0%) or atypical (38%) megakaryocytes.ConclusionsBone marrow biopsies from patients treated with ATO have unusual but characteristic features. Despite variability in marrow findings, clinical outcomes were uniformly favorable.

Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor‐related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI‐treated patients with stage I‐III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine‐learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.

Metastatic melanoma has a high rate of cardiac involvement and often presents with non-specific symptoms, including heart failure. We report a case of a 41-year-old woman with a remote history of resected flank melanoma, who presented with heart failure progressing to cardiogenic shock and death. Despite extensive workup including chest computed tomography, cardiac magnetic resonance imaging, and endomyocardial biopsy, the etiology of her heart failure was not diagnosed until autopsy revealed metastatic amelanotic melanoma. In patients with unexplained heart failure and a history of melanoma, imaging studies including fluorodeoxyglucose positron emission tomography should be included in the workup to guide early diagnosis and treatment.

Tuberculosis (TB) is the leading killer due to a single infectious disease worldwide. With the aging of the global population, the case rate and deaths due to TB are highest in the elderly population. While general immunosenescence associated with old age is thought to contribute to the susceptibility of the elderly to develop active TB disease, very few studies of immune function in elderly individuals with Mycobacterium tuberculosis ( M.tb ) infection or disease have been performed. In particular, impaired adaptive T cell immunity to M.tb is one proposed mechanism for the elderly's increased susceptibility primarily on the basis of the decreased delayed type hypersensitivity response to tuberculin-purified protein derivative in the skin of elderly individuals. To investigate immunological reasons why the elderly are susceptible to develop active TB disease, we performed a cross-sectional observational study over a five year period (2012–2016) enrolling participants from 2 age groups (adults: 25–44 years; elderly: 65 and older) and 3 M.tb infection statuses (active TB, latent TB infection, and healthy controls without history of M.tb infection). We hypothesized that impaired peripheral T cell immunity plays a role in the biological susceptibility of the elderly to TB. Contrary to our hypothesis, we observed no evidence of impaired M.tb specific T cell frequency or altered production of cytokines implicated in M.tb control (IFN-γ, IL-10) in peripheral blood in the elderly. Instead, we observed alterations in monocyte proportion and phenotype with age and M.tb infection that suggest their potential role in the susceptibility of the elderly to develop active TB. Our results suggest a potential link between the known widespread low-grade systemic inflammation of old age, termed “inflammaging,” with the elderly's specific susceptibility to developing active TB. Moreover, our results highlight the need for further research into the biological reasons why the elderly are more susceptible to disease and death from TB, so that public health systems can be better equipped to face the present and future problem of TB in an aging global population.

ObjectiveThis study aims to determine the prevalence of programmed death ligand 1 (PD-L1) expression in endometrial carcinoma (EC) and determine clinical and pathological associations.MethodsImmunohistochemistry for PD-L1 was performed on sections of a triple-core tissue microarray of 700 ECs. Positive PD-L1 expression, defined as 1% of cells staining positive, was evaluated in tumor and stromal compartments. Using age-adjusted logistic regression, we estimated odds ratios and 95% confidence intervals for associations between PD-L1 expression (overall and by staining compartment) with clinical and tumor characteristics. Kaplan-Meier plots and log-rank tests were used to evaluate associations between PD-L1 expression and EC-specific survival.ResultsPD-L1 expression was observed in 100 cases (14.3%), including 27 (3.9%) with expression in tumor cells only, 35 (5.0%) with expression in both tumor cells and stroma, and 38 (5.4%) with expression in stroma only. Expression was observed in ECs of different histologic types. Tumors characterized by loss of mismatch repair proteins were significantly associated with tumoral PD-L1 expression (P< 0.0001), but not with stromal PD-L1 expression. Both tumoral and stromal PD-L1 expressions were associated with high-grade endometrioid histology, nonendometrioid histology, and lymphovascular space invasion. We observed no significant associations between PD-L1 expression and EC-specific survival.ConclusionsPD-L1 is expressed in a significant proportion of EC and is associated with mismatch repair deficiency, potentially representing a mechanism of tumor immune evasion and a therapeutic target in EC.

10102 Background: Many BC patients treated with aromatase inhibitors (AIs) develop AIA; 20% have symptoms severe enough to effect treatment compliance. Results of candidate gene studies to identify AIA risk are limited in scope. In this case-controlled study, we evaluated the potential of a NAA to predict AIA using germline single nucleotide polymorphism (SNP) data obtained prior to treatment initiation. Methods: Systematic chart review of 700 AI-treated patients with stage I-III BC between 2003-2012 identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained from peripheral blood cells and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. The identity of the cluster of SNPs that most closely defined AIA risk was discovered using an NAA that sequentially combined statistical filtering and a machine learning algorithm. NCBI PhenGenI and Ensemble databases were used to define gene attribution of the 200 most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Results: Cases and controls were similar in demographic characteristics. A cluster of 70 SNPs, correlated to 57 genes (accounting for linkage disequilibrium), was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally and ontologically consistent. Conclusions: Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias. An ongoing prospective companion study will be used to validate and to expand upon results.

Owners and municipalities face the choice to renovate or rebuild buildings in order to improve energy efficiency and sustainability. The process of upgrading the existing building stock can be supported by land management tools, i.e. , municipal energy plans (MEP) or sustainable building codes (BC), that municipalities use to plan, check and monitor actions taken. Many local and regional authorities are involved in the Covenant of Mayors supported by the European Union (EU): the sustainable energy action plan (SEAP) is the key document in which the Covenant signatory outlines how it intends to reach CO 2 reduction target by 2020. Sustainability at the urban scale is also supported by voluntary certification schemes such as Leadership in Energy and Environmental Design (LEED) ® for neighbourhood development proposed by the United States Green Building Council (USGBC), Building Research Establishment Environmental Assessment Method (BREEAM) Communities proposed by UK Building Research Establishment (BRE) and Comprehensive Assessment System for Built Environment Efficiency (CASBEE) for Urban Development proposed by the Japan GreenBuild Council. The fact that there are so many tools to manage urban sustainability is positive, but what happens when multiple tools are applied to the same territory? Overlap, redundancy, and conflicts in management may be critical elements. The purpose of this article is to analyze these critical issues, highlighting the elements of integration and possible synergies for effective management of sustainability at the local level.

Background. This study surveyed opinions and self-reported practices of physicians involved in the care of elderly individuals regarding geriatric hypertension management and included a national random sample (n = 1060) of health care professionals in the United States. Methods. This is a cross-sectional self-conducted survey using a questionnaire developed to assess the opinions related to blood pressure (BP) and aging, BP selection, BP target, lifestyle modifications, and first-line drug choice. We also tested the impact of the patient's age on the respondents' answers. A national random sample (n = 1060) of health care professionals in the United States was selected. Results. We received 412 (39%) questionnaires. Thirty-five percent considered that the increase in BP with age is a normal process of aging, and 25% considered treating hypertension in an 85-year-old patient to have more risks than benefits. Sixty-nine percent considered systolic blood pressure to be the most important pressure. Respondents were more likely to start antihypertensive therapy at a lower BP and target a lower BP in 65-year-old patients compared with 85-year-old patients (p

e20601 Background: Aromatase Inhibitors (AIs) are associated with arthralgia development, leading to therapy non-adherence and premature discontinuation. Clinical and genetic risk factors have been...

For many years the calcium ion has repeatedly cropped up in research work concerning the transformation of the normal cell to the malignant state. When these results are collected together they indicate that calcium may hold the key to the solution of many of the problems concerning the cancer cell.

The preparation of a fluorescein-labeled Gardnerella vaginalis polyclonal antibody is described, and its usefulness is assessed for the detection of this microorganism in vaginal samples obtained from 263 women attending the gynecological department of a general hospital, 66 of whom harbored an intrauterine device. The direct immunofluorescence technique was positive for G. vaginalis in 21% of the specimens, whereas only 12.5% of the total bacteriological cultures were positive. The frequency was higher in patients harboring intrauterine devices since 34.8% exhibited positive immunofluorescence and 30.3% exhibited positive cultures.