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Anthracyclines are a highly effective component of curative breast cancer chemotherapy but are associated with substantial morbidity.sup.1,2. Because anthracyclines work in part by inhibiting topoisomerase-II (TOP2) on accessible DNA.sup.3,4, we hypothesized that chromatin regulatory genes (CRGs) that mediate DNA accessibility might predict anthracycline response. We studied the role of CRGs in anthracycline sensitivity in breast cancer through integrative analysis of patient and cell line data. We identified a consensus set of 38 CRGs associated with anthracycline response across ten cell line datasets. By evaluating the interaction between expression and treatment in predicting survival in a metacohort of 1006 patients with early-stage breast cancer, we identified 54 CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups; of these CRGs, 12 overlapped with those identified in vitro. CRGs that promote DNA accessibility, including Trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility, such as Polycomb complex proteins, were associated with decreased anthracycline sensitivity. We show that KDM4B modulates TOP2 accessibility to chromatin, elucidating a mechanism of TOP2 inhibitor sensitivity. These findings indicate that CRGs mediate anthracycline benefit by altering DNA accessibility, with implications for the stratification of patients with breast cancer and treatment decision making. Epigenetic regulators modulating chromatin accessibility dictate sensitivity to anthracycline-based therapy in early breast cancer and represent potential biomarkers for patient stratification., Author(s): Jose A. Seoane [sup.1] [sup.2] [sup.3] , Jacob G. Kirkland [sup.2] [sup.4] , Jennifer L. Caswell-Jin [sup.1] , Gerald R. Crabtree [sup.4] [sup.5] [sup.6] , Christina Curtis [sup.1] [sup.2] [...]

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals. Rectal cancer organoids retain the pathological features of matched patient tumors and recapitulate clinical responses to chemoradiation., Author(s): Karuna Ganesh [sup.1] [sup.2] , Chao Wu [sup.3] [sup.4] , Kevin P. O'Rourke [sup.5] [sup.6] , Bryan C. Szeglin [sup.4] [sup.7] , Youyun Zheng [sup.8] [sup.9] , Charles-Etienne Gabriel [...]

* Context.--Gestational trophoblastic tumors include 3 distinct entities: gestational choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Accurate diagnosis is important for clinical management of the patient.Objective.--To review clinical features and pathologic diagnosis of gestational trophoblastic tumors.Data Sources.--Literature and personal experience are the sources for this study.Conclusions.--Trophoblastic tumors are rare encounters in modern medicine, as a result of clinical practice of molar surveillance programs and early chemotherapeutic intervention for persistent gestational trophoblastic neoplasia. Diagnostic recognition of these tumors requires a high index of suspicion, awareness of their histologic characteristics, and appropriate application of immuno-histo-chemical and molecular biomarkers. Recent attention has been given to a few precursor lesions of gestational trophoblastic tumors, including early/in situ choriocarcinoma and atypical placental site nodule.doi: 10.5858/arpa.2018-0234-RA), Gestational trophoblastic diseases are proliferative disorders of the placental trophoblast, of either nonneoplastic (hydatidiform moles) or true neoplastic (gestational trophoblastic tumors) proliferation. Gestational trophoblastic tumors include 3 well-defined pathologic entities: [...]

BackgroundSchistosomiasis is caused by 6 species of trematodes of the genus Schistosoma: S. guineensis, S. haematobium, S. intercalatum, S. japonicum, S. mansoni and S. mekongi. The predominant causes of disease [...]

The aging-associated increase of cancer risk is linked with stromal fibroblast senescence and concomitant cancer- associated fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signaling in this context.We have found downmodulated AR expression in dermal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses and dysplastic nevi) as well as in CAFs from the 3 major skin cancer types, squamous cell carcinomas (SCCs), basal cell carcinomas, and melanomas. Functionally, decreased AR expression in primary human dermal fibroblasts (HDFs) from multiple individuals induced early steps of CAF activation, and in an orthotopic skin cancer model, AR loss in HDFs enhanced tumorigenicity of SCC and melanoma cells. Forming a complex, AR converged with CSL/RBP-J[kappa] in transcriptional repression of key CAF effector genes. AR and CSL were positive determinants of each other's expression, with BET inhibitors, which counteract the effects of decreased CSL, restoring AR expression and activity in CAFs. Increased AR expression in these cells overcame the consequences of CSL loss and was by itself sufficient to block the growth and tumor-enhancing effects of CAFs on neighboring cancer cells. As such, the findings establish AR as a target for stroma-focused cancer chemoprevention and treatment., IntroductionThe aging-associated increase of many cancer types has been linked with stromal fibroblast senescence and concomitant production of diffusible growth factors, cytokines, and extracellular matrix/ remodeling proteins (1) that are [...]

After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapyresistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy., IntroductionDNA double-strand breaks (DSBs) are believed to be the most critical lesions induced by many cancer therapies, including chemotherapy and ionizing radiation (IR). Homology-directed repair (HDR), or homologous recombination repair, [...]

Context.--Early diagnosis of malignant mesothelioma (MM) is urgently needed because life expectancies and treatment options are limited in advanced stages of the disease. Malignant mesothelioma often presents with recurrent hemorrhagic or inflammatory effusions, which might mask the incipient stages of the disease and thereby delay the diagnosis. Despite difficulties in recognizing the malignant cells present in those early effusions, they are often the first available biologic material for diagnosis. Therefore, awareness is needed, and efforts should be made to distinguish the malignant cells by well-defined morphological criteria, combined with ancillary methods. Objectives.--To summarize the diagnostic criteria for the cytopathologic diagnosis of MM based on recently published guidelines and to evaluate the clinical utility of those criteria in clinical practice. Data Sources.--The guidelines for the cytopathologic diagnosis of epithelioid and mixed-type MM and data in recent literature constitute the sources of this review. Eighty-five epithelioid or mixed-type MMs diagnosed between 2004 and 2013 at the Department of Clinical Pathology and Cytology, Karolinska University Hospital, Huddinge (Stockholm, Sweden), were evaluated to determine the clinical utility of the criteria defined by the guidelines. Conclusions.--A conclusive diagnosis of MM can be obtained based on the criteria defined by the guidelines with high positive predictive value. When diagnosed in this way, subsequent therapy should be initiated without further delay. With the earlier diagnosis obtained by cytology, a better effect of chemotherapy can be expected, as shown by the longer overall survival in these patients compared with those with a histopathologic diagnosis. doi: 10.5858/arpa.2018-0020-RA, Malignant mesothelioma (MM) is mechanistically linked to previous asbestos exposure, (1,2) and it develops several decades after the initial exposure to asbestos fibers. Despite a ban on asbestos in Western [...]