Suggested role for neutrophil extracellular trap formation in Ewing sarcoma immune microenvironment.

Ewing sarcoma (EWS) is a highly aggressive cancer with a survival rate of 70%-80% for patients with localized disease and under 30% for those with metastatic disease. Tumor-infiltrating neutrophils (TIN) can generate extracellular net-like DNA structures known as neutrophil extracellular traps (NETs). However, little is known about the presence and prognostic significance of tumor-infiltrating NETs in EWS. Herein, we investigated 46 patients diagnosed with EWS and treated in the Tel Aviv Medical Center between 2010 and 2021. TINs and NETs were identified in diagnostic biopsies of EWS by immunofluorescence. In addition, NETs were investigated in neutrophils isolated from peripheral blood samples of EWS patients at diagnosis and following neoadjuvant chemotherapy. The relationships between the presence of TINs and NETs, pathological and clinical features, and outcomes were analyzed. Our results demonstrate that TIN and NETs at diagnosis were higher in EWS patients with metastatic disease compared with those with local disease. High NET formation at diagnosis predicted poor response to neoadjuvant chemotherapy, relapse, and death from disease (p < 0.05). NET formation in peripheral blood samples at diagnosis was significantly elevated among patients with EWS compared with pediatric controls and decreased significantly following neoadjuvant chemotherapy. In conclusion, NET formation seems to have a role in the EWS immune microenvironment. Their presence can refine risk stratification, predict chemotherapy resistance and survival, and serve as a therapeutic target in patients with EWS.

NCAM1/FGF module serves as a putative pleuropulmonary blastoma therapeutic target.

Pleuropulmonary blastoma (PPB) is a rare pediatric lung neoplasm that recapitulates developmental pathways of early embryonic lungs. As lung development proceeds with highly regulated mesenchymal-epithelial interactions, a DICER1 mutation in PPB generates a faulty lung differentiation program with resultant biphasic tumors composed of a primitive epithelial and mesenchymal stroma with early progenitor blastomatous cells. Deciphering of PPB progression has been hampered by the difficulty of culturing PPB cells, and specifically progenitor blastomatous cells. Here, we show that in contrast with in-vitro culture, establishment of PPB patient-derived xenograft (PDX) in NOD-SCID mice selects for highly proliferating progenitor blastoma overexpressing critical regulators of lung development and multiple imprinted genes. These stem-like tumors were sequentially interrogated by gene profiling to show a FGF module that is activated alongside Neural cell adhesion molecule 1 (NCAM1). Targeting the progenitor blastoma and these transitions with an anti-NCAM1 immunoconjugate (Lorvotuzumab mertansine) inhibited tumor growth and progression providing new paradigms for PPB therapeutics. Altogether, our novel in-vivo PPB xenograft model allowed us to enrich for highly proliferating stem-like cells and to identify FGFR and NCAM1 as two key players that can serve as therapeutic targets in this poorly understood and aggressive disease.

In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example.

Cancer stem cell (CSC) identification relies on transplantation assays of cell subpopulations sorted from fresh tumor samples. Here, we attempt to bypass limitations of abundant tumor source and predetermined immune selection by in vivo propagating patient-derived xenografts (PDX) from human malignant rhabdoid tumor (MRT), a rare and lethal pediatric neoplasm, to an advanced state in which most cells behave as CSCs. Stemness is then probed by comparative transcriptomics of serial PDXs generating a gene signature of epithelial to mesenchymal transition, invasion/motility, metastasis, and self-renewal, pinpointing putative MRT CSC markers. The relevance of these putative CSC molecules is analyzed by sorting tumorigenic fractions from early-passaged PDX according to one such molecule, deciphering expression in archived primary tumors, and testing the effects of CSC molecule inhibition on MRT growth. Using this platform, we identify ALDH1 and lysyl oxidase (LOX) as relevant targets and provide a larger framework for target and drug discovery in rare pediatric cancers.

Wilms Tumor NCAM-Expressing Cancer Stem Cells as Potential Therapeutic Target for Polymeric Nanomedicine.

Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted. We have recently developed an NCAM-targeted nanosized conjugate of paclitaxel bound to a biodegradable polyglutamic acid polymer. In this work, we examined the ability of the conjugate to inhibit Wilms tumor by targeting the NCAM-expressing CSCs. Results show that the conjugate selectively depleted the CSC population of the tumors and effectively inhibited tumor growth without causing toxicity. We propose that the NCAM-targeted conjugate could be an effective therapeutic for Wilms tumor. Mol Cancer Ther; 16(11); 2462-72. ©2017 AACR.

Do women prefer a female breast surgeon?

BACKGROUND: Patient preferences regarding the gender of their physicians is a highly sensitive issue, which can be particularly salient in intimate medical situations. Previously published studies found that women tend to prefer female physicians, especially in the case of obstetricians and gynecologists. Data regarding other intimate specialties, such as breast surgery, are scarce. The present study was undertaken to assess gender preferences of women regarding their choice of a breast surgeon. METHODS: Five hundred and fifteen consecutive women who attended breast clinics in two university-affiliated tertiary hospitals were prospectively enrolled. A 25-item anonymous questionnaire was completed by women independently and used to assess their preferences in selecting their breast surgeon. Of the 515 women, 500 (97 % response rate; mean age 50.6 ± 15.4 years) completed the anonymous questionnaire. RESULTS: Overall, 160 (32 %) women preferred to undergo breast examination by a female breast surgeon, 296 (59 %) had no preference, and only 44 (9 %) preferred a male surgeon. A same-gender preference was significantly and independently associated with younger age of the patients (Odds Ratio = 0.978, 95 % Confidence Interval 0.962-0.994, P = 0.007) and being married (Odds Ratio = 0.563, 95 % Confidence Interval 0.347-0.916, P = 0.021). However, only small and equal numbers of patients preferred to undergo breast surgery by a female (14 %) or a male (13 %) surgeon, and most patients (73 %) had no gender preferences. Furthermore, the three most important factors, which affected in general the actual selection, were surgical ability (93 %), experience (91.2 %) and knowledge (78.6 %), rather than physician gender per se. CONCLUSIONS: Overall, about a third of women prefer a female breast surgeon for their breast examination. Embarrassment during the examination was the major reason for same-gender preference. In contrast, when it comes to breast operations, preference for a female surgeon is less pronounced, with the professional skills of the surgeons becoming the predominant consideration. The fact that almost a third of the potential patients prefer female surgeons with regard to their breast examinations emphasizes the need to increase the number of female surgeons. Such an increase can be achieved through academic and economic changes that will enable more women to specialize in general surgery. TRIAL REGISTRATION: Trial registration is not required for this type of research.

Dissecting Stages of Human Kidney Development and Tumorigenesis with Surface Markers Affords Simple Prospective Purification of Nephron Stem Cells.

When assembling a nephron during development a multipotent stem cell pool becomes restricted as differentiation ensues. A faulty differentiation arrest in this process leads to transformation and initiation of a Wilms' tumor. Mapping these transitions with respective surface markers affords accessibility to specific cell subpopulations. NCAM1 and CD133 have been previously suggested to mark human renal progenitor populations. Herein, using cell sorting, RNA sequencing, in vitro studies with serum-free media and in vivo xenotransplantation we demonstrate a sequential map that links human kidney development and tumorigenesis; In nephrogenesis, NCAM1(+)CD133(-) marks SIX2(+) multipotent renal stem cells transiting to NCAM1(+)CD133(+) differentiating segment-specific SIX2(-) epithelial progenitors and NCAM1(-)CD133(+) differentiated nephron cells. In tumorigenesis, NCAM1(+)CD133(-) marks SIX2(+) blastema that includes the ALDH1(+) WT cancer stem/initiating cells, while NCAM1(+)CD133(+) and NCAM1(-)CD133(+) specifying early and late epithelial differentiation, are severely restricted in tumor initiation capacity and tumor self-renewal. Thus, negative selection for CD133 is required for defining NCAM1(+) nephron stem cells in normal and malignant nephrogenesis.

Screening for Cervical Cancer Among Low-Risk Populations: Orthodox Jewish Women as a Model.

OBJECTIVE: To explore the prevalence of abnormal Papanicolaou (PAP) smears among asymptomatic Orthodox Jewish women, characterized by conservative sexual habits, in comparison to secular Jewish women. METHODS: A retrospective analytical cohort study of 600 consecutive PAP smears, performed as a screening test on asymptomatic Orthodox Jewish women (mean age 43.4 ± 12.6 years), compared to 600 consecutive smears performed on secular Jewish women (mean age 38.2 ± 11.5 years). Primary outcome measures comprised incidence and clinical significance of abnormal cytological findings among the two subgroups. Secondary outcome measures included possible risk factors for abnormal cytological findings within the study population. RESULTS: In the Orthodox group, only seven (1.2%) PAP smears were interpreted as abnormal, compared with 33 (5.5%) abnormal smears among the secular group (p < 0.001). All seven abnormal PAP smears from the Orthodox Jewish group were classified as atypical squamous cells of undetermined significance (ASCUS), compared with 16 ASCUS smears and 17 low-grade squamous intraepithelial lesion smears in the secular group (2.67% and 2.83% of the secular women, respectively). The vast majority of ASCUS cases in the Orthodox Jewish group were followed up with repeated normal PAP smears. CONCLUSIONS: The incidence rate of abnormal PAP smears taken as a routine screening test among Orthodox Jewish women is very low (1.2%). Furthermore, the vast majority of abnormal smears in these women were later found to be false positive, with no clinical significance. These findings raise doubt as to the need for systematic screening and/or comprehensive vaccination against the papilloma virus among low-risk populations.