Clinical breast concerns in low-risk pediatric patients: practice review with proposed recommendations.

BACKGROUND: Fibroadenoma is overwhelmingly the most common pediatric breast lesion. Breast malignancy is quite uncommon in children, most frequently metastatic or hematological malignancy. Core biopsy has largely replaced excision for diagnosis of breast masses in adults. OBJECTIVE: The purpose of this study is two-fold: (1) compare utilization at our institution of interventional procedures vs. surgery for breast mass diagnosis in patients ≤18 years and (2) propose guidelines for breast imaging and biopsy in this population. MATERIALS AND METHODS: We extracted data for all patients ≤18 who, between 2004 and 2016, underwent either (a) imaging and/or intervention procedure, or (b) breast surgery, from the Radiology Information System and Pathology Data System, respectively. We recorded age, gender, imaging, procedure, lesion size and histopathology. RESULTS: We found 1,050 pediatric patients ≤18 years who underwent diagnostic breast ultrasound between 2004 and 2016. Of these, 168 patients underwent 199 interventional procedures. One hundred thirty patients underwent 160 core biopsies of solid lesions. Core biopsy pathology diagnosed benign lesions in 99%, of which 84.3% were fibroadenomas (n=135). One malignancy was diagnosed, B cell lymphoma. Two hundred three patients underwent surgical excision for 266 discrete lesions, and 89% were fibroadenomas. Seven benign phyllodes tumors were surgically diagnosed. No malignancies were diagnosed. CONCLUSION: Core biopsy in patients 18 years and younger is well-tolerated, has few risks, and is preferable to surgery in developing breasts, but the goal is to avoid any breast procedure whenever possible. We propose guidelines for pediatric breast imaging, follow-up, core biopsy and excisions.

Effect of cationic ionophore monensin on the lipid composition and fluidity of rat epididymal spermatozoal membrane.

The present study was aimed at exploring the effect of monensin, an antibiotic carboxylic polyether ionophore specific for Na(+), on the structural, chemical, and physiological changes of the epididymal sperm of Wistar rats. Animals received monensin at the dose of 3.5 mg/kg body weight daily orally for 70 days, a treatment duration that corresponds to the spermatogenic cycle in rats. At the end of the treatment regime, three regions of the epididymis were separated and the spermatozoa were collected. The plasma membranes of the spermatozoa were isolated and lipid composition, such total lipid, phospholipid, cholesterol, and ganglioside-sialic acid, was studied. Membrane dynamic behavior was investigated by lipid translational fluidity by pyrene excimer formation and rotational diffusion by diphenyl hexatriene polarization and anisotropy parameter. Structural changes in membrane were also evaluated by the dye-binding study with anilino naphthalene sulphonic acid. The results showed marked changes in lipid compositions, fluidity parameters, and kinetics of fluorescent dye binding in the epididymis, and it can be concluded that monensin, by interfering with normal physiological changes in spermatozoal maturation, may provide the basis of certain molecular intervention in the fertilizing capability of the epididymal spermatozoa and thereby may induce antifertility properties in male rats.

BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFß Signaling to Durably Suppress Tumor Growth.

The EGFR and TGFß signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFß could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFßRII. The TGFß "trap" fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGFß by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer-cell activation, while suppressing VEGF secretion. In addition, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFß "trap." TGFß in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFßRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR-expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy. SIGNIFICANCE: The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFß to induce immune activation and to suppress tumor growth.

Innovation in cancer therapeutics and regulatory perspectives.

Cancer therapy has undergone a drastic revolution in the past few decades with the introduction of several novel therapies, like immunotherapy (active and passive), stem cell-based therapies, and nanocarrier-based therapies. These therapies have addressed the issues of conventional cancer therapy (chemotherapy or radiotherapy), like specificity and off-target effects. Further, the introduction of such treatments has improved survival and converted a terminal disease into a more manageable condition. However, many clinical, ethical, and regulatory issues are raised with such novel additions. Several effective therapies are under research but could not come to market or are delayed due to regulatory concerns for marketing approval. The scope of this review encompasses the examination of these regulatory issues and discuss their possible solutions. A practical and flexible regulatory approach, harmonized globally, could help the patients suffering from a terminal illness to lead a quality life.

The cyclooxygenase-2 inhibitor etoricoxib is a potent chemopreventive agent of colon carcinogenesis in the rat model.

Cyclooxygenase-2 (COX-2), an inducible prostaglandin G/H synthase, is overexpressed in several human cancers, including colon cancer, and therefore the potential ability of a selective COX-2 inhibitor, etoricoxib, is considered in the prevention of the 1,2-dimethyl hydrazine (DMH)-induced colon carcinogenesis in the rat model. DMH was injected s.c. for 6 weeks, whereas etoricoxib was fed orally to the rats on a daily basis. The results showed that DMH produced a very high number of multiple plaque lesions (MPLs), putative neoplastic biomarkers, localized throughout the colon, whereas considerable regression was observed with etoricoxib treatment. In addition, the etoricoxib group was the only group that exhibited very few of these lesions. Histopathological analysis revealed extreme dysplasia, a few adenomas, and other carcinogenic changes in the DMH group, which are distinctly absent in the etoricoxib-treated group. COX-2 was also seen to be highly expressed following DMH treatment. The DMH treatment caused very few apoptotic cells, as determined by the TUNEL assay of the colonic mucosa in paraffin sections whose number greatly increased following etoricoxib treatment. Because all these changes were clearly reversed by etoricoxib in DMH-treated animals, and the use of etoricoxib alone did not produce a neoplastic effect per se, it appears that etoricoxib, a selective COX-2 inhibitor, might be a safe and potentially chemopreventive agent in colon cancer.

Oxidative effects of Na+--specific ionophore monensin on the rat epididymis.

The carboxylic antibiotic ionophore monensin is well-known for the Na+/H+ exchanger activity across the biological membranes. The current study has been designed to investigate the effect of monensin on spermatozoal concentration, motility, and oxidative stress-related parameters in the rat epididymis. Monensin was administered orally at a dose of 3.5 mg/kg body weight daily for 70 days, a duration that coincides with the completion of the spermatogenic cycle. At the end of the respective treatment, the epididymis was isolated into three separate regions--the capitum, corpus, and the cauda--successively away from the head of the testis. Marked changes were noted in the body weight, organ (epididymis) weight, sperm concentration and motility, as well as the morphologic observations of the sperm and the histologic architecture of the epididymal epithelium. Significant alterations were also recorded in the oxidative stress parameters such as the lipid peroxidation product, malonyldialdehyde, and the activity of superoxide dismutase, glutathione sulfotransferase, glutathione reductase, and catalase. The nonenzymatic thiol content such as the total, oxidized, and reduced glutathione showed significant changes and the tissue phosphatases such as alkaline and acid phosphatase were increased, indicative of the interference of the drug in lysosomal and Golgi membrane complex. The findings of the current study indicate interactions during the spermatozoal maturational process in the epididymis, and a significant potential use of monensin in male contraception may be suggested.