FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4.

Cancer cells re-program normal lung endothelial cells (EC) into tumor-associated endothelial cells (TEC) that form leaky vessels supporting carcinogenesis. Transcriptional regulators that control the reprogramming of EC into TEC are poorly understood. We identified Forkhead box F1 (FOXF1) as a critical regulator of EC-to-TEC transition. FOXF1 was highly expressed in normal lung vasculature but was decreased in TEC within non-small cell lung cancers (NSCLC). Low FOXF1 correlated with poor overall survival of NSCLC patients. In mice, endothelial-specific deletion of FOXF1 decreased pericyte coverage, increased vessel permeability and hypoxia, and promoted lung tumor growth and metastasis. Endothelial-specific overexpression of FOXF1 normalized tumor vessels and inhibited the progression of lung cancer. FOXF1 deficiency decreased Wnt/ß-catenin signaling in TECs through direct transcriptional activation of Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs through endothelial-specific nanoparticle delivery of Fzd4 cDNA rescued Wnt/ß-catenin signaling in TECs, normalized tumor vessels and inhibited the progression of lung cancer. Altogether, FOXF1 increases tumor vessel stability, and inhibits lung cancer progression by stimulating FZD4/Wnt/ß-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has promise for future therapies in NSCLC.

The Promise of Combination Therapies with FOXM1 Inhibitors for Cancer Treatment.

Forkhead box M1 (FOXM1) is a transcription factor in the forkhead (FOX) family, which is required for cellular proliferation in normal and neoplastic cells. FOXM1 is highly expressed in many different cancers, and its expression is associated with a higher tumor stage and worse patient-related outcomes. Abnormally high expression of FOXM1 in cancers compared to normal tissue makes FOXM1 an attractive target for pharmacological inhibition. FOXM1-inhibiting agents and specific FOXM1-targeted small-molecule inhibitors have been developed in the lab and some of them have shown promising efficacy and safety profiles in mouse models. While the future goal is to translate FOXM1 inhibitors to clinical trials, potential synergistic drug combinations can maximize anti-tumor efficacy while minimizing off-target side effects. Hence, we discuss the rationale and efficacy of all previously studied drug combinations with FOXM1 inhibitors for cancer therapies.

Strategies for the Treatment of Infantile Soft Tissue Sarcomas With BCOR Alterations.

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a "hybrid morphology" in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.

Chemotherapy-induced thrombocytopenia in Ewing sarcoma: Implications and potential for romiplostim supportive care.

BACKGROUND: Maintaining dose-dense, interval-compressed chemotherapy improves survival in patients with Ewing sarcoma but is limited by myelosuppression. Romiplostim is a thrombopoietin receptor agonist that may be useful in the treatment of chemotherapy-induced thrombocytopenia (CIT). METHODS: Patients aged between 3 and 33 years with Ewing sarcoma from 2010 to 2020 were reviewed. CIT was defined as a failure to achieve 75,000 platelets per microliter by day 21 after the start of any chemotherapy cycle. Fisher's exact test was used for univariate analysis and Pearson's correlation coefficient was used for the association between continuous variables. RESULTS: Twenty-seven out of 42 patients (64%) developed isolated CIT, delaying one to four chemotherapy cycles per patient. CIT occurred during consolidation therapy in 24/27(88.9%) and with ifosfamide/etoposide cycles in 24/27 (88.9%). Univariate analysis failed to identify risk factors for CIT. The use of radiation approached significance (p-value = .056). Ten patients received romiplostim. The median starting dose was 3 µg/kg (range 1-5). Doses were escalated weekly by 1-2 to 4-10 µg/kg and continued throughout chemotherapy. A higher romiplostim dose was associated with a higher change in average platelet counts from baseline, r = .73 (p = .04). No romiplostim-related adverse events were identified aside from mild headache. CONCLUSIONS: CIT is the primary reason for the inability to maintain treatment intensity in Ewing sarcoma. The concurrent use of romiplostim with chemotherapy was safe and feasible, and efficacy was associated with higher romiplostim doses.

The impact on the exclusive breastfeeding rate at 6 months of life of introducing supplementary donor milk into the level 1 newborn nursery.

OBJECTIVES: This study explored whether donor-milk supplementation increases breastfeeding exclusivity at 6 months of life. In 10/2015, we implemented donor milk for breastfed newborns who needed nutritional supplements for hypoglycemia, hyperbilirubinemia, and >8% weight loss at 40 h of life. STUDY DESIGN: We conducted a retrospective chart review on 122 qualified neonates admitted to newborn nursery at University of Florida Jacksonville 4 months before donor-milk implementation and 6 months after. RESULTS: 73 (60%) of the neonates received formula and 49 (40%) received donor milk. 39 (54%) in the formula group and 33 (46%) in the donor-milk group were surveyed after 6 months of life. Multivariate logistic regression showed that newborns who received donor milk had five times greater odds of being exclusively breastfed at 6 months of life. CONCLUSIONS: Donor milk as feeding supplementation for newborns is associated with increased exclusive breastfeeding at 6 months of life.