A majority of breast cancers are driven by estrogen via estrogen receptor-α (ERα). Our previous studies indicate that hypoxia-inducible factor 1α (HIF-1α) cooperates with ERα in breast cancer cells. However, whether ERα is implicated in the direct regulation of HIF-1α and the role of HIF-1α in endocrine therapy response are unknown. In this study we found that a subpopulation of HIF-1α targets, many of them bearing both hypoxia response elements and estrogen response elements, are regulated by ERα in normoxia and hypoxia. Interestingly, the HIF-1α gene itself also bears an estrogen response element, and its expression is directly regulated by ERα. Clinical data revealed that expression of the HIF-1α gene or a hypoxia metagene signature is associated with a poor outcome to endocrine treatment in ERα + breast cancer. HIF-1α was able to confer endocrine therapy resistance to ERα + breast cancer cells. Our findings define, for the first time to our knowledge, a direct regulatory pathway between ERα and HIF-1α, which might modulate hormone response in treatment.ERα | HIF-1α | tamoxifen
Histone lysine demethylases facilitate the activity of oncogenic transcription factors including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells where MYC is often overexpressed. We also identified the approved small molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC targeting approach for cancer therapy.
Purpose Antiangiogenic agents show significant antitumor activity against various tumor types. In a study evaluating the combination of sorafenib, bevacizumab, and low-dose cyclophosphamide in children with solid tumors, an unexpectedly high incidence of pneumothorax was observed. We evaluated patient characteristics and risk factors for the development of pneumothorax in patients receiving this therapy. Patients and Methods Demographics, clinical course, and radiographic data of 44 patients treated with sorafenib, bevacizumab and cyclophosphamide were reviewed. Risk factors associated with the development of pneumothorax were analyzed. Results Pneumothorax likely related to study therapy developed in 11 of 44 (25%) patients of whom 33 had pulmonary abnormalities. Median age of patients was 14.7 years (range, 1.08–24.5). Histologies associated with pneumothorax included rhabdoid tumor, synovial sarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, and renal cell carcinoma. Cavitation of pulmonary nodules in response to therapy was associated with pneumothorax development (P<0.001). Median time from start of therapy to development of pneumothorax was 5.7 weeks (range, 2.4–31). Conclusion The development of cavitary pulmonary nodules in response to therapy is a risk factor for pneumothorax. As pneumothorax is a potentially life-threatening complication of antiangiogenic therapy in children with solid tumors, its risk needs to be evaluated when considering this therapy.
Objectives Wilms tumor (WT) is the most common renal cancer in children. Approximately 5% of children with WT present with disease in both kidneys. The treatment challenge is to achieve a high cure rate while maintaining long-term renal function. We retrospectively reviewed our institutional experience with nephron-sparing surgery (NSS) in patients with synchronous bilateral Wilms tumor (BWT) operated on between 2001-2014. Methods Imaging studies, surgical approach, adjuvant therapy and pathology reports were reviewed. Outcomes evaluated included surgical complications, tumor recurrence, patient survival and renal function, as assessed by estimated glomerular filtration rate (eGFR). Results Forty-two patients with BWT were identified. Thirty-nine (92.9%) patients underwent bilateral NSS; only three patients (7.1%) underwent unilateral nephrectomy with contralateral NSS. Post-operative complications included prolonged urine leak (10), infection (6), intussusception (2) and transient renal insufficiency (1). Three patients required early (within four months) repeat NSS for residual tumor. Long-term, seven (16.7%) patients had local tumor recurrence (managed with repeat NSS in 6 and completion nephrectomy in 1) and three had an episode of intestinal obstruction requiring surgical intervention. Overall survival was 85.7% (mean follow-up, 4.1 years). Of the 6 patients who died, 5 had diffuse anaplastic histology. All patients had an eGFR>60mL/min/1.73m2 at last follow-up; no patient developed end-stage renal disease. Conclusions In patients with synchronous, bilateral Wilms tumor, bilateral nephron-sparing surgery is safe and almost always feasible, there by preserving maximal renal parenchyma. With this approach, survival was excellent, as was maintenance of renal function.
Background. Mesenchymal chondrosarcoma is an aggressive, uncommon histologic entity arising in bone and soft tissues. We reviewed our institutional experience with this rare diagnosis. Methods. We conducted a retrospective chart review on patients with mesenchymal chondrosarcoma over a 24-year period. Clinicopathologic and radiographic features were reviewed. Results. Twelve patients were identified. Nine were females; median age was 14.5 years (1.2–19.7 years). The most common site was the head/neck (7/12). Disease was localized in 11/12 patients (one with lung nodules). Six with available tissue demonstrated NCOA2 rearrangement by FISH. Six underwent upfront surgical resection, and six received neoadjuvant therapy (2 chemotherapy alone and 4 chemotherapy and radiation). All patients received adjuvant chemotherapy (most commonly ifosfamide/doxorubicin) and/or radiation (median dose 59.4 Gy). At a median follow-up of 4.8 years, 5-year disease-free survival and overall survival were 68.2% (95% CI 39.8%, 96.6%) and 88.9% (95% CI 66.9%, 100%). Two patients had distant recurrences at 15 and 42 months, respectively. Conclusion. Aggressive surgical resection of mesenchymal chondrosarcoma with chemoradiotherapy yields excellent local control and may reduce likelihood of late recurrence. Characterization of downstream targets of the HEY1-NCOA2 fusion protein, xenograft models, and drug screening are needed to identify novel therapeutic strategies.
Purpose Partial nephrectomy is being considered by some for children with unilateral Wilms tumor (UWT) to avoid the theoretical complication of renal insufficiency. We evaluated the prevalence of hypertension and impaired renal function in long-term survivors of non-syndromic UWT treated without nephrotoxic chemotherapy or ionizing radiation. Patients and Methods Eligibility included: age ≤15 years at diagnosis of non-syndromic UWT, treatment prior to 2002 and maintenance of remission following unilateral nephrectomy without abdominal irradiation or nephrotoxic chemotherapy. Renal function was assessed by urinalysis and estimated glomerular filtration rate (eGFR). Patients on anti-hypertensive medication or with blood pressure >140/90mmHg were defined as hypertensive. Results Seventy-five patients with median age at diagnosis of 3.2 (range: 0.2-12.1) years met eligibility criteria. The median length of follow-up was 19.6 (range: 10.0-32.8) years. All but one patient had stage 1/2 disease. Sixty-eight (90.7%) patients had favorable histology WT; seven had anaplastic histology. Sixteen (21.3%) patients had an eGFR <90 ml/min/1.73m2, two of whom also had proteinuria (12.5%). No patient had an eGFR<60 ml/min/1.73m2. Five (6.7%) patients had hypertension, three of whom were taking anti-hypertensive medications. No patient has developed end-stage renal disease. Conclusions Patients with UWT treated with unilateral radical nephrectomy without nephrotoxic chemotherapy or ionizing radiation are at low risk for significant long-term renal dysfunction. For this patient population, routine use of partial nephrectomy does not appear justified. However, monitoring and counseling are important for identifying the rare patient who develops subtle renal insufficiency and so might be at increased risk for adverse cardiovascular sequelae.
Malignant glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal), which may arise from different glioblastoma stem-like cell (GSC) populations. We previously showed that adherent cultures of GSCs grown on laminin-coated plates (Ad-GSCs) and spheroid cultures of GSCs (Sp-GSCs) had high expression of stem cell markers (CD133, Sox2 and Nestin), but low expression of differentiation markers (βIII-tubulin and glial fibrillary acid protein). In the present study, we characterized GBM tumors produced by subcutaneous and intracranial injection of Ad-GSCs and Sp-GSCs isolated from a patient-derived xenoline. Although they formed tumors with identical histological features, gene expression analysis revealed that xenografts of Sp-GSCs had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of Ad-GSCs expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression, and enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Therefore, Ad-GSCs and Sp-GSCs produced histologically identical tumors with different gene expression patterns, and a STAT3/ANGPTL4 pathway is identified in glioblastoma that may serve as a target for therapeutic intervention.
Background Osteosarcoma (OS) and the Ewing sarcoma family of tumors (ESFT) are the most common primary pediatric bone malignancies. We sought to assess the diagnostic accuracy of initial tumor biopsies in patients with OS or ESFT at a pediatric cancer center. Methods All biopsies performed at initial presentation of patients with OS or ESFT at our institution from 2003 to 2012 were retrospectively reviewed. Diagnostic accuracy and incidence of complications were correlated with study variables using logistic regression analysis. Results One hundred forty-two biopsies were performed in 105 patients (median age 13.4 years, range: 1.8-23.0), 104 (73.2%) OS and 38 (27.8%) ESFT. Thirty-one (21.8%) were performed on metastatic sites. Eighty-five (76.6%) of 111 primary site biopsies were open procedures, and 26 were percutaneous (23.4%). Primary site biopsies were successful in 94.1% of open and 73.1% of percutaneous procedures. Odds of obtaining a successful diagnostic specimen were 7.8 times higher with open approach (CI: 1.6-36.8). Metastatic site biopsies were successful in 66.7% of percutaneous and 100% of open and thoracoscopic procedures. Conclusion Biopsy of metastatic sites was equal to primary site in obtaining diagnostic material with the added benefit of accurate staging, with few adverse events and high diagnostic yield.
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