E.P. Connolly

Hypoxia Inhibits Protein Synthesis through a 4E-BP1 and Elongation Factor 2 Kinase Pathway Controlled by mTOR and Uncoupled in Breast Cancer Cells

ABSTRACT Hypoxia is a state of low oxygen availability that limits tumor growth. The mechanism of protein synthesis inhibition by hypoxia and its circumvention by transformation are not well understood. Hypoxic breast epithelial cells are shown to downregulate protein synthesis by inhibition of the kinase mTOR, which suppresses mRNA translation through a novel mechanism mitigated in transformed cells: disruption of proteasome-targeted degradation of eukaryotic elongation factor 2 (eEF2) kinase and activation of the regulatory protein 4E-BP1. In transformed breast epithelial cells under hypoxia, the mTOR and S6 kinases are constitutively activated and the mTOR negative regulator tuberous sclerosis complex 2 (TSC2) protein fails to function. Gene silencing of 4E-BP1 and eEF2 kinase or TSC2 confers resistance to hypoxia inhibition of protein synthesis in immortalized breast epithelial cells. Breast cancer cells therefore acquire resistance to hypoxia by uncoupling oxygen-responsive signaling pathways from mTOR function, eliminating inhibition of protein synthesis mediated by 4E-BP1 and eEF2.

Secretory carcinoma of the breast: Results from the survival, epidemiology and end results database

BACKGROUND Secretory carcinoma of the breast is a rare breast cancer that is associated with incidence at a young age and an indolent course. The role for breast conservation and adjuvant radiation is unknown. METHODS The SEER database was reviewed and 83 patients were identified with secretory carcinoma of the breast between the years 1983 and 2007. Baseline characteristics were compared with χ(2) or Fishers exact test. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan-Meier method. Analyses were performed using PASW Statistics, version 18. RESULTS Median follow-up was 70 months. Median patient age was 53 years (range 11-86 years). 29 patients (34.9%) had involved regional lymph nodes. 39 patients (47.0%) underwent lumpectomy and 44 patients (53.0%) underwent mastectomy. 35 patients (42.2%) received radiation. Patients receiving radiation were more likely to have undergone lumpectomy, and the use of radiation increased over time. 5-year OS was 87.2%; 10-year OS was 76.5%. 5-year CSS was 94.4%; 10-year CSS was 91.4%. Among the lumpectomy patients, 25 patients (64.1%) received radiation. For lumpectomy patients, those who did not receive radiation had a 5-year OS of 92.9% and 10-year OS of 72.2% while patients who did receive radiation had a 5-year OS of 95.5% and 10-year OS of 85.9%. Only 1 patient treated with lumpectomy only died of cancer (92.9% CSS) and no patients treated with lumpectomy and radiation died of cancer (100% CSS). CONCLUSIONS Secretory carcinoma of the breast commonly occurs at a later age than previously recognized, and is associated with good long-term survival.

Involved field radiation therapy after surgical resection of solitary brain metastases—mature results

BACKGROUND Whole brain radiation therapy (WBRT) reduces local recurrence in patients after surgical resection of brain metastases without improving overall survival. Involved field radiation therapy (IFRT) has been used at our center to avoid delayed neurotoxicity associated with WBRT in well-selected patients with surgically resected single brain metastases. The purpose of this study was to evaluate the long-term outcomes of these patients. METHODS Thirty-three consecutive patients with single brain metastases from a known primary tumor were treated with gross total resection followed by IFRT between 2006 and 2011. The postoperative surgical bed was treated to 40.05 Gy in 15 fractions of 2.67 Gy with conformal radiation therapy. Patients received serial MRIs and neurological exams in follow-up. Surgery, WBRT, or stereotactic radiosurgery was performed as salvage treatment when necessary. RESULTS The median follow-up was 16 months (range: 2-65 months). Local control, distant brain recurrence-free survival, and overall survival at 12 and 24 months were 90.3% and 85.8%, 60.7% and 51.4%, and 65.6% and 61.5%, respectively. Overall, 5 (15%) patients developed recurrence at the resection cavity, and 13 (39%) patients experienced recurrence at a new intracranial site. Two patients received WBRT, 8 stereotactic radiosurgery, 2 surgery, and 2 both chemotherapy and IFRT as salvage. Four patients died from CNS disease progression. CONCLUSION For patients with newly diagnosed single brain metastases treated with surgical resection, postoperative IFRT to the resection cavity achieves reasonable rates of local control and is an excellent alternative to WBRT.

Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma

Abstract We describe the clinical course of a recurrent case of congenital fibrosarcoma diagnosed in a 9-mo-old boy with a history of hemimelia. Following complete surgical resection of the primary tumor, the patient subsequently presented with bulky bilateral pulmonary metastases 6 mo following surgery. Molecular characterization of the tumor revealed the absence of the prototypical ETV6-NTRK3 translocation. However, tumor characterization incorporating cytogenetic, array comparative genomic hybridization, and RNA sequencing analyses, revealed a somatic t(2;15)(2p21;15q25) translocation resulting in the novel fusion of EML4 with NTRK3. Cloning and expression of EML4-NTRK3 in murine fibroblast NIH 3T3 cells revealed a potent tumorigenic phenotype as assessed in vitro and in vivo. These results demonstrate that multiple fusion partners targeting NTRK3 can contribute to the development of congenital fibrosarcoma.

Hypofractionated Radiation Therapy for Early Stage Breast Cancer: Outcomes, Toxicities, and Cost Analysis

A French prospective randomized trial comparing whole breast radiotherapy with 45 Gy in 25 fractions versus 23 Gy in four fractions demonstrated equivalent 5‐year local control and survival. On the basis of this data, we offer the hypofractionated regimen to women who refuse to undergo standard radiotherapy. We report our outcomes and a cost analysis. Between 2000 and 2012, 84 patients participated in this IRB‐approved study and underwent whole breast radiation to 23 Gy in four fractions. Local control and survival were analyzed using the Kaplan–Meier method. Acute toxicities and overall long‐term cosmetic results were assessed. Costs were estimated from 2012 Medicare reimbursement data and compared to costs from standard courses of 25 and 16 fractions. All 84 patients are included in this report. Median age was 83 (range 42–98). Most patients had stage I (80%), hormone receptor positive (90%) breast cancer. Fifty‐eight patients (69%) were treated prone and 26 (31%) supine. At a median follow‐up of 3 years, one local recurrence has occurred, of ductal carcinoma in situ histology. Among the 13 patients deceased, two died of metastatic breast cancer. Five‐year actuarial local control is 99%, breast cancer‐specific survival is 98%, and overall survival is 79%. Toxicities were limited to grade 1 dermatitis in 32 patients (38%) and grade 2 fatigue in three (4%). Sixty‐three patients (75%) reported good or excellent cosmetic outcome at their last follow‐up. Collected Medicare reimbursement was

Inhibition of Cap-initiation complexes linked to a novel mechanism of eIF4G depletion in acute myocardial ischemia

4,798 for the hypofractionated course. Compared to the projected reimbursement of standard regimens,

mTORC1 and 2 coordinate transcriptional and translational reprogramming in resistance to DNA damage and replicative stress in breast cancer cells.

10,372 for 25 fractions and

The Role of Definitive Radiotherapy in Craniopharyngioma: A Seer Analysis

8,382 for 16 fractions, it resulted in a difference of

High-Dose, Single-Fraction Irradiation Rapidly Reduces Tumor Vasculature and Perfusion in a Xenograft Model of Neuroblastoma

5,574 and

Breast cancer subtype and stage are prognostic of time from breast cancer diagnosis to brain metastasis development

3,584, respectively. At a follow‐up of 3 years, this hypofractionated regimen appears to be a promising approach, primarily for elderly women who are unable to undergo longer treatment courses but have indications for whole breast radiotherapy.