Karen Drumea

Radiogenomics: Radiobiology enters the era of big data and team science

Reprint requests to: Barry S. Rosenstein,PhD, Department of RadiationOncology, Icahn School of Medicine at Mount Sinai, One Gustave L. LevyPlace, Box 1236, New York, NY 10029. Tel: (212) 824-8960; E-mail:barry.rosenstein@mssm.eduSupported by grants from the National Institutes of Health and theDepartment of Defense (1R01CA134444 and PC074201 to B.S.R. andH.O.), the American Cancer Society (RSGT-05-200-01-CCE to B.S.R.),the Instituto de Salud Carlos III (FIS PI10/00164 and PI13/02030 to A.V.),Fondo Europeo de Desarrollo Regional (FEDER 2007e2013) in Spain, aMiguel Servet contract from the Spanish Carlos III Health Institute (CP10/00617 to S.G.-E.), and in the UK by Cancer Research UK.Conflict of interest: E.Y. Chuang holds a patent on biomarkers forpredicting response of esophageal cancer patients to chemoradiationtherapy. The authors report no other conflict of interest.Int J Radiation Oncol Biol Phys, Vol. 89, No. 4, pp. 709e713, 20140360-3016/

GABP Transcription Factor (Nuclear Respiratory Factor 2) is Required for Mitochondrial Biogenesis

- see front matter 2014 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.ijrobp.2014.03.009

GABP transcription factor is required for myeloid differentiation, in part, through its control of Gfi-1 expression.

ABSTRACT Mitochondria are membrane-bound cytoplasmic organelles that serve as the major source of ATP production in eukaryotic cells. GABP (also known as nuclear respiratory factor 2) is a nuclear E26 transformation-specific transcription factor (ETS) that binds and activates mitochondrial genes that are required for electron transport and oxidative phosphorylation. We conditionally deleted Gabpa, the DNA-binding component of this transcription factor complex, from mouse embryonic fibroblasts (MEFs) to examine the role of Gabp in mitochondrial biogenesis, function, and gene expression. Gabpα loss modestly reduced mitochondrial mass, ATP production, oxygen consumption, and mitochondrial protein synthesis but did not alter mitochondrial morphology, membrane potential, apoptosis, or the expression of several genes that were previously reported to be GABP targets. However, the expression of Tfb1m, a methyltransferase that modifies ribosomal rRNA and is required for mitochondrial protein translation, was markedly reduced in Gabpα-null MEFs. We conclude that Gabp regulates Tfb1m expression and plays an essential, nonredundant role in mitochondrial biogenesis.

Retinoic acid signaling in myelopoiesis

GABP is an ets transcription factor that regulates genes that are required for myeloid differentiation. The tetrameric GABP complex includes GABPα, which binds DNA via its ets domain, and GABPβ, which contains the transcription activation domain. To examine the role of GABP in myeloid differentiation, we generated mice in which Gabpa can be conditionally deleted in hematopoietic tissues. Gabpa knockout mice rapidly lost myeloid cells, and residual myeloid cells were dysplastic and immunophenotypically abnormal. Bone marrow transplantation demonstrated that Gabpα null cells could not contribute to the myeloid compartment because of cell intrinsic defects. Disruption of Gabpa was associated with a marked reduction in myeloid progenitor cells, and Gabpα null myeloid cells express reduced levels of the transcriptional repressor, Gfi-1. Gabp bound and activated the Gfi1 promoter, and transduction of Gabpa knockout bone marrow with Gfi1 partially rescued defects in myeloid colony formation and myeloid differentiation. We conclude that Gabp is required for myeloid differentiation due, in part, to its regulation of the tran-scriptional repressor Gfi-1.

ATM heterozygosity and breast cancer: screening of 37 breast cancer patients for ATM mutations using a non-isotopic RNase cleavage-based assay

Purpose of reviewFor decades, retinoic acid has been known to alter the proliferation and differentiation of myeloid cells. Currently, retinoic acid is a front-line agent in the treatment of certain forms of acute myelogenous leukemia. In this review, we focus on recent advances in our understanding of the mechanisms by which retinoids affect growth and proliferation of myeloid cells and contribute to the pathogenesis of leukemia. We have not attempted to summarize the related clinical literature. Recent findingsThe past 2 years have yielded important understanding of the mechanisms by which retinoids and their nuclear receptors interact with other signal transduction pathways and transcription factors to modify chromatin, alter gene expression, and participate in normal myeloid differentiation and leukemogenesis. Important advances regarding cell biology, molecular biology, biochemistry, and animal studies of retinoids and myeloid differentiation are reviewed. SummaryGreater understanding of the role of retinoids and their receptors in myeloid cell growth and differentiation provides important insight into normal myelopoiesis. These findings have resulted in successful rational approaches to the treatment of acute leukemia and provide the promise of improved treatments in the near future.

Cancer-related fatigue and depression in breast cancer patients postchemotherapy: Different associations with optimism and stress appraisals—CORRIGENDUM

Based upon the results of several epidemiologic studies, it has been suggested that women who are carriers for a mutation in the ataxia telangiectasia-mutated (ATM) gene are susceptible for the development of breast cancer. Therefore, 37 consecutive breast cancer patients were screened for the presence of a germline ATM mutation using a non-isotopic RNase cleavage-based assay (NIRCA). This paper reports the first use of NIRCA for detection of ATM mutations in breast cancer patients. Using this assay, no ATM mutations were found in our patient population. This result is similar to the findings of other studies that have employed approaches complementary to NIRCA.

Chemoimmunohormonal therapy with carmustine, dacarbazine, cisplatin, tamoxifen, and interferon for metastatic melanoma: a prospective phase II study.

OBJECTIVE Symptoms of depression and cancer-related fatigue (CRF) are common among breast cancer patients postchemotherapy and may seriously impair quality of life (QoL). This study aimed to assess the relationship between depression and CRF in breast cancer patients postchemotherapy and to examine their relationships to optimism and to threat and challenge appraisals. METHOD Participants included 95 breast cancer patients (stages 1-3) 1 to 6 months after completion of chemotherapy. Patients submitted personal and medical details and completed the following: physical symptom questionnaires (EORTC QLQ-C30, and QLQ-BR23), a symptoms of depression questionnaire (CES-D), the Fatigue Symptom Inventory (FSI), the Life Orientation Test (LOT-R), and a stress appraisals questionnaire. RESULTS We found levels of depression, CRF, and appraisals of cancer as a threat to bemoderate and levels of optimism and appraisals of cancer as a challenge to be high. Depression and CRF were positively associated. A multivariate regression analysis revealed that 51% of the CRF variancewas explained; physical symptoms and threat appraisal were significantly associated with CRF. A 67% of the CRF variance of depression was explained; challenge and threat appraisals were significantly associated with depression [corrected]. SIGNIFICANCE OF RESULTS Although CRF and depression were often experienced simultaneously and both were found to be higher among individuals who gave higher appraisals of cancer as a threat, only depression was related to optimism and challenge appraisals, while CRF was related mainly to intensity of physical symptoms. The different pattern of associations between optimism and appraisals warrants further clinical attention as well as future study.

Prospective comparison of whole-body bone SPECT and sodium 18F-fluoride PET in the detection of bone metastases from breast cancer.

The objective of this study was to investigate the efficacy of our treatment regimen in metastatic melanoma. Thirty patients entered the study after undergoing a thorough metastatic workup. Treatment protocol included carmustine (BCNU) (150 mg/m2 IV, day 1) every 6 weeks, dacarbazine (DTIC) (220 mg/m2 IV, days 1–3), and cisplatin (25 mg/m2 IV, days 1–3) every 3 weeks, interferon A-2B (6 × 106 U/m2 daily s.c. on days 4–8 and 16–20) and tamoxifen 20 mg/day for 6 weeks. Among 29 evaluable patients, overall response was seen in 15 (52%) and complete response in 5 (17%) patients. Median duration of partial response was 4 months (range, 1–12 months); of complete response was 8 months (range, 2–14 months). Complete response continues in two patients with lung metastases. Median survival time was 8.7 months. Side effects were tolerable. Four (13%) patients developed neutropenic fever, and platelet transfusions were required in five (17%) patients. One patient died of neutropenic sepsis. Thrombocytopenia caused prolongation of the median interval between the first and second courses, and drug doses were reduced in the second course in 8 of 26 (31%) patients. Our chemoimmunohormonal regimen is efficient in metastatic malignant melanoma and can induce durable remission. Severe thrombocytopenia leads to a reduction of carmustine dose in a new protocol.

Anaplastic Variant of Classical Seminoma of the Testis: Northern Israel Oncology Center Experience and Brief Review of Literature

ObjectiveThe superiority of sodium 18F-fluoride PET (18F-PET)/computed tomography (CT) over planar and single field-of-view single-photon emission computed tomography (SPECT) bone scintigraphy with 99mTc-methylene diphosphonate in bone metastases detection has been established. The present study prospectively compares whole-body 99mTc-methylene diphosphonate SPECT (WB-SPECT) and 18F-PET performance indices for the detection of bone metastases in breast cancer. MethodsA total of 41 pairs of studies in female breast cancer patients (average age 58 years, range 30–75) were included. Half-time WB-SPECT and 18F-PET/CT were performed at a 4-day average interval (range 0–36 days), with subsequent fusion of CT to WB-SPECT. Two readers independently interpreted the studies, with differences resolved by consensus. Composite gold standard included the CT component of the 18F-PET/CT study with follow-up CT, MRI, 18F-fluoro-deoxyglucose-PET/CT, and bone scans. ResultsOn patient-based analysis, metastases were diagnosed in 21 patients, with 19 patients detected by WB-SPECT and 21 with 18F-PET, the latter being the only modality to detect a single metastasis in two patients. The sensitivity of WB-SPECT and 18F-PET was 90 and 100% (P=NS), and the specificity were 95 and 85%, respectively (P=NS). On lesion-based analysis, 284 total sites of increased uptake were found. WB-SPECT detected 171/284 (60%) and 18F-PET 268/284 (94%) lesions, with good interobserver agreement for WB-SPECT (&kgr;=0.679) and excellent agreement for 18F-PET (&kgr;=0.798). The final analysis classified 204 lesions as benign and 80 as metastases. WB-SPECT identified 121 benign and 50 malignant sites compared with 192 and 76, respectively, for 18F-PET. WB-SPECT and 18F-PET had a sensitivity of 63 vs. 95%, P-value of less than 0.001, and a specificity of 97 vs. 96% (P=NS), respectively, on lesion-based analysis. Conclusion18F-PET had higher sensitivity for the diagnosis of bone metastases from breast cancer compared with WB-SPECT, showing a statistically significant 32% increase on lesion-based analysis.

Spermatocytic Variant of Classic Seminoma: A Report of Five Cases and a Brief Review of the Literature

Objectives: There are only sporadic reports on the clinical behavior and appropriate treatment of anaplastic seminoma. This retrospective study summarizes our experience with the anaplastic variant of classical (typical) seminoma. Methods: Between 1986 and 2006, seven anaplastic seminoma patients were staged and treated at the Northern Israel Oncology Center. Staging procedures included meticulous physical and neurological examinations, complete blood count, full biochemistry profile, specific tumor markers, testicular ultrasound, and other radiological measures. All patients underwent inguinal orchiectomy and were staged properly. Six patients had stage I disease, and one patient had stage IIA disease. Patients were irradiated with doses ranging from 2,500 to 3,000 cGy, and the stage IIA patient received an additional 1,000 cGy boost to radiographically involved lymph nodes. Results: After a mean follow-up of 11 years, six patients are alive with no evidence of disease. One patient died due to an unknown, non-oncological, cause, unrelated to his previous testicular tumor, while in complete remission. Conclusions: Despite the low patient numbers and the retrospective nature of our study, it can be concluded that radiotherapy treatment for early-stage anaplastic seminoma patients might achieve the same excellent survival as for classical seminoma. However, the general consensus achieved through large-scale studies suggests that active surveillance should be offered to all stage I seminoma patients, regardless of the pathologic variant.