Guy Storme

Activated macrophages as a novel determinant of tumor cell radioresponse: the role of nitric oxide-mediated inhibition of cellular respiration and oxygen sparing

PURPOSEnNitric oxide (NO), synthesized by the inducible nitric oxide synthase (iNOS), is known to inhibit metabolic oxygen consumption because of interference with mitochondrial respiratory activity. This study examined whether activation of iNOS (a) directly in tumor cells or (b) in bystander macrophages may improve radioresponse through sparing of oxygen.nnnMETHODS AND MATERIALSnEMT-6 tumor cells and RAW 264.7 macrophages were exposed to bacterial lipopolysaccharide plus interferon-gamma, and examined for iNOS expression by reverse transcription polymerase chain reaction, Western blotting and enzymatic activity. Tumor cells alone, or combined with macrophages were subjected to metabolic hypoxia and analyzed for radiosensitivity by clonogenic assay, and for oxygen consumption by electron paramagnetic resonance and a Clark-type electrode.nnnRESULTSnBoth tumor cells and macrophages displayed a coherent picture of iNOS induction at transcriptional/translational levels and NO/nitrite production, whereas macrophages showed also co-induction of the inducible heme oxygenase-1, which is associated with carbon monoxide (CO) and bilirubin production. Activation of iNOS in tumor cells resulted in a profound oxygen sparing and a 2.3-fold radiosensitization. Bystander NO-producing, but not CO-producing, macrophages were able to block oxygen consumption by 1.9-fold and to radiosensitize tumor cells by 2.2-fold. Both effects could be neutralized by aminoguanidine, a metabolic iNOS inhibitor. An improved radioresponse was clearly observed at macrophages to tumor cells ratios ranging between 1:16 to 1:1.nnnCONCLUSIONSnOur study is the first, as far as we are aware, to provide evidence that iNOS may induce radiosensitization through oxygen sparing, and illuminates NO-producing macrophages as a novel determinant of tumor cell radioresponse within the hypoxic tumor microenvironment.

Early Contralateral Shoulder-Arm Morbidity in Breast Cancer Patients Enrolled in a Randomized Trial of Post-Surgery Radiation Therapy:

Introduction Shoulder/arm morbidity is a common complication of breast cancer surgery and radiotherapy (RT), but little is known about acute contralateral morbidity. Methods Patients were 118 women enrolled in a RT trial. Arm volume and shoulder mobility were assessed before and 1–3 months after RT. Correlations and linear regression were used to analyze changes affecting ipsilateral and contralateral arms, and changes affecting relative interlimb differences (RID). Results Changes affecting one limb correlated with changes affecting the other limb. Arm volume between the two limbs correlated (R = 0.57). Risk factors were weight increase and axillary dissection. Contralateral and ipsilateral loss of abduction strongly correlated (R = 0.78). Changes of combined RID exceeding 10% affected the ipsilateral limb in 25% of patients, and the contralateral limb in 18%. Aromatase inhibitor therapy was significantly associated with contralateral loss of abduction. Conclusions High incidence of early contralateral arm morbidity warrants further investigations.

In vivo Estimation of Extracranial Doses in Stereotactic Radiosurgery with the Gamma Knife and Novalis Systems

Objective: The purpose of this work is to investigate the extracranial doses in vivo during nintracranial treatments comparing the Gamma Knife system with the Novalis system for nidentical pathologies

The creation of a radiotherapy archive using Internet technology

The electronic patient dataflow in a radiotherapy department is quite complicated. The main purpose of the computer network within the radiotherapy department is the sharing of computing resources and information (e.g. CT images, electronic portal images, isodose maps etc.). The Intranet is also used to facilitate working in groups (e.g. staff meetings). It uses TCP/IP, HTTP, and other Internet protocols and in general looks like a private version of the Internet. The purpose of this study was to create an easily accessible radiotherapy archive using Internet technology.

Impact of Management Changes on Loco-Regional Control of Breast Carcinoma: A 30-year Single Institution Experience Breast Cancer: Basic and Clinical Research

Purpose: This institutional-based study aims to reflect changes in diagnosis, surgery, radiotherapy, systemic therapy by retrospectively analysing treatment modalities and outcome during the past 30 years of breast cancer. We hypothesized these changes result in better outcome. nMaterial and methods: 2990 women are included, aged 18–95, no previous cancer, unilateral stage I-III primary breast tumors, breast-conserving surgery (BCS) or mastectomy (ME), postoperative radiotherapy (RT) and where indicated systemic treatment. Patients were divided in 3 cohorts stratified by year of diagnosis: 1984-1991, 1992- 1999 and 2000-2008. The interval of cohorts was based on institutional changes in systemic regimens. nResults: Over time, median age at diagnosis was similar, patients >70 year increased (19.5 to 25.7%). Over the 3 cohorts: stage migration is observed, determination of tumor grading became routine, proportions of known ER/PR status increased. Over time an obvious shift to less mutilating surgery is observed. Systemic treatment increased significantly during the observed period. In stage I disease, overall (OS), local control (LC) and disease free survival (DFS) didn’t change. In stage II, a significant increase in 10 years OS and DFS (p= 0.02 and 0.001) is observed. In stage III we noticed a significant increase in 10 years DFS (p=0.04) and trend in increase of 10 years OS (p= 0.06). Local Recurrence free survival (RFS) didn’t change significantly for all stages. nConclusion: This study demonstrated an improved outcome for stage II and III over time in our population with the same local control. This is multifactorial, reflecting changes in diagnostic imaging, surgery and increased use of systemic therapy.