Space Medicine: Why Do Recently Published Papers about Telomere Length Alterations Increase our Uncertainty Rather than Reduce it?

There is a growing interest in examining alterations in telomere length as a reliable biomarker of general health, as well as a marker for predicting later morbidity and mortality. Substantial evidence shows that telomere length is associated with aging; telomere shortening acts as a "counting mechanism" that drives replicative senescence by limiting the mitotic potential of normal (but not malignant) cells. In this Correspondence, we attempt to answer the question of why recently published papers about telomere length alterations increase our uncertainty rather than reduce it. This discussion includes three major research areas regarding telomere length: environmental stressors, aging, and life span. Our review suggests that activation of telomerase activity due to stressors in space might be a double-edged sword with both favorable and unfavorable consequences. The selection of an effect's consequence must clearly elucidate the experimental conditions as well as associated stressors. In this Correspondence, we attempt to answer the question of why recently published papers about telomere length alterations increase our uncertainty rather than reduce it. The selection of an effect's consequence must clearly elucidate the experimental conditions as well as associated stressors. Both positive and negative consequences must be clearly addressed in order to bolster the conclusions, as well as identify future research directions.

Vitamin D regulation of HAS2, hyaluronan synthesis and metabolism in triple negative breast cancer cells.

The vitamin D receptor (VDR) and its ligand 1,25(OH)2D3 (1,25D) exert anti-tumor effects, but considerable heterogeneity has been reported in different model systems. In general, cell lines derived from aggressive tumor subtypes such as Triple Negative Breast Cancer (TNBC) express low levels of VDR and are less sensitive to 1,25D than those derived from more differentiated tumor types. We have previously reported that 1,25D inhibits hyaluronic acid synthase 2 (HAS2) expression and hyaluronic acid (HA) synthesis in murine TNBC cells. Here we confirmed the inhibitory effect of 1,25D on HA synthesis in human Hs578T cells representative of the mesenchymal/stem-like (MSL) subtype of TNBC. Because HA synthesis requires the production of hexoses for incorporation into HA, we predicted that the high HA production characteristic of Hs578T cells would require sustained metabolic changes through the hexosamine biosynthetic pathway (HBP). We thus examined metabolic gene expression in Hs578T cell variants sorted for High (HAHigh) and Low (HALow) HA production, and the ability of 1,25D to reverse these adaptive changes. HAHigh populations exhibited elevated HA production, smaller size, increased proliferation and higher motility than HALow populations. Despite their more aggressive phenotype, HAHigh populations retained expression of VDR protein at levels comparable to that of parental Hs578T cells and HALow subclones. Treatment with 1,25D decreased production of HA in both HAHigh and HALow populations. We also found that multiple metabolic enzymes were aberrantly expressed in HAHigh cells, especially those involved in glutamine and glucose metabolism. Notably, Glutaminase (GLS), a known oncogene for breast cancer, was strongly upregulated in HAHigh vs. HALow cells and its expression was significantly reduced by 1,25D (100 nM, 24 h). Consistent with this finding, Seahorse extracellular flux analysis indicated that respiration in HAHigh cells was significantly more dependent on exogenous glutamine than HALow cells, however, acute 1,25D exposure did not alter metabolic flux. In contrast to GLS, the glutamate transporter SLC1A7 was significantly reduced in HAHigh cells compared to HALow cells and its expression was enhanced by 1,25D. These findings support the concept that 1,25D can reverse the metabolic gene expression changes associated with HA production in cancer cells with aggressive phenotypes.

Risks of restrictive red blood cell transfusion strategies in patients with cardiovascular disease (CVD): a meta-analysis.

AIM: To evaluate the risks of restrictive red blood cell transfusion strategies (haemoglobin 7-8 g dL-1 ) in patients with and without known cardiovascular disease (CVD). BACKGROUND: Recent guidelines recommend restrictive strategies for CVD patients hospitalised for non-CVD indications, patients without known CVD and patients hospitalised for CVD corrective procedures. METHODS/MATERIALS: Database searches were conducted through December 2017 for randomised clinical trials that enrolled patients with and without known CVD, hospitalised either for CVD-corrective procedures or non-cardiac indications, comparing effects of liberal with restrictive strategies on major adverse coronary events (MACE) and death. RESULTS: In CVD patients not undergoing cardiac interventions, a liberal strategy decreased (P = 0·01) the relative risk (95% CI) (RR) of MACE [0·50 (0·29-0·86)] (I2  = 0%). Among patients without known CVD, the incidence of MACE was lower (1·7 vs 3·9%), and the effect of a liberal strategy on MACE [0·79, (0·39-1·58)] was smaller and non-significant but not different from CVD patients (P = 0·30). Combining all CVD and non-CVD patients, a liberal strategy decreased MACE [0·59, (0·39-0·91); P = 0·02]. Conversely, among studies reporting mortality, a liberal strategy decreased mortality in CVD patients (11·7% vs·13·3%) but increased mortality (19·2% vs 18·0%) in patients without known CVD [interaction P = 0·05; ratio of RR 0·73, (0·53-1·00)]. A liberal strategy also did not benefit patients undergoing cardiac surgery; data were insufficient for percutaneous cardiac procedures. CONCLUSIONS: In patients hospitalised for non-cardiac indications, liberal transfusion strategies are associated with a decreased risk of MACE in both those with and without known CVD. However, this only provides a survival benefit to CVD patients not admitted for CVD-corrective procedures.

Hierarchical organization of the hemostatic response to penetrating injuries in the mouse macrovasculature.

Essentials Methods were developed to image the hemostatic response in mouse femoral arteries in real time. Penetrating injuries produced thrombi consisting primarily of platelets. Similar to arterioles, a core-shell architecture of platelet activation occurs in the femoral artery. Differences from arterioles included slower platelet activation and reduced thrombin dependence. SUMMARY: Background Intravital studies performed in the mouse microcirculation show that hemostatic thrombi formed after penetrating injuries develop a characteristic architecture in which a core of fully activated, densely packed platelets is overlaid with a shell of less activated platelets. Objective Large differences in hemodynamics and vessel wall biology distinguish arteries from arterioles. Here we asked whether these differences affect the hemostatic response and alter the impact of anticoagulants and antiplatelet agents. Methods Approaches previously developed for intravital imaging in the mouse microcirculation were adapted to the femoral artery, enabling real-time fluorescence imaging despite the markedly thicker vessel wall. Results Arterial thrombi initiated by penetrating injuries developed the core-and-shell architecture previously observed in the microcirculation. However, although platelet accumulation was greater in arterial thrombi, the kinetics of platelet activation were slower. Inhibiting platelet ADP P2Y12 receptors destabilized the shell and reduced thrombus size without affecting the core. Inhibiting thrombin with hirudin suppressed fibrin accumulation, but had little impact on thrombus size. Removing the platelet collagen receptor, glycoprotein VI, had no effect. Conclusions These results (i) demonstrate the feasibility of performing high-speed fluorescence imaging in larger vessels and (ii) highlight differences as well as similarities in the hemostatic response in the macro- and microcirculation. Similarities include the overall core-and-shell architecture. Differences include the slower kinetics of platelet activation and a smaller contribution from thrombin, which may be due in part to the greater thickness of the arterial wall and the correspondingly greater separation of tissue factor from the vessel lumen.

Platelet-targeting thiol reduction sensor detects thiol isomerase activity on activated platelets in mouse and human blood under flow.

UNLABELLED: Essentials Protein disulfide isomerases may have an essential role in thrombus formation. A platelet-binding sensor (PDI-sAb) was developed to detect thiol reductase activity under flow. Primary human platelet adhesion to collagen at 200 s(-1) was correlated with the PDI-sAb signal. Detected thiol reductase activity was localized in the core of growing thrombi at the site of injury in mice. SUMMARY: Background Protein disulfide isomerases (PDIs) may regulate thrombus formation in vivo, although the sources and targets of PDIs are not fully understood. Methods and results Using click chemistry to link anti-CD61 and a C-terminal azido disulfide-linked peptide construct with a quenched reporter, we developed a fluorogenic platelet-targeting antibody (PDI-sAb) for thiol reductase activity detection in whole blood under flow conditions. PDI-sAb was highly responsive to various exogenous reducing agents (dithiothreitol, glutathione and recombinant PDI) and detected thiol reductase activity on P-selectin/phosphatidylserine-positive platelets activated with convulxin/PAR1 agonist peptide, a signal partially blocked by PDI inhibitors and antibody. In a microfluidic thrombosis model using 4 µg mL(-1) corn trypsin inhibitor-treated human blood perfused over collagen (wall shear rate = 100 s(-1) ), the PDI-sAb signal increased mostly over the first 200 s, whereas platelets continually accumulated for over 500 s, indicating that primary adhesion to collagen, but not secondary aggregation, was correlated with the PDI-sAb signal. Rutin and the PDI blocking antibody RL90 reduced platelet adhesion and the PDI-sAb signal only when thrombin production was inhibited with PPACK, suggesting limited effects of platelet thiol isomerase activity on platelet aggregation on collagen in the presence of thrombin. With anti-mouse CD41 PDI-sAb used in an arteriolar laser injury model, thiol reductase activity was localized in the core of growing thrombi where platelets displayed P-selectin and were in close proximity to disrupted endothelium. Conclusion PDI-sAb is a sensitive and real-time reporter of platelet- and vascular-derived disulfide reduction that targets clots as they form under flow to reveal spatial gradients.

Induction of STEAP4 correlates with 1,25-dihydroxyvitamin D3 stimulation of adipogenesis in mesenchymal progenitor cells derived from human adipose tissue.

The vitamin D receptor (VDR) is expressed in human adipocytes and is transiently induced during early adipogenesis in mesenchymal progenitor cell models. VDR null mice exhibit enhanced energy expenditure and reduced adiposity even when fed high fat diets. Adipocyte-specific transgenic-expression of human VDR in mice enhances adipose tissue mass, indicating that VDR activation in adipocytes enhances lipid storage in vivo. In these studies, we conducted genomic profiling and differentiation assays in primary cultures of human adipose-derived mesenchymal progenitor cells to define the role of the VDR and its ligand 1,25-dihydroxyvitamin D3 (1,25D) in adipogenesis. In the presence of adipogenic media, 1,25D promoted lipid accumulation and enhanced the expression of FABP4, FASN, and PPARγ. Mesenchymal cells derived from 6-month old VDR null mice exhibited impaired adipogenesis ex vivo but differentiation was restored by stable expression of human VDR. STEAP4, a gene that encodes a metalloreductase linked to obesity, insulin sensitivity, metabolic homeostasis and inflammation, was highly induced in human adipose cells differentiated in the presence of 1,25D but was minimally affected by 1,25D in undifferentiated precursors. These studies provide a molecular basis for recent epidemiological associations between vitamin D status, body weight and insulin resistance which may have relevance for prevention or treatment of metabolic syndrome and obesity.

New era of radiotherapy: an update in radiation-induced lung disease.

Over the last few decades, advances in radiotherapy (RT) technology have improved delivery of radiation therapy dramatically. Advances in treatment planning with the development of image-guided radiotherapy and in techniques such as proton therapy, allows the radiation therapist to direct high doses of radiation to the tumour. These advancements result in improved local regional control while reducing potentially damaging dosage to surrounding normal tissues. It is important for radiologists to be aware of the radiological findings from these advances in order to differentiate expected radiation-induced lung injury (RILD) from recurrence, infection, and other lung diseases. In order to understand these changes and correlate them with imaging, the radiologist should have access to the radiation therapy treatment plans.

Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial.

BACKGROUND: Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma. DESIGN: Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon's accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored. RESULTS: Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 µM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months. CONCLUSIONS: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.

Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy.

BACKGROUND: Preclinical studies have shown that norepinephrine can directly stimulate tumor cell migration and that this effect is mediated by the beta-adrenergic receptor. PATIENTS AND METHODS: We retrospectively reviewed 722 patients with non-small-cell lung cancer (NSCLC) who received definitive radiotherapy (RT). A Cox proportional hazard model was utilized to determine the association between beta-blocker intake and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). RESULTS: In univariate analysis, patients taking beta-blockers (n = 155) had improved DMFS (P < 0.01), DFS (P < 0.01), and OS (P = 0.01), but not LRPFS (P = 0.33) compared with patients not taking beta-blockers (n = 567). In multivariate analysis, beta-blocker intake was associated with a significantly better DMFS [hazard ratio (HR), 0.67; P = 0.01], DFS (HR, 0.74; P = 0.02), and OS (HR, 0.78; P = 0.02) with adjustment for age, Karnofsky performance score, stage, histology type, concurrent chemotherapy, radiation dose, gross tumor volume, hypertension, chronic obstructive pulmonary disease and the use of aspirin. There was no association of beta-blocker use with LRPFS (HR = 0.91, P = 0.63). CONCLUSION: Beta-blocker use is associated with improved DMFS, DFS, and OS in this large cohort of NSCLC patients. Future prospective trials can validate these retrospective findings and determine whether the length and timing of beta-blocker use influence survival outcomes.

Platelet-targeting sensor reveals thrombin gradients within blood clots forming in microfluidic assays and in mouse.

BACKGROUND: Thrombin undergoes convective and diffusive transport, making it difficult to visualize during thrombosis. We developed the first sensor capable of revealing inner clot thrombin dynamics. METHODS AND RESULTS: An N-terminal-azido thrombin-sensitive fluorescent peptide (ThS-P) with a thrombin-releasable quencher was linked to anti-CD41 using click chemistry to generate a thrombin-sensitive platelet binding sensor (ThS-Ab). Rapid thrombin cleavage of ThS-P (K(m) = 40.3 µm, k(cat) = 1.5 s(-1) ) allowed thrombin monitoring by ThS-P or ThS-Ab in blood treated with 2-25 pm tissue factor (TF). Individual platelets had > 20-fold more ThS-Ab fluorescence after clotting. In a microfluidic assay of whole blood perfusion over collagen ± linked TF (wall shear rate = 100 s(-1) ), ThS-Ab fluorescence increased between 90 and 450 s for 0.1-1 molecule-TF µm(-2) and co-localized with platelets near fibrin. Without TF, neither thrombin nor fibrin was detected on the platelet deposits by 450 s. Using a microfluidic device to control the pressure drop across a thrombus forming on a porous collagen/TF plug (521 s(-1) ), thrombin and fibrin were detected at the thrombus-collagen interface at a zero pressure drop, whereas 80% less thrombin was detected at 3200 Pa in concert with fibrin polymerizing within the collagen. With anti-mouse CD41 ThS-Ab deployed in a mouse laser injury model, the highest levels of thrombin arose between 40 and 160 s nearest the injury site where fibrin co-localized and where the thrombus was most mechanically stable. CONCLUSION: ThS-Ab reveals thrombin locality, which depends on surface TF, flow and intrathrombus pressure gradients.

Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (≥60%) probability. PATIENTS AND METHODS: We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model. RESULTS: The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias-corrected AU-ROC was 0.70 (95% CI 0.643-0.728). CONCLUSION: Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR.

Tissue factor expression determines tumour cell coagulation kinetics.

INTRODUCTION: Cancers are associated with varying degrees of an increased risk of venous thromboembotic events (VTE) occurring. This increased risk is tumour driven and associated with tumour expression of tissue factor (TF) and tumour-derived microparticles (MP). In this study, cancer cell lines from phenotypically distinct tumours were assessed for cell surface TF expression and prothrombin time (PT) taken as a measure of procoagulant potential. METHODS: Breast (T47D, MCF-7), colorectal (Colo320 and LoVo), head and neck (USCC 11b, 12, 81b and SIHN-011A) and pancreatic tumour cell lines (ASPC-1 and CFPAC-1) were assessed for TF expression by flow cytometry and relative mean fluorescence determined. Procoagulant potential of the cells was then determined by PT assay. RESULTS: Cell-supported coagulation was shown to be cell number dependent, defined by a logarithmic relationship that was consistent across all cell lines. Single cell PT was determined for each cell line from the slope of a logarithmically transformed data plot. A near linear relationship was observed between TF expression and single cell clotting time where a higher expression of TF results in a proportionally faster PT (P < 0.001). CONCLUSIONS: This study shows that across a range of tumour sites a consistent relationship is seen between procoagulant potential and both cell number and TF cell surface expression.

Patients with high body mass index tend to have lower stage of esophageal carcinoma at diagnosis.

High body mass index (H-BMI; ≥25 kg/m(2) ) is common in US adults. In a small cohort of esophageal cancer (EC) patients treated with surgery, H-BMI and diagnosis of early stage EC appeared associated. We evaluated a much larger cohort of EC patients. From a prospectively maintained database, we analyzed 925 EC patients who had surgery with or without adjunctive therapy. Various statistical methods were used. Among 925 patients, 69% had H-BMI, and 31% had normal body mass index (<25 kg/m(2) ; N-BMI). H-BMI was associated with men (P<0.001), Caucasians (P=0.064; trend), lower esophageal localization (P<0.001), adenocarcinoma histology (P<0.001), low baseline cT-stage (P=0.003), low baseline overall clinical stage (P=0.003), coronary artery disease (P=0.036), and diabetes (P<0.001). N-BMI was associated with weight loss (P<0.001), alcohol abuse (P=0.056; trend), ever/current smoking (P=0.014), and baseline cN+ (P=0.018). H-BMI patients with cT1 tumors (n=110) had significantly higher rates of gastresophageal reflux disease symptoms (P<0.001), gastresophageal reflux disease history (P<0.001), and Barrett's esophagus history (P<0.001) compared with H-BMI patients with cT2 tumors (n=114). Median survival of N-BMI patients was 36.66 months compared with 53.20 months for H-BMI patients (P=0.005). In multivariate analysis, older age (P<0.001), squamous histology (P=0.002), smoking (P=0.040), weight loss (P=0.002), high baseline stage (P<0.001), high number of ypN+ (P=0.005), high surgical stage (P<0.001), and American Society of Anesthesia scores, three out of four (P<0.001) were independent prognosticators for poor overall survival. We were able to perform propensity-based analysis of surgical complications between H-BMI and N-BMI patients. A comparison of fully matched 376 patients (188 with H-BMI and 188 with N-BMI) found no significant differences in the rate of complications between the two groups. This larger data set confirms that a fraction of H-BMI patients with antecedent history is diagnosed with early baseline EC. Upon validation of our data in an independent cohort, refinements in surveillance of symptomatic H-BMI patients are warranted and could be implemented. Our data also suggest that H-BMI patients do not experience higher rate of surgical complications compared with N-BMI patients.

Primary lymphedema and acute leukemia--is there a link?

The lymphedema service in Glasgow has been treating patients with lymphedema of all causes since 1991. In the past five years 3 patients with primary lymphedema have been diagnosed with myelodysplasia (leading to acute leukemia) or acute leukemia. These are relatively unusual malignancies given the ages of the patients and all three of these patients died within an average of 12 months of diagnosis. A connection between the presence of primary lymphedema and the subsequent development of the hematological disorder is postulated. Standard marrow cytogenetics failed to identify a common abnormality but the authors feel that further study is warranted.

Human breast tumor slices: a model for identification of vitamin D regulated genes in the tumor microenvironment.

While many studies have addressed the direct effects of 1alpha,25(OH)2D3 on breast cancer (BC) cells, stromal-epithelial interactions, which are important for the tumor development, have been largely ignored. In addition, high concentrations of the hormone, which cannot be attained in vivo, have been used. Our aim was to establish a more physiological breast cancer model, represented by BC tissue slices, which maintain epithelial-mesenchymal interactions, cultured with a relatively low 1alpha,25(OH)2D3 concentration, in order to evaluate the vitamin D pathway. Freshly excised human BC samples were sliced and cultured in complete culture media containing vehicle, 0.5 nM or 100 nM 1alpha,25(OH)2D3 for 24 h. BC slices remained viable for at least 24 h, as evaluated by preserved tissue morphology in hematoxylin and eosin (HE) stained sections and bromodeoxyuridine (BrdU) incorporation by 10% of tumor cells. VDR mRNA expression was detected in all samples and CYP24A1 mRNA expression was induced by 1alpha,25(OH)2D3 in both concentrations (but mainly with 100 nM). Our results indicate that the vitamin D signaling pathway is functional in BC slices, a model which preserves stromal-epithelial interactions and mimics in vivo conditions.

Safety and effectiveness of vascular endoprosthesis for malignant superior vena cava syndrome.

BACKGROUND: Superior vena cava syndrome management has been traditionally radiation therapy, chemotherapy or chemoradiation, depending on the underlying malignancy involved and individual clinicopathological features of the case. Recent emergence of endovascular stents offer the opportunity for immediate relief of the venous stenosis. This review examines findings from the published series which used endovascular prosthesis for this syndrome with regards to efficacy and safety. METHODS: Literature search identified studies using endovascular stents as initial therapy or for recurrence of malignant superior vena cava syndrome. Effectiveness and toxicity from stent placement was assessed. RESULTS: Endovascular stent placement provides immediate haemodynamic relief of venous compression either before or after definitive therapy in the majority of cancer patients. Severe bleedings, cardiopulmonary complications and stent migrations remain significant problems for patient management. CONCLUSIONS: Endovascular prosthesis is an effective modality for malignant superior vena cava syndrome with acceptable morbidity. Prospective studies should be performed to determine the optimal anticoagulation regimen.

Microscopic and macroscopic tumor and parenchymal effects of liver stereotactic body radiotherapy.

PURPOSE: To describe the histologic and volumetric changes in normal liver tissue after stereotactic body radiotherapy (SBRT) for liver metastases. METHODS AND MATERIALS: Pre- and post-SBRT imaging studies were analyzed to evaluate the effect of SBRT on normal liver volume (NLV) in 15 patients treated in a prospective clinical trial. Two other patients underwent exploratory surgery after SBRT and histologic analyses of the irradiated liver were performed to characterize the pathologic effects of SBRT. RESULTS: In the 15 patients studied quantitatively, the total NLV had decreased transiently at 2-3 months after SBRT and then began to regenerate at 3-8 months after SBRT. The median NLV reduction at the maximal observed effect was 315 cm(3) (range, 125-600) or 19% (range, 13-33%). Among the several dosimetric parameters evaluated, the strongest linear correlation was noted for the NLV percentage receiving 30 Gy as a predictor of maximal NLV reduction (r(2) = 0.72). The histologic changes observed 2 and 8 months after SBRT demonstrated distinct zones of tissue injury consistent with localized veno-occlusive disease. CONCLUSION: The well-demarcated focal parenchymal changes after liver SBRT (demonstrated both radiographically and histologically) within the high-dose zone are consistent with a threshold dose-induced set of phenomena. In contrast, the more global effect of NLV reduction, which is roughly proportional to whole organ dose parameters, resembles more closely an effect determined from radiobiologically parallel architecture. These observations suggest that modeling of normal tissue effects after liver SBRT might require different governing equations for different classes of effects.

Hypofractionated breast and chest wall irradiation using simultaneous in-field boost IMRT delivered via helical tomotherapy.

Although helical tomotherapy has been described as a means of administering accelerated partial breast irradiation, its practicality in routine whole breast irradiation as part of breast conserving therapy or chest wall irradiation has been questioned. In this technical note we describe our method of whole breast or chest wall irradiation using helical tomotherapy based image-guided, hypofractionated, simultaneous in-field boost intensity modulated radiation therapy. We have observed that excellent dose-distributions can be achieved with helical tomotherapy through a careful selection of treatment planning parameters. Dose homogeneity to the whole breast and simultaneously targeted lumpectomy region appears superior to conventional "tangents" with minimal hot or cold spots. Dose-volume histogram analysis documents effective reduction of high dose to critical sensitive structures (heart and lung) although a greater volume of these non-target organs receives low dose compared to what is typical with tangential beams. Treatment planning is efficient and is usually completed within one to two hours, although physician contouring requires more time and attention than non-IMRT approaches. Pretreatment megavoltage CT (MVCT) imaging has proved invaluable in aiding set-up and engenders greater confidence that the planned IMRT dose distributions are truly being delivered. In some situations, MVCT can provide visual feedback when a seroma or overall breast volume has changed significantly since simulation, thereby identifying cases where replanning might be prudent. Treatment is brief, typically completed in 6 to 9 minutes. Initial clinical application has confirmed the feasibility and practicality of helical tomotherapy as an efficient means of administering radiation therapy for routine breast-conserving therapy and post-mastectomy chest wall irradiation. A simultaneous in-field boost technique reduces the length of the overall course by about a week thereby adding convenience and reducing costs. Further refinements of our technique are being explored and formal prospective clinical evaluation is underway.